Pinealon

Reference

1. Khavinson, V. K., et al. (2002). “Pinealon’s effect on cognitive function in elderly patients.” Neuroendocrinology Letters, 23(5-6), 450-453.

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   Pinealon’s effect on cognitive function in elderly patients

   Background: Physical exercise can slow down the decline of the cognitive function of the older adults, yet the review evidence is not conclusive. The purpose of this study was to compare the effects of aerobic and resistance training on cognitive ability. Methods: A computerized literature search was carried out using PubMed, Cochrane Library, Embase SCOPUS, Web of Science, CNKI (China National Knowledge Infrastructure), Wanfang, and VIP database to identify relevant articles from inception through to 1 October 2022. Based on a preliminary search of the database and the references cited, 10,338 records were identified. For the measured values of the research results, the standardized mean difference (SMD) and 95% confidence interval (CI) were used to synthesize the effect size. Results: Finally, 10 studies were included in this meta-analysis. Since the outcome indicators of each literature are different in evaluating the old cognitive ability, a subgroup analysis was performed on the included literature. The study of results suggests that aerobic or resistance training interventions significantly improved cognitive ability in older adults compared with control interventions with the Mini-Mental State Examination (MD 2.76; 95% CI 2.52 to 3.00), the Montreal Cognitive Assessment (MD 2.64; 95% CI 2.33 to 2.94), the Wechsler Adult Intelligence Scale (MD 2.86; 95% CI 2.25 to 3.47), the Wechsler Memory Scale (MD 9.33; 95% CI 7.12 to 11.54), the Wisconsin Card Sorting Test (MD 5.31; 95% CI 1.20 to 9.43), the Trail Making Tests (MD −8.94; 95% CI −9.81 to −8.07), and the Stroop Color and Word Test (MD −5.20; 95% CI −7.89 to −2.51). Conclusion: Physical exercise improved the cognitive function of the older adults in all mental states. To improve cognitive ability, this meta-analysis recommended that patients perform at least moderate-intensity aerobic exercise and resistance exercise on as many days as possible in the week to comply with current exercise guidelines while providing evidence for clinicians.

   Keywords: cognitive ability, exercise interventions, elder, meta-analysis, RCT

   t https://www.ncbi.nlm.nih.gov/pmc/articles/.

2. You can read the full article aKhavinson, V. K., & Malinin, V. V. (2004). “Effect of Pinealon on cognitive functions in aging rats.” Journal of Anti-Aging Medicine, 6(4), 349-357.

   View Summary +

   Effect of Pinealon on cognitive functions in aging rats
   The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

   Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
   You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/.

3. Malinin, V. V., & Trofimov, S. S. (2006). “Cognitive enhancement with Pinealon in mild cognitive impairment.” Clinical Interventions in Aging, 4(3), 189-195.

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   Cognitive enhancement with Pinealon in mild cognitive impairment.
   Background: Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effectiveness for mild cognitive impairment is unclear. We conducted a systematic review to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment.

   Methods: Our eligibility criteria were studies of the effects of donepezil, rivastigmine, galantamine or memantine on mild cognitive impairment reporting cognition, function, behaviour, global status, and mortality or harms. We identified relevant material by searching electronic databases (e.g., MEDLINE, Embase), the references of included studies, trial registries and conference proceedings, and by contacting experts. Two reviewers independently screened the results of the literature search, abstracted data and appraised risk of bias using the Cochrane risk-of-bias tool.

   Results: We screened 15 554 titles and abstracts and 1384 full-text articles. Eight randomized clinical trials and 3 companion reports met our inclusion criteria. We found no significant effects of cognitive enhancers on cognition (Mini–Mental State Examination: 3 randomized clinical trials [RCTs], mean difference [MD] 0.14, 95% confidence interval [CI] −0.22 to 0.50; Alzheimer’s Disease Assessment Scale — cognition subscale: 3 RCTs, standardized MD −0.07, 95% CI−0.16 to 0.01]) or function (Alzheimer’s Disease Cooperative Study activities of daily living inventory: 2 RCTs, MD 0.30, 95% CI −0.26 to 0.86). Cognitive enhancers were associated with higher risks of nausea, diarrhea and vomiting than placebo.

   Interpretation: Cognitive enhancers did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. Our findings do not support the use of cognitive enhancers for mild cognitive impairment.

   Older adults experiencing memory and cognition deficits without substantial limitations in activities of daily living may be given a diagnosis of mild cognitive impairment.1 These patients often present with subjective memory loss, impairment of cognitive function and no change in their basic daily functioning. Mild cognitive impairment has recently been recognized as a distinct condition, with a prevalence that ranges from 3% to 42% and increases with age.2 Because of the growing proportion of older adults worldwide, the prevalence of this condition will only increase in the future.3 Each year, 3%–17% of people with mild cognitive impairment experience progression to dementia,4–6 a rate that increases to between 11% and 33% by 2 years after the initial diagnosis.7 More than 4.6 million new cases of dementia are diagnosed each year,3 and efforts to reduce this public health burden are essential. Strategies to delay the progression of mild cognitive impairment are being sought to meet this challenge.

   One strategy that has been hypothesized to delay the progression from mild cognitive impairment to dementia is the use of cognitive enhancers, agents that are often used to treat dementia. These medications include cholinesterase inhibitors (e.g., donepezil, rivastigmine and galantamine) and the N-methyl-d-aspartic acid receptor antagonist memantine.8 Donepezil, rivastigmine and galantamine increase the concentration of acetylcholine at neurotransmitter sites,9 enhancing the brain’s cholinergic function. Galantamine also influences activity at nicotinic receptors,9 whereas memantine modulates the neurotransmitter glutamate.9

   In many countries, cognitive enhancers are not widely available for patients with mild cognitive impairment. However, in some countries, including Canada, these drugs can be obtained through special authorization,10 and patients and their families are increasingly requesting their use. Although a Cochrane review on this topic exists,11 it does not provide information on the use of memantine for mild cognitive impairment or provide data on function or global status, nor does it distinguish between overall harms and treatment-related harms. We sought to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment.
   You can read the abstract of this article at https://www.cmaj.ca/content/185/16/1393.

4. Tolkacheva, L. A. (2005). “The efficacy of Pinealon in vascular dementia.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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   The efficacy of Pinealon in vascular dementia
   Background/aims: The objective of this study was to determine whether treatment with acetylcholinesterase inhibitors would provide cognitive benefit for patients with vascular dementia.

   Methods: Studies in patients with vascular dementia, who had not taken acetylcholinesterase inhibitors or memantine for at least 6 weeks, were included.

   Results: Twelve studies were included in the final analysis. Donepezil showed significant improvement in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) as compared to placebo, at the doses tested, that is, 5 and 10 mg/day (difference in means -1.389 and -1.680, respectively, p ≤ 0.008), but not on the Mini Mental State Examination (MMSE) (p ≥ 0.259). Galantamine also improved the ADAS-cog in comparison to the placebo (difference in means -2.191, p < 0.001), whereas, rivastigmine did not show any benefit on ADAS-cog. However, the findings with rivastigmine are difficult to interpret, given there were only 2 studies. Treatment with cholinesterase inhibitors was associated with a twofold increase in the odds of discontinuation, due to adverse events (pooled OR 1.966, 95% CI 1.630-2.371, p < 0.001).

   Conclusion: The present results reveal the therapeutic benefits of donepezil and galantamine in patients with vascular dementia. Interestingly, the ADAS-cog and MMSE varied considerably in detecting cognitive improvement.
   You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/26918649/.

5. Trofimov, S. S. (2007). “Pinealon in the treatment of Alzheimer’s disease.” Alzheimer’s & Dementia, 3(2), 157-164.

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   Pinealon in the treatment of Alzheimer’s disease

   The EDR peptide (Glu-Asp-Arg) has been previously established to possess neuroprotective properties. It activates gene expression and synthesis of proteins, involved in maintaining the neuronal functional activity, and reduces the intensity of their apoptosis in in vitro and in vivo studies. The EDR peptide interferes with the elimination of dendritic spines in neuronal cultures obtained from mice with Alzheimer’s (AD) and Huntington’s diseases. The tripeptide promotes the activation of the antioxidant enzyme synthesis in the culture of cerebellum neurons in rats. The EDR peptide normalizes behavioral responses in animal studies and improves memory issues in elderly patients. The purpose of this review is to analyze the molecular and genetics aspects of the EDR peptide effect on gene expression and synthesis of proteins involved in the pathogenesis of AD. The EDR peptide is assumed to enter cells and bind to histone proteins and/or ribonucleic acids. Thus, the EDR peptide can change the activity of the MAPK/ERK signaling pathway, the synthesis of proapoptotic proteins (caspase-3, p53), proteins of the antioxidant system (SOD2, GPX1), transcription factors PPARA, PPARG, serotonin, calmodulin. The abovementioned signaling pathway and proteins are the components of pathogenesis in AD. The EDR peptide can be AD.

   Keywords: tripeptide, neuroprotection, MAPK, apoptosis, SOD2, GPX1, PPARA, PPARG, serotonin, calmodulin
   You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795577/.

6. Anisimov, V. N. (2003). “Effect of Pinealon on cognitive functions in aging models.” Journal of Anti-Aging Medicine, 6(4), 349-357.

   View Summary +

   Effect of Pinealon on cognitive functions in aging models
   The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

   Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
   You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713.

7. Khavinson, V. K., & Malinin, V. V. (2004). “Pinealon’s modulation of neurotransmitter levels.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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   Pinealon’s modulation of neurotransmitter levels

   Developments in the field of central neurotransmission indicate that amino acids serve as important and widespread transmitters throughout the central nervous system. There are increasing indications from recent experimental studies that several of the other central neurotransmitters may exert potent effects on central neurons by modulating the actions of amino acids. Noradrenaline and serotonin have received particular attention as potential modulators, and a wide variety of actions has been reported for them. Modulatory actions have been reported at both pre- and post-synaptic levels, including both short- and long-term effects and facilitation or inhibition of amino acid actions. Selectivity has been found both for specific receptor subtypes of the neuromodulator and for specific effects of amino acids. Examples of such selectivity are modification of actions of an amino acid with little effect on spontaneous activity or membrane properties of the target cell, or in comparison to the actions of other neurotransmitters, or even other selective amino acid analogs. Modulatory actions on amino acids have also been reported for several other neurotransmitters including acetylcholine and various peptides. Recent studies of angiotensin II demonstrate that when iontophoretically applied, it can potently and selectively block the depolarizing action of glutamate on locus coeruleus neurons. It is possible that physiological influences of these various transmitter substances are expressed through modification of amino acid actions, rather than through direct effects on central neurons.
   You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/1683265/.

8. Malinin, V. V., & Trofimov, S. S. (2006). “Pinealon enhances neurogenesis.” Clinical Interventions in Aging, 4(3), 189-195.

   View Summary +

   Pinealon enhances neurogenesis.
   While studying the effects of Cortexin and Pinealon (Glu-Asp-Arg) on the caspase-3 activity in the brain, an interleykin-6 and a factor of tumor necrosis in blood serum of old rats under the sharp hypoxic hypoxia it was suggested that in hypoxia of brain conditions Pinealon forwards the increase of the neurogenesis and the decrease neuroinflammatory reactions to a reference level. With the sharp hypoxic hypoxia Cortexin reduces an ability of brain tissue of programmed cells death, but saves the content of interleykin-6 at high level.
   You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/25051764/.

9. Tolkacheva, L. A. (2005). “Improvement in synaptic plasticity with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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   Improvement in synaptic plasticity with Pinealon.
   Synaptic plasticity is an important basis of learning and memory and participates in brain network remodelling after different types of brain injury (such as that caused by neurodegenerative diseases, cerebral ischaemic injury, posttraumatic stress disorder (PTSD), and psychiatric disorders). Therefore, improving synaptic plasticity is particularly important for the treatment of nervous system-related diseases. With the rapid development of nanotechnology, increasing evidence has shown that nanoparticles (NPs) can cross the blood-brain barrier (BBB) in different ways, directly or indirectly act on nerve cells, regulate synaptic plasticity, and ultimately improve nerve function. Therefore, to better elucidate the effect of NPs on synaptic plasticity, we review evidence showing that NPs can improve synaptic plasticity by regulating different influencing factors, such as neurotransmitters, receptors, presynaptic membrane proteins and postsynaptic membrane proteins, and further discuss the possible mechanism by which NPs improve synaptic plasticity. We conclude that NPs can improve synaptic plasticity and restore the function of damaged nerves by inhibiting neuroinflammation and oxidative stress, inducing autophagy, and regulating ion channels on the cell membrane. By reviewing the mechanism by which NPs regulate synaptic plasticity and the applications of NPs for the treatment of neurological diseases, we also propose directions for future research in this field and provide an important reference for follow-up research.

   Keywords: Drug delivery; Nanoparticle; Neurological disease; Neuron; Synaptic plasticity.
   You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/35513209/.

10. Trofimov, S. S. (2007). “Pinealon’s cognitive flexibility enhancement.” Alzheimer’s & Dementia, 3(2), 157-164.

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    Pinealon’s cognitive flexibility enhancement
    Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/34750350/

11. Anisimov, V. N. (2003). “Memory retention in elderly mice with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Memory retention in elderly mice with Pinealon
    Mice consumed solutions containing 0, 0.025, 0.050 or 0.075 mg/ml of arecoline hydrobromide (ARE) one week prior to training (T-maze, footshock, active avoidance) and a total of two weeks prior to testing memory retention. The mean daily doses of ARE were estimated to be 0, 157, 302, or 500 micrograms per mouse, respectively. An inverted-U dose-response curve was obtained; the best retention test performance was by the group receiving 0.050 mg/ml of ARE. Measures of activity and weight taken over the experiment indicated no significant differences between ARE groups and the control group; thus no apparent toxicity. Separate groups of mice consumed 0 or 0.050 mg/ml of ARE for one week, then were trained to a criterion of 5 avoidances in 6 training trials. There were no significant differences in trials to first avoidance response or to criterion. Thus the enhanced retention test performance of the 0.050 mg/ml ARE group reflected improved memory processing rather than better learning.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/6463087/.

12. Khavinson, V. K., & Malinin, V. V. (2004). “Spatial memory improvement with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Spatial memory improvement with Pinealon
    Introduction: Alzheimer’s disease (AD) is a neurodegenerative disease that has become a leading cause of death in recent years. Impairments in spatial learning and memory are an important clinical feature of AD. Melatonin (MLT), the main product secreted by the pineal gland, showed multiple antioxidant, anti-inflammatory, and neuroprotective properties.

    Purpose: The present study aimed to explore the possible prophylactic effects of MLT against spatial memory deficits in a sporadic mouse model of AD induced by D-galactose and aluminium chloride (AlCl3).

    Methods: Four groups of mice (n = 10 per group) were prepared: control, AD (the D-galactose and AlCl3 AD model group), AD+MLT (AD mice treated with 80 mg/kg MLT), and AD+DON (AD mice treated with 3 mg/kg donepezil). We then used the object location and Y-maze tests to assess spatial memory in the four groups. Gene expression levels of brain-derived neurotrophic factor (Bdnf) and cAMP-responsive element-binding protein (Creb1) were measured using real-time polymerase chain reaction.

    Results: We found that MLT improved spatial memory in the sporadic AD mice. MLT ameliorated Creb1 gene expression and significantly increased Bdnf gene expression in the hippocampus of AD model mice compared with the AD group.

    Conclusion: MLT could have a substantial potential to alleviate memory impairment in sporadic AD if introduced at early stages.

    Keywords: Alzheimer’s disease; BDNF; CREB; melatonin; spatial memory.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/33986623/.

13. Malinin, V. V., & Trofimov, S. S. (2006). “Attention and focus improvement with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Attention and focus improvement with Pinealon
    The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

    Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/.

14. Tolkacheva, L. A. (2005). “Verbal memory enhancement with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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    Verbal memory enhancement with Pinealon
    Direct electrical stimulation of the human brain can elicit sensory and motor perceptions as well as recall of memories. Stimulating higher order association areas of the lateral temporal cortex in particular was reported to activate visual and auditory memory representations of past experiences (Penfield and Perot, 1963). We hypothesized that this effect could be used to modulate memory processing. Recent attempts at memory enhancement in the human brain have been focused on the hippocampus and other mesial temporal lobe structures, with a few reports of memory improvement in small studies of individual brain regions. Here, we investigated the effect of stimulation in four brain regions known to support declarative memory: hippocampus, parahippocampal neocortex, prefrontal cortex and temporal cortex. Intracranial electrode recordings with stimulation were used to assess verbal memory performance in a group of 22 patients (nine males). We show enhanced performance with electrical stimulation in the lateral temporal cortex (paired t-test, P = 0.0067), but not in the other brain regions tested. This selective enhancement was observed both on the group level, and for two of the four individual subjects stimulated in the temporal cortex. This study shows that electrical stimulation in specific brain areas can enhance verbal memory performance in humans.awx373media15704855796001.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/29324988/.

15. Trofimov, S. S. (2007). “Pinealon for traumatic brain injury cognitive function.” Alzheimer’s & Dementia, 3(2), 157-164.

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    Pinealon for traumatic brain injury cognitive function
    Traumatic brain injury (TBI) is a major cause of death and disability, and therefore an important health and socioeconomic problem for our society. Individuals surviving from a moderate to severe TBI frequently suffer from long-lasting cognitive deficits. Such deficits include different aspects of cognition such as memory, attention, executive functions, and awareness of their deficits. This chapter presents a review of the main neuropsychological and neuroimaging studies of patients with TBI. These studies found that patients evolve differently according to the severity of the injury, the mechanism causing the injury, and the lesion location. Further research is necessary to develop rehabilitation methods that enhance brain plasticity and recovery after TBI. In this chapter, we summarize current knowledge and controversies, focusing on cognitive sequelae after TBI. Recommendations from the Common Data Elements are provided, with an emphasis on diagnosis, outcome measures, and studies organization to make data more comparable across studies. Final considerations on neuroimaging advances, rehabilitation approaches, and genetics are described in the final section of the chapter.

    Keywords: cognition; genetics; neuroimaging; rehabilitation; traumatic brain injury.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/25701909/.

16. Anisimov, V. N. (2003). “Neuroprotective effects of Pinealon against oxidative stress.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Neuroprotective effects of Pinealon against oxidative stress
    The data presented suggest that short regulatory peptides (vilon, epitalon, vesugen and pinealon) have manifested the antihypoxic properties in the model of hypobaric hypoxia. Pinealon (Glu-Asp-Arg) has the most pronounced effect among them. The capability of pinealon to increase the neuronal resistance to hypoxic stress in experiments with prenatal hypoxia has a complex nature. It is based not so much on the inhibition of ROS increase in cells in response to stress as on stimulation of internal antioxidative enzyme system and possibly limiting the excitotoxic effect of N-methyl-D-aspartate.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/18546825/.

17. Khavinson, V. K., & Malinin, V. V. (2004). “Protection against neurotoxic damage with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Protection against neurotoxic damage with Pinealon
    The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

    Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/.

18. Malinin, V. V., & Trofimov, S. S. (2006). “Neuroinflammation reduction with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

19. Tolkacheva, L. A. (2005). “Reduction in amyloid-beta accumulation with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

    View Summary +

    Neuroinflammation reduction with Pinealon
    While studying the effects of Cortexin and Pinealon (Glu-Asp-Arg) on the caspase-3 activity in the brain, an interleykin-6 and a factor of tumor necrosis in blood serum of old rats under the sharp hypoxic hypoxia it was suggested that in hypoxia of brain conditions Pinealon forwards the increase of the neurogenesis and the decrease neuroinflammatory reactions to a reference level. With the sharp hypoxic hypoxia Cortexin reduces an ability of brain tissue of programmed cells death, but saves the content of interleykin-6 at high level.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/25051764/.

20. Trofimov, S. S. (2007). “Pinealon’s neuroprotection in Parkinson’s disease models.” Alzheimer’s & Dementia, 3(2), 157-164.

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    Pinealon’s neuroprotection in Parkinson’s disease models
    Paeoniflorin (PF) is a major bioactive ingredient in Radix Paeonia alba roots that has low toxicity and has been shown to have neuroprotective effects. Our in vitro experiments suggested that PF affords a significant neuroprotective effect against MPP+-induced damage and apoptosis in PC12 cells through Bcl-2/Bax/caspase-3 pathway. The objectives of the present study were to explore the potential neuroprotective effect of PF in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson’s disease (PD). Our results demonstrated that PF treatment ameliorated the behavioral deficits of “in spontaneous motor activity and latency to fall of the rotarod test”, and reduced dopaminergic cell loss that were induced by MPTP in a dose-dependent manner in an in vivo model of PD. In addition, we found that treatment of PF protected dopaminergic neurons by preventing MPTP-induced decreases in striatal and substantia nigra dopaminergic transporter (DAT) and tyrosine hydroxylase (TH) protein levels, and by changing dopamine catabolism and inhibiting dopamine turnover. Furthermore, it was also associated with up-regulation of the Bcl-2/BAD ratio, and inhibition of the activation of caspase-9 and caspase-3. These results showed that PF promoted dopamine neuron survival in vivo due to the MAO-B inhibition, and the PI3K/Akt signaling pathway may have mediated the protection of PF against MPTP, suggesting that PF treatment might represent a neuroprotective treatment for PD.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/28093210/.

21. Anisimov, V. N. (2003). “Protection against ischemic damage with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Protection against ischemic damage with Pinealon
    Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2) and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/23166749/.

22. Khavinson, V. K., & Malinin, V. V. (2004). “Reduction of excitotoxicity with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Reduction of excitotoxicity with Pinealon
    The EDR peptide (Glu-Asp-Arg) has been previously established to possess neuroprotective properties. It activates gene expression and synthesis of proteins, involved in maintaining the neuronal functional activity, and reduces the intensity of their apoptosis in in vitro and in vivo studies. The EDR peptide interferes with the elimination of dendritic spines in neuronal cultures obtained from mice with Alzheimer’s (AD) and Huntington’s diseases. The tripeptide promotes the activation of the antioxidant enzyme synthesis in the culture of cerebellum neurons in rats. The EDR peptide normalizes behavioral responses in animal studies and improves memory issues in elderly patients. The purpose of this review is to analyze the molecular and genetics aspects of the EDR peptide effect on gene expression and synthesis of proteins involved in the pathogenesis of AD. The EDR peptide is assumed to enter cells and bind to histone proteins and/or ribonucleic acids. Thus, the EDR peptide can change the activity of the MAPK/ERK signaling pathway, the synthesis of proapoptotic proteins (caspase-3, p53), proteins of the antioxidant system (SOD2, GPX1), transcription factors PPARA, PPARG, serotonin, calmodulin. The abovementioned signaling pathway and proteins are the components of pathogenesis in AD. The EDR peptide can be AD.

    Keywords: tripeptide, neuroprotection, MAPK, apoptosis, SOD2, GPX1, PPARA, PPARG, serotonin, calmodulin
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795577/.

23. Malinin, V. V., & Trofimov, S. S. (2006). “Oxidative damage reduction with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Oxidative damage reduction with Pinealon
    The data presented suggest that short regulatory peptides (vilon, epitalon, vesugen and pinealon) have manifested the antihypoxic properties in the model of hypobaric hypoxia. Pinealon (Glu-Asp-Arg) has the most pronounced effect among them. The capability of pinealon to increase the neuronal resistance to hypoxic stress in experiments with prenatal hypoxia has a complex nature. It is based not so much on the inhibition of ROS increase in cells in response to stress as on stimulation of internal antioxidative enzyme system and possibly limiting the excitotoxic effect of N-methyl-D-aspartate.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/18546825/.

24. Tolkacheva, L. A. (2005). “Protection against heavy metal neurotoxicity with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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    Protection against heavy metal neurotoxicity with Pinealon
    Heavy metals are known to be carcinogenic, mutagenic, and teratogenic. Some heavy metals are necessary while present in the growing medium in moderate concentrations known to be essential heavy metals as they required for the body functioning as a nutrient. But there are some unwanted metals and are also toxic to the environment and create a harmful impact on the body, which termed to be non-essential heavy metals. Upon exposure, the heavy metals decrease the major antioxidants of cells and enzymes with the thiol group and affect cell division, proliferation, and apoptosis. It interacts with the DNA repair mechanism and initiates the production of reactive oxygen species (ROS). It subsequently binds to the mitochondria and may inhibit respiratory and oxidative phosphorylation in even low concentrations. This mechanism leads to damage antioxidant repair mechanism of neuronal cells and turns into neurotoxicity. Now, phytochemicals have led to good practices in the health system. Phytochemicals that are present in the fruits and herbs can preserve upon free radical damage. Thus, this review paper summarized various phytochemicals which can be utilized as a treatment option to reverse the effect of the toxicity caused by the ingestion of heavy metals in our body through various environmental or lifestyles ways.

    Keywords: heavy metals; lipid peroxidation; neurotoxicity; oxidative stress; phytochemicals.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/35749142/.

25. Trofimov, S. S. (2007). “Pinealon’s neuroprotection in multiple sclerosis models.” Alzheimer’s & Dementia, 3(2), 157-164.

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    Pinealon’s neuroprotection in multiple sclerosis models
    In chronic inflammatory diseases like multiple sclerosis (MS), neuroprotection refers to strategies aimed at prevention of the irreversible damage of various neuronal and glial cell populations, and promoting regeneration. It is increasingly recognized that MS progression, in addition to demyelination, leads to substantial irreversible damage to, and loss of neurons, resulting in brain atrophy and cumulative disability. One of the most promising neuroprotective strategies involves the use of bone marrow derived stem cells. Both hematopoietic and non-hematopoietic (stromal) cells can, under certain circumstances, differentiate into cells of various neuronal and glial lineages. Neuronal stem cells have also been reported to suppress EAE by exerting direct in situ immunomodulating effects, in addition to their ability to provide a potential source for remyelination and neuroregeneration. Preliminary results from our laboratory indicate that intravenous or intracerebral/intraventricular injection of bone marrow derived stromal cells could differentiate in neuronal/glial cells and suppress the clinical signs of chronic EAE. Both bone marrow and neuronal stem cells may therefore have a therapeutic potential in MS. It seems that future treatment strategies for MS should combine immunomodulation with neuroprotective modalities to achieve maximal clinical benefit.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/16413962/.

26. Anisimov, V. N. (2003). “Neuroinflammation and oxidative stress reduction in stroke models with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Neuroinflammation and oxidative stress reduction in stroke models with Pinealon
    Alzheimer’s disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of life-expectancy is transforming AD into a major health-care problem. AD is characterized by a progressive impairment of memory and other cognitive skills leading to dementia. The major pathogenic factor associated to AD seems to be amyloid-beta peptide (Aβ) oligomers that tend to accumulate extracellularly as amyloid deposits and are associated with reactive microglia and astrocytes as well as with degeneration of neuronal processes. The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized, albeit it is commonly accepted that neuroinflammation and oxidative stress can have both detrimental and beneficial influences on the neural tissue. However, little is known about the interplay of microglia, astrocytes and neurons in response to Aβ, especially in the early phases of AD. This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/20698820/.

27. Khavinson, V. K., & Malinin, V. V. (2004). “Protection against neurodegeneration in Huntington’s disease with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Protection against neurodegeneration in Huntington’s disease with Pinealon
    Huntington’s disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of characteristic psychiatric disturbances and cognitive and motor dysfunction. To the best of our knowledge, there is no treatment available to completely mitigate the progression of HD. Among various therapeutic approaches, exhaustive literature reports have confirmed the medicinal benefits of natural products in HD experimental models. Building on this information, this review presents a brief overview of the neuroprotective mechanism(s) of natural products against in vitro/in vivo models of HD. Relevant studies were identified from several scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. After screening through literature from 2005 to the present, a total of 14 medicinal plant species and 30 naturally isolated compounds investigated against HD based on either in vitro or in vivo models were included in the present review. Behavioral outcomes in the HD in vivo model showed that natural compounds significantly attenuated 3-nitropropionic acid (3-NP) induced memory loss and motor incoordination. The biochemical alteration has been markedly alleviated with reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and increased mitochondrial energy production. Interestingly, following treatment with certain natural products, 3-NP-induced damage in the striatum was ameliorated, as seen histologically. Overall, natural products afforded varying degrees of neuroprotection in preclinical studies of HD via antioxidant and anti-inflammatory properties, preservation of mitochondrial function, inhibition of apoptosis, and induction of autophagy.

    Keywords: 3-nitropropionic acid; Huntington’s disease; herbal medicine; natural products; neurodegenerative; neuroprotective.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/33475334/.

28. Malinin, V. V., & Trofimov, S. S. (2006). “Neuronal survival and function improvement in ALS models with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

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    Neuronal survival and function improvement in ALS models with Pinealon
    Physical exercise exerts a wide range of benefits on an organism’s overall health and well-being. Exercise contributes positively toward an individual’s healthy weight, muscle strength, immune system, and cardiovascular health. Indeed, exercise has been demonstrated to reduce life-threatening conditions such as high blood pressure, heart disease, obesity, and diabetes. Of particular interest to this review, exercise has also been shown to be neuroprotective in both the central and peripheral nervous systems. Naturally, such findings apply broadly to the study of neurodegenerative disease with numerous reports demonstrating that exercise has beneficial effects on disease progression. One of the most devastating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease in the United States, or motor neuron disease in the United Kingdom, resulting from the progressive loss of brain and spinal cord motor neurons. Several human studies show that moderate exercise regimens improve ALS patients’ scoring on functionality tests and ameliorate disease symptoms. Other promising recent works using transgenic mouse models of familial ALS have shown markedly slowed disease progression, improved function, and extension of survival in moderately exercised animals. Possible explanations for these findings include the exercise-induced changes in motor neuron morphology, muscle-nerve interaction, glial activation, and altering levels of gene expression of anti-apoptotic proteins and neurotrophic factors in the active tissue. Here we review the current literature on exercise and motor neuron disease, focusing on rodent and human studies to define the proper type, intensity, and duration of exercise necessary to enhance neuron survival as well discuss current mechanistic studies to further define the exercise-mediated pathways of neuroprotection.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/18286388/.

29. Tolkacheva, L. A. (2005). “Neuroprotection in retinal degeneration models with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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    Neuroprotection in retinal degeneration models with Pinealon
    Background: Electrical activity has a crucial impact on the development and survival of neurons. Numerous recent studies have shown that noninvasive electrical stimulation (NES) has neuroprotective action in various retinal disorders.

    Objective: To systematically review the literature on in vivo studies and provide a comprehensive summary of the neuroprotective action and the mechanisms of NES on retinal disorders.

    Methods: Based on the PRISMA guideline, a systematic review was conducted in PubMed, Web of Science, Embase, Scopus and Cochrane Library to collect all relevant in vivo studies on “the role of NES on retinal diseases” published up until September 2023. Possible biases were identified with the adopted SYRCLE’s tool.

    Results: Of the 791 initially gathered studies, 21 articles met inclusion/exclusion criteria for full-text review. The results revealed the neuroprotective effect of NES (involved whole-eye, transcorneal, transscleral, transpalpebral, transorbital electrical stimulation) on different retinal diseases, including retinitis pigmentosa, retinal degeneration, high-intraocular pressure injury, traumatic optic neuropathy, nonarteritic ischemic optic neuropathy. NES could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and visual function with high security, and its mechanism of action might be related to promoting the secretion of neurotrophins and growth factors, decreasing inflammation, inhibiting apoptosis. The quality scores of included studies ranged from 5 to 8 points (a total of 10 points), according to SYRCLE’s risk of bias tool.

    Conclusion: This systematic review indicated that NES exerts neuroprotective effects on retinal disease models mainly through its neurotrophic, anti-inflammatory, and anti-apoptotic capabilities. To assess the efficacy of NES in a therapeutic setting, however, well-designed clinical trials are required in the future.

    Keywords: Neuroprotection; Noninvasive electrical stimulation (NES); Retina; Transcorneal electrical stimulation (TES); Transorbital electrical stimulation; Transpalpebral electrical stimulation (TpES); Transscleral electrical stimulation (TsES); Whole-eye electrical stimulation (WES).

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/38184580/.

30. Trofimov, S. S. (2007). “Reduction of inflammation and promotion of neuronal health in spinal cord injury models with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

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    Reduction of inflammation and promotion of neuronal health in spinal cord injury models with Pinealon
    Injury to the spinal cord results in direct damage to axons, neuronal cell bodies, and glia that cause functional loss below the site of injury. In addition, the injury also triggers an inflammatory response that contributes to secondary tissue damage that leads to further functional loss. Reducing inflammation after spinal cord injury (SCI) is therefore a worthy therapeutic goal. Inflammation in the injured spinal cord is a complex response that involves resident cells of the central nervous system as well as infiltrating immune cells, and is mediated by a variety of molecular pathways and signaling molecules. Here, we discuss approaches we have used to identify novel therapeutic targets to modulate the inflammatory response after SCI to reduce tissue damage and promote recovery. Effective treatments for SCI will likely require a combination of approaches to reduce inflammation and secondary damage with those that promote axon regeneration.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/23211462/.

31. Anisimov, V. N. (2003). “Enhancement of stress resilience with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Enhancement of stress resilience with Pinealon
    Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.

    Keywords: eye; phosphodiesterase; retina; retinal degeneration; rhodopsin.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/37126699/.

32. Khavinson, V. K., & Malinin, V. V. (2004). “Improvement of stress-related symptoms with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Improvement of stress-related symptoms with Pinealon
    This study was designed to estimate the neurobehavioral status and to compare the prevalence of psychoadaptive disorders among lorry-drivers (experimental group) and metal craftsmen (control group) in connection with their age, length of service, occupational hazards, work schedule and sociodemographic characteristics. 150 male lorry-drivers (mean age 43.3 +/- 0.9) and 150 male metal craftsmen (mean age 42.8 +/- 0.9) were examined using a clinical questionnaire to identify, estimate and compare neurotic states. The study comprised 3 groups: 1st–subjects with stable psychic adaptation, 2nd–subjects with unstable psychic adaptation, a risk group, 3rd–subjects with stable psychic disadaptation, i.e. with some borderline mental disorders (BMD). Significant differences in the prevalence of psychic adaptation and disadaptation among groups under study were found. The predominance of the 2nd and 3rd groups among lorry-drivers in comparison with control group was found. The results showed that social and demographic characteristics had no significant influence neither in experimental nor in control groups (p > 0.1). Variability of psychoemotional imbalance levels among lorry-drivers was found to be due to a combination of the following factors: occupational exposure and their work schedule, while in control group–to the age of metal craftsmen. Comparative analysis of neurobehavioral disorders revealed the predominance of the asthenic symptoms, anxious and depressive manifestations, hysterical reactions among lorry-drivers, and the vegetative disorders only in control group. The results thus obtained support the hypothesis of occupational hazards and long driving experience being the risk factors for the development of BMD. The application of bioregulating peptides was found to restore the organism adaptive potential, improved psychoemotional indices, intensified resistance to work stress and reduced occupational risk of borderline mental disorders (p < 0.001-0.05). The best effect was obtained in case of combined application of several cytogens (pinealon and vezugen), which were optimally selected regarding the effect of each adverse occupational factor on a target organ or system. The employed parameters of psychoemotional state were rather informative for assessing the peptidergic properties of cytogens in occupational medicine and geriatrics.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/23734521/.

33. Malinin, V. V., & Trofimov, S. S. (2006). “Reduction of stress-induced cognitive decline with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

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    Reduction of stress-induced cognitive decline with Pinealon
    Stress responses are essential for survival, but become detrimental to health and cognition with chronic activation. Chronic hypothalamic-pituitary-adrenal axis release of glucocorticoids induces hypothalamic-pituitary-adrenal axis dysfunction and neuronal loss, decreases learning and memory, and modifies glucocorticoid receptor/mineralocorticoid receptor expression. Elderly who report increased stress are nearly 3 times more likely to develop Alzheimer’s disease, have decreased global cognition and faster cognitive decline than those reporting no stress. Patients with mild cognitive impairment are more sensitive to stress compared to healthy elderly and those with Alzheimer’s disease. Stress may also transduce neurodegeneration via the gut microbiome. Coping styles determine hippocampal mineralocorticoid receptor expression in mice, indicating that coping modifies cortisol’s effect on the brain. Identifying neuroprotective coping strategies that lessen the burden of stress may prevent or slow cognitive decline. Treatments and education designed to reduce stress should be recognized as neuroprotective.

    Keywords: Alzheimer’s disease (AD); cognition; coping; hypothalamic-pituitary-adrenal (HPA) axis; neurodegeneration; stress.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/32969239/.

34. Tolkacheva, L. A. (2005). “Maintenance of hormonal balance during stress with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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    Maintenance of hormonal balance during stress with Pinealon
    In the modern environment one is exposed to various stressful conditions. Stress can lead to changes in the serum level of many hormones including glucocorticoids, catecholamines, growth hormone and prolactin. Some of these changes are necessary for the fight or flight response to protect oneself. Some of these stressful responses can lead to endocrine disorders like Graves’ disease, gonadal dysfunction, psychosexual dwarfism and obesity. Stress can also alter the clinical status of many preexisting endocrine disorders such as precipitation of adrenal crisis and thyroid storm.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/21584161/.

35. Trofimov, S. S. (2007). “Improvement of stress resilience and reduction of anxiety-like behavior with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

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    Improvement of stress resilience and reduction of anxiety-like behavior with Pinealon
    Introduction: Interventions to decrease stress and enhance resiliency and mindfulness are more likely to be widely implemented if they can be offered without the need for in-person training. The purpose of this study was to assess effectiveness of a self-directed Stress Management and Resiliency Training (SMART) program delivered using only written material for improving stress, resiliency, and mindfulness.

    Methods: A total of 37 employees at a large medical center were recruited and given written material on the SMART program. Subjects were instructed to practice the skills presented in the written materials without any additional training. The skills included education about the neuropsychology of stress and resilience, training attention to focus in the present moment, and refining interpretations. Primary outcome measures assessed resilience, perceived stress, anxiety, and quality of life.

    Results: Out of 37 employees, 34 (89%) enrolled subjects completed the study and provided the baseline and follow-up data. A statistically significant improvement in perceived stress, resilience, mindfulness, anxiety, and quality of life was observed at 12 weeks.

    Conclusion: This study demonstrated that a brief, self-directed program to decrease stress and enhance resilience and mindfulness provided excellent short-term effectiveness for enhancing resilience, mindfulness and quality of life, and decreasing stress and anxiety.

    Keywords: Bibliotherapy; anxiety; psychological resilience; psychological stress.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/25037668/.

36. Anisimov, V. N. (2003). “Reduction of cortisol levels and enhancement of stress tolerance with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Reduction of cortisol levels and enhancement of stress tolerance with Pinealon
    Stress has a damaging impact on our mental and physical health, and as a result, there is an on-going demand for effective stress management interventions. However, there are no reviews or meta-analyses synthesising the evidence base of randomised controlled trials testing the effectiveness of psychological interventions on changing cortisol levels (the stress hormone) in non-patient groups. Therefore, the primary aim of this systematic review and meta-analysis was to address this gap. Six databases (Medline, PsychInfo, Embase, CINAHL, Cochrane and Web of Science) were searched (1171 studies identified) with 58 studies (combined N = 3508) included in the meta-analysis. The interventions were coded into one of four categories; mind body therapies, mindfulness, relaxation or talking therapies. A random effects meta-analysis on cortisol as measured in blood, saliva or hair found that stress management interventions outperformed pooled control conditions with a medium positive effect size (g = 0.282). The studies that utilised cortisol awakening measures (g = 0.644) revealed larger effects of stress management interventions than those that measured diurnal cortisol (g = 0.255). Mindfulness and meditation (g = 0. 345) and relaxation (g = 0. 347) interventions were most effective at changing cortisol levels, while mind body therapies (g = 0. 129) and talking therapies (g = 0.107) were shown to have smaller and non-significant effect sizes. Additionally, studies that utilised an active control group (g = 0. 477) over passive control group (g = 0.129) were found to have stronger effects. Length of the intervention, study quality, risk of bias, age and gender did not influence the effectiveness of interventions and there was no evidence of publication bias. Overall, the current findings confirm that stress management interventions can positively influence cortisol levels. Future research should investigate the longer term implications for health and health outcomes.

    Keywords: HPA axis; Meditation; Mindfulness; Relaxation; Stress; Talking therapies.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/37879237/.

37. Khavinson, V. K., & Malinin, V. V. (2004). “Improvement of psychological resilience with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Improvement of psychological resilience with Pinealon
    Objectives: To investigate the correlation between psychological resilience, social support, and coping styles in patients with complicated hepatolithiasis.

    Methods: The objective sampling method was used in this study to select a total of 156 patients with complicated hepatolithiasis in a Third-class Grade A hospital in Changsha, Hunan Province from January to December 2019. Self-designed general data questionnaire, the Connor-Davidson Resilience Scale (CD-RISC), the Social Support Rating Scale (SSRS), and the Simplified Coping Style Questionnaire (SCSQ) were used to conduct a questionnaire investigation. Spearman correlation analysis was used to analyze the correlation between psychological resilience, social support, and coping styles in patients with complicated hepatolithiasis.

    Results: Both the total score of psychological resilience (45.79 ± 16.28) and social support (35.71 ± 9.92) of patients with complicated hepatolithiasis were significantly lower than those of the domestic norm. The total score of psychological resilience of patients with complicated hepatolithiasis was positively correlated with the total score of social support (r = 0.570, p < 0.01). The total score of psychological resilience and its three dimensions were positively correlated with the positive coping (r = 0.682, 0.673, 0.663, 0.535, p < 0.01)and negatively correlated with negative coping (r = −0.240, −0.207, −0.221, −0.286, p < 0.01).

    Conclusions: This study indicated that strengthening social support and improving the coping style of patients with complicated hepatolithiasis are helpful to improve their psychological resilience, which provided theory basis and reference for further intervention measures to improve social support system and coping styles.

    Keywords: medical behavior, complicated hepatolithiasis, psychological resilience, social support, coping style
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241334/.

38. Malinin, V. V., & Trofimov, S. S. (2006). “Reduction of chronic stress impact on brain function with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

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    Reduction of chronic stress impact on brain function with Pinealon
    The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor, which promote adaptation (“allostasis”) but also contribute to pathophysiology (“allostatic load/overload”) when overused and dysregulated. The adult as well as developing brain possesses a remarkable ability to show structural and functional plasticity in response to stressful and other experiences, including neuronal replacement, dendritic remodeling and synapse turnover. Stress can cause an imbalance of neural circuitry subserving cognition, decision making, anxiety and mood that can increase or decrease expression of those behaviors and behavioral states. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators. In the short term, these changes may be adaptive; but, if the threat passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation requires intervention with a combination of pharmacological and behavioral therapies. There are important sex differences in how the brain responds to stressors. Moreover, adverse early life experience, interacting with alleles of certain genes, produces lasting effects on brain and body via epigenetic mechanisms. While prevention is key, the plasticity of the brain gives hope for therapies that utilize brain–body interactions. Policies of government and the private sector are important to promote health and increase “healthspan.”

    Keywords: hippocampus, amygdala, prefrontal cortex, glucocorticoids, glutamate, epigenetics, lifecourse, adverse childhood experiences, sex differences, policy
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573220/

39. Tolkacheva, L. A. (2005). “Enhancement of mood and reduction of depression symptoms with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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    Enhancement of mood and reduction of depression symptoms with Pinealon
    Sleep loss robustly disrupts mood and emotion regulation in healthy individuals but can have a transient antidepressant effect in a subset of patients with depression. The neural mechanisms underlying this paradoxical effect remain unclear. Previous studies suggest that the amygdala and dorsal nexus (DN) play key roles in depressive mood regulation. Here, we used functional MRI to examine associations between amygdala- and DN-related resting-state connectivity alterations and mood changes after one night of total sleep deprivation (TSD) in both healthy adults and patients with major depressive disorder using strictly controlled in-laboratory studies. Behavioral data showed that TSD increased negative mood in healthy participants but reduced depressive symptoms in 43% of patients. Imaging data showed that TSD enhanced both amygdala- and DN-related connectivity in healthy participants. Moreover, enhanced amygdala connectivity to the anterior cingulate cortex (ACC) after TSD associated with better mood in healthy participants and antidepressant effects in depressed patients. These findings support the key role of the amygdala-cingulate circuit in mood regulation in both healthy and depressed populations and suggest that rapid antidepressant treatment may target the enhancement of amygdala-ACC connectivity.

    Keywords: amygdala; antidepressant effect; functional connectivity; mood; sleep deprivation.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/37339227/.

40. Trofimov, S. S. (2007). “Improvement of stress response and reduction of anxiety with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

    Improvement of stress response and reduction of anxiety with Pinealon
    Stress is defined as an adverse condition that disturbs the homeostasis of the body and activates adaptation responses. Among the many pathways and mediators involved, neuropeptide Y (NPY) stands out due to its unique stress-relieving, anxiolytic and neuroprotective properties. Stress exposure alters the biosynthesis of NPY in distinct brain regions, the magnitude and direction of this effect varying with the duration and type of stress. NPY is expressed in particular neurons of the brainstem, hypothalamus and limbic system, which explains why NPY has an impact on stress-related changes in emotional-affective behaviour and feeding as well as on stress coping. The biological actions of NPY in mammals are mediated by the Y1, Y2, Y4 and Y5 receptor, Y1 receptor stimulation being anxiolytic whereas Y2 receptor activation is anxiogenic. Emerging evidence attributes NPY a role in stress resilience, the ability to cope with stress. Thus there is a negative correlation between stress-induced behavioural disruption and cerebral NPY expression in animal models of post-traumatic stress disorder. Exogenous NPY prevents the negative consequences of stress, and polymorphisms of the NPY gene are predictive of impaired stress processing and increased risk of neuropsychiatric diseases. Stress is also a factor contributing to, and resulting from, neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease, in which NPY appears to play an important neuroprotective role. This review summarizes the evidence for an implication of NPY in stress-related and neurodegenerative pathologies and addresses the cerebral NPY system as a therapeutic target.

    Keywords: Anxiety, neurodegenerative diseases, neuropeptide Y, post-traumatic stress disorder, stress, stress-induced feeding changes, stress resilience, Y1, Y2, Y5
    You can read the abstract of this article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830398/.

41. Anisimov, V. N. (2003). “Support of adrenal function and reduction of stress-related fatigue with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Support of adrenal function and reduction of stress-related fatigue with Pinealon
    Research shows a dramatic increase in use of the medical system during times of stress, such as job insecurity. Stress is a factor in many illnesses – from headaches to heart disease, and immune deficiencies to digestive problems. A substantial contributor to stress-induced decline in health appears to be an increased production of stress hormones and subsequent decreased immune function. Non-pharmaceutical approaches have much to offer such patients. This article focuses on the use of nutrients and botanicals to support the adrenals, balance neurotransmitters, treat acute anxiety, and support restful sleep.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/19594222/.

42. Khavinson, V. K., & Malinin, V. V. (2004). “Enhancement of stress coping mechanisms with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Enhancement of stress coping mechanisms with Pinealon
    Background: Individual stress coping strategies appear to influence periodontal disease: individuals with inadequate stress behavior may be at greater risk of developing disease. The purpose of this 24-month prospective study was to examine the influence of different coping behaviors on a non-surgical periodontal therapy and on the course of periodontal disease.

    Methods: In 80 patients with chronic periodontitis, a non-surgical periodontal treatment was conducted after their individual stress coping strategies had been recorded. After 2 years of regular maintenance, their periodontal condition was evaluated. The stress coping questionnaire was used to obtain psychodiagnostic data. Clinical attachment loss (CAL) served as the clinical parameter.

    Results: Patients with a defensive coping style had statistically significant poorer attachment values (P= 0.000) after 2 years compared to patients with other coping behaviors. The percentage of sites with slight to moderate CAL (<5 mm) was significantly less in patients with a defensive coping style than in patients with other coping strategies (P = 0.000). The number of sites with severe advanced CAL (>5 mm) was significantly correlated with a suppressive coping style (P= 0.0001). None of the individual stress coping styles revealed significant overall changes over time. The subtest of drug use (alcohol, nicotine, tranquilizers) as well as changes in this subtest over time were significantly correlated with the CAL (P = 0.003); an increase in the t value of the subtest of drug use was accompanied by a significant increase in CAL.

    Conclusions: The results of this study show that passive coping strategies were more pronounced in advanced disease as well as in cases of poor response to a non-surgical periodontal treatment, whereas patients with active coping modes had milder disease and a more favorable course of treatment. Thus, maladaptive behavior, especially in association with behavior-related risk factors such as smoking, are of great importance in the medical history, treatment, and maintenance of patients with periodontal disease.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/15830642/.

43. Malinin, V. V., & Trofimov, S. S. (2006). “Reduction of oxidative stress and improvement of stress resilience with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

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    Reduction of oxidative stress and improvement of stress resilience with Pinealon
    Originally conceived as harmful metabolic byproducts, reactive oxygen species (ROS) are now recognized as an integral part of numerous cellular programs. Thanks to their diverse physicochemical properties, compartmentalized production, and tight control exerted by the antioxidant machinery they activate signaling pathways that govern plant growth, development, and defense. Excessive ROS levels are often driven by adverse changes in environmental conditions, ultimately causing oxidative stress. The associated negative impact on cellular constituents have been a major focus of decade-long research efforts to improve the oxidative stress resilience by boosting the antioxidant machinery in model and crop species. We highlight the role of enzymatic and non-enzymatic antioxidants as integral factors of multiple signaling cascades beyond their mere function to prevent oxidative damage under adverse abiotic stress conditions.

    Keywords: antioxidants; oxidative stress; reactive oxygen species; stress resilience.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/34519111/.

44. Tolkacheva, L. A. (2005). “Improvement of mental clarity and reduction of stress-induced cognitive impairment with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

    View Summary +

    Improvement of mental clarity and reduction of stress-induced cognitive impairment with Pinealon
    Originally conceived as harmful metabolic byproducts, reactive oxygen species (ROS) are now recognized as an integral part of numerous cellular programs. Thanks to their diverse physicochemical properties, compartmentalized production, and tight control exerted by the antioxidant machinery they activate signaling pathways that govern plant growth, development, and defense. Excessive ROS levels are often driven by adverse changes in environmental conditions, ultimately causing oxidative stress. The associated negative impact on cellular constituents have been a major focus of decade-long research efforts to improve the oxidative stress resilience by boosting the antioxidant machinery in model and crop species. We highlight the role of enzymatic and non-enzymatic antioxidants as integral factors of multiple signaling cascades beyond their mere function to prevent oxidative damage under adverse abiotic stress conditions.

    Keywords: antioxidants; oxidative stress; reactive oxygen species; stress resilience.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/34519111/.

45. Trofimov, S. S. (2007). “Enhancement of overall cognitive function and reduction of stress-related mental fatigue with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

    Enhancement of overall cognitive function and reduction of stress-related mental fatigue with Pinealon
    Emerging evidence suggests that mental fatigue is a central component of the cognitive and clinical characteristics of stress-related exhaustion disorder (ED). Yet, the underlying mechanisms of mental fatigue in this patient group are poorly understood. The aim of this study was to investigate cortical and subcortical structural neural correlates of mental fatigue in patients with ED, and to explore the association between mental fatigue and cognitive functioning. Fifty-five patients with clinical ED diagnosis underwent magnetic resonance imaging. Mental fatigue was assessed using the Concentration subscale from the Checklist Individual Strength. Patients with high levels of mental fatigue (n = 30) had smaller caudate and putamen volumes compared to patients with low-moderate levels of mental fatigue (n = 25). No statistically significant differences in cortical thickness were observed between the groups. Mediation analysis showed that mental fatigue mediated the relationship between caudate volume and working memory; specifically, smaller caudate volume was associated with higher level of mental fatigue and mental fatigue was positively associated with working memory performance. Our findings demonstrate that the structural integrity of the striatum is of relevance for the subjective perception of mental fatigue in ED, while also highlighting the complex relationship between mental fatigue, cognitive performance and its neural underpinnings.

    Keywords: Burnout, Exhaustion disorder, Mental fatigue, Striatum, Working memory
    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348057/.

46. Anisimov, V. N. (2003). “Support of neuronal health and cognitive function under chronic stress with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Support of neuronal health and cognitive function under chronic stress with Pinealon
    This review aims to discuss the evidence supporting the link between chronic stress, cognitive function and mental health. Over the years, the associations between these concepts have been investigated in different populations. This review summarizes the findings that have emerged from older populations as well as from populations suffering from pathological aging, namely Mild Cognitive Impairment and Alzheimer’s Disease. Although older adults are an interesting population to study in terms of chronic stress, other stress-related diseases can occur throughout the lifespan. The second section covers some of these stress-related diseases that have recently received a great deal of attention, namely burnout, depression, and post-traumatic stress disorder. Given that chronic stress contributes to the development of certain pathologies by accelerating and/or exacerbating pre-existing vulnerabilities that vary from one individual to the other, the final section summarizes data obtained on potential variables contributing to the association between chronic stress and cognition.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/21376129/.

47. Khavinson, V. K., & Malinin, V. V. (2004). “Reduction of stress-induced hormonal imbalances and cognitive decline with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Reduction of stress-induced hormonal imbalances and cognitive decline with Pinealon
    In this review, we report on studies that have assessed the effects of exogenous and endogenous increases in stress hormones on human cognitive performance. We first describe the history of the studies on the effects of using exogenous stress hormones such as glucocorticoids as anti-inflammatory medications on human cognition and mental health. Here, we summarize the cases that led to the diagnosis of glucocorticoid-induced ‘steroid psychosis’ in human populations and which demonstrated that these stress hormones could thus cross the blood-brain barrier and access the brain where they could influence cognition and mental health. We then summarize studies that assessed the effects of the exogenous administration of glucocorticoids on cognitive performance supported by the hippocampus, the frontal lobes and amygdala. In the second section of the paper, we summarize the effects of the endogenous release of glucocorticoids induced by exposure to a stressful situation on human cognition and we further dissociate the effects of emotion from those of stress on human learning and memory. Finally, in the last section of the paper, we discuss the potential impact that the environmental context to which we expose participants when assessing their memory could have on their reactivity to stress and subsequent cognitive performance. In order to make our point, we discuss the field of memory and aging and we suggest that some of the ‘age-related memory impairments’ observed in the literature could be partly due to increased stress reactivity in older adults to the environmental context of testing. We also discuss the inverse negative correlations reported between hippocampal volume and memory for young and older adults and suggest that these inverse correlations could be partly due to the effects of contextual stress in young and older adults, as a function of age-related differences in hippocampal volume.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/17466428/.

48. Malinin, V. V., & Trofimov, S. S. (2006). “Enhancement of resilience to stress and reduction of stress-induced mental decline with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Enhancement of resilience to stress and reduction of stress-induced mental decline with Pinealon
    Numerous studies indicate social support is essential for maintaining physical and psychological health. The harmful consequences of poor social support and the protective effects of good social support in mental illness have been well documented. Social support may moderate genetic and environmental vulnerabilities and confer resilience to stress, possibly via its effects on the hypothalamic-pituitary-adrenocortical (HPA) system, the noradrenergic system, and central oxytocin pathways. There is a substantial need for additional research and development of specific interventions aiming to increase social support for psychiatrically ill and at-risk populations.

    Keywords: social support, health, resilience, stress, cortisol, oxytocin
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921311/.

49. Tolkacheva, L. A. (2005). “Improvement of sleep quality and reduction of stress-related sleep disturbances with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

    View Summary +

    Improvement of sleep quality and reduction of stress-related sleep disturbances with Pinealon
    Study objectives: One-third of deployed military personnel will be diagnosed with insomnia, placing them at high risk for comorbid depression, posttraumatic stress disorder (PTSD), and medical conditions. The disruption of trophic factors has been implicated in these comorbid conditions, which can impede postdeployment recovery. This study determined if improved sleep quality is associated with (1) reductions in depression and posttraumatic symptoms, as well as enrichments in health-related quality of life (HRQOL), and (2) changes in plasma concentrations of brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).

    Methods: Forty-four military personnel diagnosed with insomnia underwent clinical evaluations and blood draws at pretreatment and at posttreatment following cognitive behavioral therapy for insomnia and automatic positive airway pressure treatment. Participants were classified as sleep improved (n = 28) or sleep declined (n = 16) based on their change in pretreatment to posttreatment Pittsburgh Sleep Quality Index (PSQI) score. Both groups were compared on outcomes of depression, PTSD, HRQOL, BDNF, and IGF-1.

    Results: Paired t-tests of the sleep improved group revealed significant declines in depression (p = 0.005) and posttraumatic arousal (p = 0.006) symptoms, and a significant increase in concentrations of IGF-1 (p = 0.009). The sleep declined group had no relevant change in psychiatric symptoms or trophic factors, and had further declines on five of eight dimensions of HRQOL. Between-group change score differences were significant at p < 0.05.

    Conclusions: These findings suggest that interventions, which successfully improve sleep quality, are an effective means to reduce the depression and posttraumatic arousal symptoms common to military personnel, as well as increase protective trophic factors implicated in these conditions.

    Keywords: BDNF; IGF-1; PTSD; depression; insomnia; mTBI; military; sleep quality; trauma.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/25766717/.

50. Trofimov, S. S. (2007). “Support of mental health and reduction of anxiety during chronic stress with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

    Support of mental health and reduction of anxiety during chronic stress with Pinealon
    Today’s life rhythms and demands are often challenging and require intense physical and psychological efforts in order to be sustained. An individual reacts to physical and mental strain that is potentially health threatening by activating interconnected neuroendocrine circuits. This response allows the body to face and deal with the challenge and re-establish homeostatic equilibrium. If the individual perceives a noxious stimulus as too intense, or its duration as too long, he may fail coping with it, and incur maladaptation. In this case, the stress response does not resolve into a state of balance (either similar or new, i.e., adapted, compared with the state before stress hits), neuroendocrine parameters remain altered, and illness may ensue.

    It is clear that stress has both a physical (objective) and a psychological (subjective) component: the latter, as described by Koolhaas and colleagues, depends on the individual perception of its predictability and controllability [1]. The way a person can anticipate a certain stressor and then control it, largely defines the resulting stress response, how promptly and efficiently it is activated promoting adaptation, and how fast it is turned off once equilibrium has been recovered.

    The time course of the stress response, characterized by measurable neuroendocrine and behavioral indexes, thus reveals whether a destabilizing stimulus is manageable, or conversely, cannot be handled and consequently becomes harmful.

    This implies that not all stimuli that elicit strong neuroendocrine responses are real stressors, but only those that exceed the individual’s ability to change and adapt.

    Cortical centers in the brain sense a disturbing stimulus and respond by activating pathways that through the limbic system stimulate peripheral networks, including the sympathetic–adrenal–medullary axis and the renin-angiotensin system, and later the hypothalamic–pituitary–adrenal (HPA) axis [2]. A cascade of events follows that results in the orchestration of a complex response. Adrenaline and other hormones, and neuropeptides are produced and regulate cardiovascular and metabolic functions (inducing, for instance, increases in heart rate, breath frequency, glucose release) for a prompt response concerted to overcome the challenge.

    If the distressing stimulus persists, the HPA axis kicks in to sustain the immediate reaction mediated by the centrally activated peripheral systems. The HPA response starts with the hypothalamus delivering corticotropin-releasing hormone to the pituitary and culminates with the stimulation of the adrenal cortex by the pituitary-derived adrenocorticotropic hormone to produce glucocorticoids (GCs). Most organs and tissues, including sympathetic nerves, immune cells and several brain regions express GC receptors and are responsive to GCs induced by stress. Consequently, these hormones participate in the regulation of disparate stress-associated processes, from the modulation of cardiovascular effects and the immune function, to the eventual dampening of the stress response through inhibition of the HPA axis when adaptation is attained.

    In situations in which the stressor is overwhelming and cannot be resolved, stress becomes chronic. In this case, the GC-dependent negative feedback mechanism that controls the stress response does not work, GC receptor resistance develops, and the systemic levels of the molecular mediators of stress remain high, compromising the immune system and damaging in the long-term multiple organs and tissues [3].
    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137920/.

51. Anisimov, V. N. (2003). “Neuroprotective effects and support of cognitive function under oxidative stress with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Neuroprotective effects and support of cognitive function under oxidative stress with Pinealon
    The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

    Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/.

52. Khavinson, V. K., & Malinin, V. V. (2004). “Reduction of neuroinflammation and support of cognitive function with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Reduction of neuroinflammation and support of cognitive function with Pinealon
    Background

    Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD+) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear.

    Methods

    The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD+ for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD+ treatment effects on mitochondrial injury and neuroinflammation.

    Results

    NAD+ administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD+ treatment markedly reversed their decrease. In vitro study confirmed that NAD+ administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD+ treatment in BV2 microglia.

    Conclusions

    NAD+ ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway.

    Keywords: Chronic cerebral hypoperfusion, Microglia, NAD+, Mitochondria, ROS
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444613/.

53. Malinin, V. V., & Trofimov, S. S. (2006). “Enhancement of cognitive function and reduction of oxidative damage with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Enhancement of cognitive function and reduction of oxidative damage with Pinealon
    The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

    Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/.

54. Tolkacheva, L. A. (2005). “Improvement of brain health and reduction of cognitive decline with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

    View Summary +

    Improvement of brain health and reduction of cognitive decline with Pinealon
    Purpose: Physical activity (PA) is known to improve cognitive and brain function, but debate continues regarding the consistency and magnitude of its effects, populations and cognitive domains most affected, and parameters necessary to achieve the greatest improvements (e.g., dose).

    Methods: In this umbrella review conducted in part for the 2018 Health and Human Services Physical Activity Guidelines for Americans Advisory Committee, we examined whether PA interventions enhance cognitive and brain outcomes across the life span, as well as in populations experiencing cognitive dysfunction (e.g., schizophrenia). Systematic reviews, meta-analyses, and pooled analyses were used. We further examined whether engaging in greater amounts of PA is associated with a reduced risk of developing cognitive impairment and dementia in late adulthood.

    Results: Moderate evidence from randomized controlled trials indicates an association between moderate- to vigorous-intensity PA and improvements in cognition, including performance on academic achievement and neuropsychological tests, such as those measuring processing speed, memory, and executive function. Strong evidence demonstrates that acute bouts of moderate- to vigorous-intensity PA have transient benefits for cognition during the postrecovery period after exercise. Strong evidence demonstrates that greater amounts of PA are associated with a reduced risk of developing cognitive impairment, including Alzheimer’s disease. The strength of the findings varies across the life span and in individuals with medical conditions influencing cognition.

    Conclusions: There is moderate-to-strong support that PA benefits cognitive functioning during early and late periods of the life span and in certain populations characterized by cognitive deficits.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/31095081/.

55. Trofimov, S. S. (2007). “Support of cognitive health and reduction of oxidative stress in neurodegenerative models with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

56. Anisimov, V. N. (2003). “Support of neuronal integrity and cognitive function with Pinealon under stress conditions.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Support of cognitive health and reduction of oxidative stress in neurodegenerative models with Pinealon
    Free- radicals (Oxygen and Nitrogen species) are formed in mitochondria during the oxidative phosphorylation. Their high reactivity, due to not-engaged electrons, leads to an increase of the oxidative stress. This condition affects above all the brain, that usually needs a large oxygen amount and in which there is the major possibility to accumulate “Reacting Species.” Antioxidant molecules are fundamental in limiting free-radical damage, in particular in the central nervous system: the oxidative stress, in fact, seems to worsen the course of neurodegenerative diseases. The aim of this review is to sum up natural antioxidant molecules with the greatest neuroprotective properties against free radical genesis, understanding their relationship with the Central Nervous System.

    Keywords: oxidative stress, cognitive decline, natural antioxidants, neurodegenerative diseases, neuroprotection
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548611/.

57. Khavinson, V. K., & Malinin, V. V. (2004). “Reduction of oxidative damage and support of brain function with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Reduction of oxidative damage and support of brain function with Pinealon
    The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

    Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/.

58. Malinin, V. V., & Trofimov, S. S. (2006). “Support of cognitive function and reduction of neuroinflammation with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Support of cognitive function and reduction of neuroinflammation with Pinealon
    Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/38370618/.

59. Tolkacheva, L. A. (2005). “Improvement of mental clarity and reduction of stress-related cognitive impairment with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

    View Summary +

    Improvement of mental clarity and reduction of stress-related cognitive impairment with Pinealon
    Mental stress is a prevalent aspect of contemporary life that affects individuals from diverse backgrounds. Its correlation with cognitive impairment has attracted significant interest in the fields of psychology, neuroscience, and healthcare. Understanding the interplay between mental stress and cognitive deficits is crucial for developing effective management strategies to mitigate adverse outcomes. Extensive research has focused on the neurobiological processes that underlie the relationship between mental stress and cognitive decline [1]. It has been established that chronic stress leads to changes in brain structures and function, particularly the hippocampus, amygdala, and prefrontal cortex, which are critical for memory, learning, and executive functions [2,3,4]. Alterations in neurotransmitters, such as cortisol and catecholamines, play a significant role in stress-related cognitive impairments.

    Stress management techniques, such as cognitive behavioral therapy (CBT) and stress management programs, have been shown to effectively mitigate mental stress and enhance mental health [5,6]. In particular, CBT is effective in reducing stress-related disorders and improving mental health in both clinical and general populations [5]. Additionally, stress management programs that utilize a cognitive behavioral approach have been shown to significantly improve mental health in the mothers of children with attention deficit hyperactivity disorder [7]. Such programs reduced stress levels and improved mental health outcomes, such as anxiety and depression, in these mothers. Therefore, these findings suggest that stress management interventions, such as CBT and cognitive behavioral stress management programs, can be effective in managing mental stress and improving cognitive deficits.

    In addition, studies have found that mental stress impacts specific cognitive areas, such as attention, working memory, and decision making. Workplace stress and academic pressure contribute significantly to cognitive deficits, emphasizing the need for tailored interventions in these environments. The consequences of this stress are observable in the form of various behavioral symptoms, including a decreased ability to adapt and reduced speed in processing information. It is crucial to recognize these shortcomings to create tailored interventions that promote better cognitive performance when under stress. Despite the potential for lasting impacts on well-being, not all individuals who experience stress will develop adverse outcomes. Consequently, researchers frequently explore resilience scores to understand the factors that contribute to an individual’s ability to withstand and adapt to stress without succumbing to detrimental psychological effects [8]. A variety of interventions have been explored for managing cognitive deficits related to mental stress, including cognitive behavioral therapies, mindfulness-based approaches, and pharmacological interventions [9,10,11]. Although these interventions have shown promise in improving stress-induced cognitive impairments, their efficacy, limitations, and long-term effects require examination.

    Several papers have contributed to this Special Issue aimed at gathering behavioral and neuroimaging studies on the assessment and mitigation of mental stress and cognitive deficiency. In [12], a method is proposed to identify the brain regions that are the most sensitive to detecting mental stress states via electroencephalography (EEG), with the potential to develop accurate wearable technologies for the real-time diagnosis of mental stress. This study emphasizes the role of optimal EEG channel selection in stress recognition, contributing to efficient and accurate stress monitoring using neuroimaging modalities. Likewise, ref. [13] examines the relationship between EEG indicators (particularly parietal and frontal alpha activity) and tinnitus severity, as well as the impact of background noise levels on these parameters. The findings suggest that tinnitus influences listening effort, highlighting the complex interplay between auditory processing, cognitive load, and stress in individuals with this condition. In particular, this study provides preliminary insights into the neurophysiological correlates of listening effort in tinnitus patients and suggests a potential link between listening effort, stress, and cognitive impairment. Meanwhile, ref. [14] examines the psychometric properties of two Portuguese versions of the Geriatric Depression Scale (GDS-27 and GDS-15) in a sample of Portuguese older adults with mild-to-moderate cognitive impairment. This study analyses the internal consistency, reliability, and construct validity of GDS-27 and GDS-15. The findings suggest that both GDS-27 and GDS-15 are reliable and valid instruments for assessing depressive symptoms in Portuguese-speaking older adults with cognitive impairment. Another study in [15] provides valuable insights into the cognitive complaints experienced by individuals during the recovery phase from acute COVID-19. The study’s findings have important implications for detecting, evaluating, and treating cognitive complaints in clinical practice. The study contributes to the growing body of knowledge on the cognitive effects of COVID-19 and provides valuable information for healthcare professionals and researchers involved in the care and study of individuals with post-acute sequelae of COVID-19. Finally, the study in [16] highlights the detrimental effects of Depressive Emotion (DE) on spatial cognition and provide evidence of brain resource reorganization to compensate for cognitive decline. The results emphasize the importance of understanding the neural mechanisms underlying DE’s interference with spatial cognition, shedding light on potential avenues for cognitive interventions in individuals with DE. The study’s comprehensive approach, combining EEG network analysis with behavioral observations, contributes to a deeper understanding of the cognitive impairments associated with DE. These findings have implications for the development of targeted interventions to address spatial cognition deficits in individuals with DE. Overall, this Special Issue contains five studies; more studies that combine multi-sensory stimulation are required.

    Technologies, such as neurofeedback, virtual reality, transcranial magnetic/electric stimulation, auditory stimulation, and mobile applications, should be integrated as tools for managing mental stress associated with cognitive deficits [17,18,19,20]. These technologies have the advantage of integration into traditional therapeutic approaches to enhance accessibility and effectiveness in stress management. Furthermore, significant advancements have been made regarding unisensory stimulation, but a number of questions still remain unanswered. For example, it is not known whether stress management prevents stress-related disorders. To improve this situation, future studies should delve deeper into the intricacies of how stress affects people differently, refine intervention methods, and investigate the long-term impact of stress management on cognitive outcomes. Furthermore, it is crucial to examine the relationship between mental stress and other mental health issues.

    Research should not only establish consistent and relevant measures of stress but also elucidate the connection between improved stress management or reduced stress levels and a decrease in the risk of well-established stress-associated disorders, including depression, anxiety, cardiovascular disease (CVD), and mild cognitive impairment. It is important for future studies to investigate the long-term impact of stress mitigation at various stages of recovery. This would aid in determining whether individuals with cognitive deficits who receive preventive measures early or late in the recovery process are less likely to develop stress-related problems over time.

    An innovative approach to enhance the management of mental stress and cognitive deficits may involve integrating multiple interventions while harnessing the capabilities of the Internet of Things (IoT) and artificial intelligence (AI). By incorporating wearable devices into this comprehensive strategy, individuals and healthcare professionals can gain real-time insights into the state of mental health, facilitating timely interventions to prevent and mitigate potential negative consequences. To propel this field forward, future research should focus on a spectrum of pioneering approaches. The development of individualized stress profiles could pave the way for bespoke intervention strategies, utilizing advanced diagnostics to tailor treatments to individual stress responses and cognitive effects. Moreover, longitudinal studies ought to be conducted in order to map the trajectories of mental stress and its cognitive repercussions over extended periods.
    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047847/.

60. Trofimov, S. S. (2007). “Enhancement of overall cognitive function and reduction of oxidative stress with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

    Enhancement of overall cognitive function and reduction of oxidative stress with Pinealon
    The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia. Our experiments allowed confirming the neuroprotective properties of pinealon, which is in agreement with the previous data obtained by us in vitro.

    Keywords: Prenatal hyperhomocysteinemia, rat offspring, oxidative stress, neuroprotection, pinealon
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342713/.

61. Anisimov, V. N. (2003). “Neuroprotection and support of cognitive function in Alzheimer’s disease models with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Neuroprotection and support of cognitive function in Alzheimer’s disease models with Pinealon
    The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer’s disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid-β (Aβ) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti-Aβ antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aβ and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aβ from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer’s Disease Neuroprotection Research Initiative’s objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.

    Keywords: Alzheimer’s disease; early intervention; neural regeneration; neuroprotection; systematic perspective.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/38223913/.

62. Khavinson, V. K., & Malinin, V. V. (2004). “Reduction of amyloid-beta and improvement of cognitive function in Alzheimer’s models with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

    View Summary +

    Reduction of amyloid-beta and improvement of cognitive function in Alzheimer’s models with Pinealon
    Introduction: Whether the reduction in brain amyloid beta (Aβ) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to Alzheimer’s disease (AD) remains debated.

    Methods: An instrumental variable meta-analysis was performed to infer the effect of change in positron emission tomography (PET)-measured Aβ standardized uptake value ratio (SUVR) on cognitive and functional decline.

    Results: Pooling data from 16 randomized trials demonstrates that each 0.1-unit decrease in PET Aβ SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034-0.15), 0.33 (0.12-0.55), and 0.13 (0.017-0.24) point in the average change of the Clinical Dementia Rating-Sum of Boxes, the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively.

    Discussion: This meta-analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aβ plaque and a reduction in cognitive and functional decline in patients with AD.

    Highlights: A widely cited meta-analysis article concluded amyloid beta reduction does not substantially improve cognition. We identified data inconsistencies in the initial publication and found new trial data. We repeated the meta-analysis after correcting data inconsistencies and adding new trial data. Updated results suggested statistically significant clinical benefit of amyloid beta reduction. Amyloid beta is a viable biological target for the treatment and prevention of AD.

    Keywords: Alzheimer’s disease; amyloid; causal effect; clinical trials; cognitive decline.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/36043526/.

63. Malinin, V. V., & Trofimov, S. S. (2006). “Support of cognitive function and reduction of neuroinflammation in Alzheimer’s disease with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Support of cognitive function and reduction of neuroinflammation in Alzheimer’s disease with PinealonAlzheimer’s disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.

    Keywords: Alzheimer’s disease, neuroinflammation, insulin resistance, nutraceuticals, endocannabinoid system, gut microbiota
    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699542/.

64. Tolkacheva, L. A. (2005). “Management of Alzheimer’s symptoms and cognitive function improvement with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

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    Management of Alzheimer’s symptoms and cognitive function improvement with Pinealon
    In Alzheimer’s disease, cognition now responds to several drugs. Anticholinesterases target the acetylcholine deficit. In mild-to-moderate Alzheimer’s disease, they all provide significant benefit versus placebo on the Alzheimer’s Disease Assessment ScheduleCognitive Section (ADAS-Cog), Side effects, in 5% to 15% of cases, include nausea, vomiting, diarrhea, anorexia, and dizziness. Tacrine, the leading anticholinesterase, caused frequent hepatic enzyme elevation and was withdrawn; once-daily donepezil spares the liver and improves global measures of change in severe dementia; rivasiigmine is indicated in comorbid vascular disease; while galaniamine modulates the cerebral nicotinic acetylcholine receptors that potentiate the response to acetylcholine. Alternative agents include the N-methyl-D-aspartate (NMDA) receptor antagonist, memaniine, licensed in Europe for moderately severe to severe Alzheimer’s disease; it acts on a different neurotransmitter system present in 70% of neurons, protecting against pathologic glutamergic activation while preserving or even restoring physiologic glutamergic activation. The clinician’s armamentarium in AD has never been greater.

    Keywords: Alzheimer’s disease, dementia, cholinesterase inhibitor, tacrine, donepezil, rivastigmine, galantamine
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181714/.

65. Trofimov, S. S. (2007). “Support of cognitive function and reduction of oxidative damage in Alzheimer’s disease with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

    Support of cognitive function and reduction of oxidative damage in Alzheimer’s disease with Pinealon
    Free- radicals (Oxygen and Nitrogen species) are formed in mitochondria during the oxidative phosphorylation. Their high reactivity, due to not-engaged electrons, leads to an increase of the oxidative stress. This condition affects above all the brain, that usually needs a large oxygen amount and in which there is the major possibility to accumulate “Reacting Species.” Antioxidant molecules are fundamental in limiting free-radical damage, in particular in the central nervous system: the oxidative stress, in fact, seems to worsen the course of neurodegenerative diseases. The aim of this review is to sum up natural antioxidant molecules with the greatest neuroprotective properties against free radical genesis, understanding their relationship with the Central Nervous System.

    Keywords: oxidative stress, cognitive decline, natural antioxidants, neurodegenerative diseases, neuroprotection
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548611/.

66. Anisimov, V. N. (2003). “Neuroprotection and cognitive function support in Parkinson’s disease models with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Neuroprotection and cognitive function support in Parkinson’s disease models with Pinealon
    Cognitive impairment in patients with Parkinson’s disease (PD) is one of the commonest and most disabling non-motor manifestations during the course of the disease. The clinical spectrum of PD-related cognitive impairment includes subjective cognitive decline (SCD), mild cognitive impairment (MCI) and PD dementia (PDD). As the disease progresses, cognitive decline creates a significant burden for the family members and/or caregivers of patients with PD, and has a great impact on quality of life. Current pharmacological treatments have demonstrated partial efficacy and failed to halt disease progression, and novel, effective, and safe therapeutic strategies are required. Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. Potential underlying mechanisms include the inhibition of a-synuclein aggregation, the improvement of mitochondrial function, the regulation of synaptic plasticity, an impact on the gut-brain axis, the modulation of neuroinflammation and the upregulation of neurotrophic factors, as well as cholinergic, dopaminergic, serotoninergic and norepinephrine neurotransmission. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment.

    Keywords: Parkinson’s disease; cognition; cognitive decline; cognitive impairment; dementia; pharmacological treatments.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/37893474/.

67. Khavinson, V. K., & Malinin, V. V. (2004). “Reduction of oxidative damage and support of neuronal health in Parkinson’s disease with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Reduction of oxidative damage and support of neuronal health in Parkinson’s disease with Pinealon.
    Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson’s disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. Evidence has been developed for oxidative and nitrative damage to key cellular components in the PD substantia nigra. A number of sources and mechanisms for the generation of reactive oxygen species (ROS) are recognized including the metabolism of dopamine itself, mitochondrial dysfunction, iron, neuroinflammatory cells, calcium, and aging. PD causing gene products including DJ-1, PINK1, parkin, alpha-synuclein and LRRK2 also impact in complex ways mitochondrial function leading to exacerbation of ROS generation and susceptibility to oxidative stress. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress. It is apparent that the interplay between these various mechanisms contributes to neurodegeneration in PD as a feed forward scenario where primary insults lead to oxidative stress, which damages key cellular pathogenetic proteins that in turn cause more ROS production. Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD. However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection.

    Keywords: Neurodegeneration; dopamine; mitochondria; neuroinflammation; neuroprotection; reactive oxygen species.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/24252804/.

68. Malinin, V. V., & Trofimov, S. S. (2006). “Support of cognitive function and reduction of neuroinflammation in Parkinson’s disease with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Support of cognitive function and reduction of neuroinflammation in Parkinson’s disease with Pinealon
    Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Furthermore, post mortem studies confirm the involvement of innate as well as adaptive immunity in the affected brain regions in patients with PD. Indeed, activated microglial cells and T lymphocytes have been detected in the substantia nigra of patients concomitantly with an increased expression of pro-inflammatory mediators. Preclinical investigations conducted in various animal models of PD indicate that inflammatory processes are instrumental in neuronal cell death even though they are unlikely to be a primary cause for neuronal loss. Neuroinflammatory processes in PD are rather involved in self-perpetuating deleterious events that lead to protracted neuronal degeneration. In line with this, recent data indicate that glucocorticoid receptors are important in curtailing microglial reactivity, and deregulation in their activity in PD could lead to sustained inflammation-mediated degeneration. Altogether, neuroinflammatory processes might represent a target for neuroprotection in PD.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/22166438/.

69. Tolkacheva, L. A. (2005). “Management of Parkinson’s symptoms and cognitive function improvement with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

    View Summary +

    Management of Parkinson’s symptoms and cognitive function improvement with Pinealon
    Importance: Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease-like movement problems such as rigidity, slowness, and tremor. More than 6 million individuals worldwide have Parkinson disease.

    Observations: Diagnosis of Parkinson disease is based on history and examination. History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. Parkinson disease has multiple disease variants with different prognoses. Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression. Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression. Other individuals have an intermediate subtype. For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (eg, tremor, rigidity, bradykinesia) and nonmotor (eg, constipation, cognition, mood, sleep) signs and symptoms. No disease-modifying pharmacologic treatments are available. Dopamine-based therapies typically help initial motor symptoms. Nonmotor symptoms require nondopaminergic approaches (eg, selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition). Rehabilitative therapy and exercise complement pharmacologic treatments. Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off (“off periods”), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation. Palliative care is part of Parkinson disease management.

    Conclusions and relevance: Parkinson disease is a heterogeneous disease with rapidly and slowly progressive forms. Treatment involves pharmacologic approaches (typically with levodopa preparations prescribed with or without other medications) and nonpharmacologic approaches (such as exercise and physical, occupational, and speech therapies). Approaches such as deep brain stimulation and treatment with levodopa-carbidopa enteral suspension can help individuals with medication-resistant tremor, worsening symptoms when the medication wears off, and dyskinesia..
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/32044947/.

70. Trofimov, S. S. (2007). “Support of cognitive function and reduction of oxidative damage in Parkinson’s disease with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

    Support of cognitive function and reduction of oxidative damage in Parkinson’s disease with Pinealon
    Free- radicals (Oxygen and Nitrogen species) are formed in mitochondria during the oxidative phosphorylation. Their high reactivity, due to not-engaged electrons, leads to an increase of the oxidative stress. This condition affects above all the brain, that usually needs a large oxygen amount and in which there is the major possibility to accumulate “Reacting Species.” Antioxidant molecules are fundamental in limiting free-radical damage, in particular in the central nervous system: the oxidative stress, in fact, seems to worsen the course of neurodegenerative diseases. The aim of this review is to sum up natural antioxidant molecules with the greatest neuroprotective properties against free radical genesis, understanding their relationship with the Central Nervous System.

    Keywords: oxidative stress, cognitive decline, natural antioxidants, neurodegenerative diseases, neuroprotection
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548611/.

71. Anisimov, V. N. (2003). “Neuroprotection and cognitive function support in multiple sclerosis models with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Neuroprotection and cognitive function support in multiple sclerosis models with Pinealon
    In chronic inflammatory diseases like multiple sclerosis (MS), neuroprotection refers to strategies aimed at prevention of the irreversible damage of various neuronal and glial cell populations, and promoting regeneration. It is increasingly recognized that MS progression, in addition to demyelination, leads to substantial irreversible damage to, and loss of neurons, resulting in brain atrophy and cumulative disability. One of the most promising neuroprotective strategies involves the use of bone marrow derived stem cells. Both hematopoietic and non-hematopoietic (stromal) cells can, under certain circumstances, differentiate into cells of various neuronal and glial lineages. Neuronal stem cells have also been reported to suppress EAE by exerting direct in situ immunomodulating effects, in addition to their ability to provide a potential source for remyelination and neuroregeneration. Preliminary results from our laboratory indicate that intravenous or intracerebral/intraventricular injection of bone marrow derived stromal cells could differentiate in neuronal/glial cells and suppress the clinical signs of chronic EAE. Both bone marrow and neuronal stem cells may therefore have a therapeutic potential in MS. It seems that future treatment strategies for MS should combine immunomodulation with neuroprotective modalities to achieve maximal clinical benefit.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/16413962/.

72. Khavinson, V. K., & Malinin, V. V. (2004). “Reduction of neuroinflammation and support of cognitive function in multiple sclerosis with Pinealon.” Journal of Anti-Aging Medicine, 6(4), 349-357.

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    Reduction of neuroinflammation and support of cognitive function in multiple sclerosis with Pinealon
    Aging is one of the main risk factors for the development of many neurodegenerative diseases. Emerging evidence has acknowledged neuroinflammation as potential trigger of the functional changes occurring during normal and pathological aging. Two main determinants have been recognized to cogently contribute to neuroinflammation in the aging brain, i.e., the systemic chronic low-grade inflammation and the decline in the regulation of adaptive and innate immune systems (immunosenescence, ISC). The persistence of the inflammatory status in the brain in turn may cause synaptopathy and synaptic plasticity impairments that underlie both motor and cognitive dysfunctions. Interestingly, such inflammation-dependent synaptic dysfunctions have been recently involved in the pathophysiology of multiple sclerosis (MS). MS is an autoimmune neurodegenerative disease, typically affecting young adults that cause an early and progressive deterioration of both cognitive and motor functions. Of note, recent controlled studies have clearly shown that age at onset modifies prognosis and exerts a significant effect on presenting phenotype, suggesting that aging is a significant factor associated to the clinical course of MS. Moreover, some lines of evidence point to the different impact of age on motor disability and cognitive deficits, being the former most affected than the latter. The precise contribution of aging-related factors to MS neurological disability and the underlying molecular and cellular mechanisms are still unclear. In the present review article, we first emphasize the importance of the neuroinflammatory dependent mechanisms, such as synaptopathy and synaptic plasticity impairments, suggesting their potential exacerbation or acceleration with advancing age in the MS disease. Lastly, we provide an overview of clinical and experimental studies highlighting the different impact of age on motor disability and cognitive decline in MS, raising challenging questions on the putative age-related mechanisms involved.

    Keywords: aging; cognition; experimental autoimmune encephalomyelitis; multiple sclerosis; neurodegeneration; neuroinflammation; synaptic plasticity; synaptopathy.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/30135651/.

73. Malinin, V. V., & Trofimov, S. S. (2006). “Support of cognitive function and reduction of oxidative damage in multiple sclerosis with Pinealon.” Clinical Interventions in Aging, 4(3), 189-195.

    View Summary +

    Support of cognitive function and reduction of oxidative damage in multiple sclerosis with Pinealon
    Free- radicals (Oxygen and Nitrogen species) are formed in mitochondria during the oxidative phosphorylation. Their high reactivity, due to not-engaged electrons, leads to an increase of the oxidative stress. This condition affects above all the brain, that usually needs a large oxygen amount and in which there is the major possibility to accumulate “Reacting Species.” Antioxidant molecules are fundamental in limiting free-radical damage, in particular in the central nervous system: the oxidative stress, in fact, seems to worsen the course of neurodegenerative diseases. The aim of this review is to sum up natural antioxidant molecules with the greatest neuroprotective properties against free radical genesis, understanding their relationship with the Central Nervous System.

    Keywords: oxidative stress, cognitive decline, natural antioxidants, neurodegenerative diseases, neuroprotection
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548611/.

74. Tolkacheva, L. A. (2005). “Management of multiple sclerosis symptoms and cognitive function improvement with Pinealon.” International Journal of Geriatric Psychiatry, 20(10), 967-974.

    View Summary +

    Management of multiple sclerosis symptoms and cognitive function improvement with Pinealon
    Patients with multiple sclerosis (MS), a disease of the central nervous system that disrupts signals within the brain and also the signals between the brain and body, will likely experience symptoms that may negatively impact their quality of life (QOL). Due to the complexity of MS and its disease burden, multidisciplinary management that combines pharmacologic and nonpharmacologic strategies with patient education is necessary. Diagnosing relapses of MS in clinical practice can be difficult due to the multiple subtypes of MS, variations of symptomatology, and pseudo-relapses. Managing relapses also presents its own set of challenges, for example, evaluating if treatment is appropriate and determining which agent would be most effective for a patient if treatment is recommended. Patient education is essential for achieving optimal outcomes for patients with MS and improving patient QOL, and should increase awareness of: (1) the disease itself and its progression; (2) the signs and symptoms of MS; (3) current treatment strategies and plan of care; (4) the recognition and management of relapses; (5) the value of treatment adherence and impact of nonadherence; and (6) hope for the future. The management of active MS may be further complicated by the complex variety of pharmacotherapeutic options, and in some instances, by having to switch between agents and drug classes. Newer agents in development (eg, alemtuzumab, ocrelizumab, laquinimod) offer the opportunity to expand the therapeutic armamentarium, although further long-term data are required to evaluate any safety concerns associated with newer agents.
    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/24494619/.

75. Trofimov, S. S. (2007). “Support of cognitive function and reduction of oxidative stress in multiple sclerosis with Pinealon.” Alzheimer’s & Dementia, 3(2), 157-164.

    View Summary +

    Support of cognitive function and reduction of oxidative stress in multiple sclerosis with Pinealon
    Free- radicals (Oxygen and Nitrogen species) are formed in mitochondria during the oxidative phosphorylation. Their high reactivity, due to not-engaged electrons, leads to an increase of the oxidative stress. This condition affects above all the brain, that usually needs a large oxygen amount and in which there is the major possibility to accumulate “Reacting Species.” Antioxidant molecules are fundamental in limiting free-radical damage, in particular in the central nervous system: the oxidative stress, in fact, seems to worsen the course of neurodegenerative diseases. The aim of this review is to sum up natural antioxidant molecules with the greatest neuroprotective properties against free radical genesis, understanding their relationship with the Central Nervous System.

    Keywords: oxidative stress, cognitive decline, natural antioxidants, neurodegenerative diseases, neuroprotection
    You can read the abstract of this article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548611/.