KPV

Potential Benefits of KPV

• Treats a Wide Array of Inflammatory Conditions [2-24]
• Improves Wound Healing [25-30]
• Improves Skin Health [31-45]
• Strengthens the Immune System [25, 26, 46-73]
• Protects Against Nerve Damage [74-97]
• Protects Against Stroke [98-111]

What is KPV?

KPV is a tripeptide (Lysine-Proline-Valine) that possesses potent anti-inflammatory properties. It’s a C-terminal tripeptide of α-MSH (alpha-Melanocyte-stimulating hormone). Peptides like KPV often act as hormones and relay information from one tissue through the blood to another via biological messengers. Whether given orally or in the form of injections, the KPV tripeptide has the potential to treat immune-mediated inflammatory conditions such as dermatitis, bowel diseases, allergic asthma, and arthritis.

How KPV Works?

KPV exerts its anti-inflammatory function inside cells, where it inactivates inflammatory pathways. KPV enters the cell and interacts directly with inflammatory signalling molecules inside the cell. It enters the nucleus of the cell and, once there, can inhibit the interaction of inflammatory substances and molecules. In addition to its anti‐inflammatory effect, KPV also has antimicrobial effects against pathogens such as S. aureus and C. albicans.

Chemical Structure of KPV

Research on KPV

Treats a Wide Array of Inflammatory Conditions

Interestingly, KPV appears to only have an effect in the setting of inflammation and it has almost no effect in normal tissue. The main reason for this is that KPV enters the cells using a transporter that is unregulated in case of inflammation. This suggests that the peptide may serve as an effective or preventive medication in inflammatory conditions. If taken regularly, KPV will be available when necessary and the body can simply excrete it if inflammation and other symptoms are not present. Another amazing advantage of KPV is that, unlike alpha-Melanocyte-stimulating hormone, it does not cause skin pigmentation. [1] Moreover, KPV retains most of the anti-inflammatory properties of alpha-Melanocyte-stimulating hormone but without unpleasant side effects. Another appealing aspect of KPV is that it can be administered via different routes – oral, intravenous (through the veins), subcutaneous (between the muscle and fat), and transdermal (into the dermis of the skin). This allows KPV to be administered in different body areas with a higher level of safety and efficacy.

An overwhelming body of clinical evidence suggests that KPV exerts its strong anti-inflammatory properties through various important mechanisms:

1. In a mice model of colitis (colon inflammation), oral administration of KPV (added to drinking water) inhibited the activation of NF-κB and MAP kinase inflammatory signaling pathways and reduced pro-inflammatory cytokine secretion. [2]
2. A 2001 study published in Biochem Pharmacology found that KPV exerts its anti-inflammatory activities through inhibition of NF-kappaB translocation and activation of MC(1) receptor/cAMP. [3-4]
3. In an animal model of colitis, KPV significantly reduced intestinal inflammation. [5-6]
4. As a C-terminal tripeptide of α-MSH, KPV fights inflammation by inhibiting tumor necrosis factor-α stimulated NF-κB activity and suppressing antigen-induced lymphocyte proliferation. [7-8]
5. A study published in the Journal of Federation of American Societies for Experimental Biology found that KPV suppresses inflammation through modulation of physiological responses in host defense. [9]
6. A 2003 study published in the Journal of Pharmacology and Experimental Therapeutics found that KPV exhibits its anti-inflammatory effect through inhibition of IL-1beta functions. [10]
7. A 2006 study published in the Basic & Clinical Pharmacology & Toxicology found that KPV fights inflammation by stimulating cAMP generation in a concentration-dependent way. [11]
8. One study found that KPV combats inflammation by significantly inhibiting NF-kappaB-luciferase activity. [12]
9. A 2010 study published in Advances in Experimental Medicine and Biology reported that KPV has significant similarities to the anti-inflammatory signaling of α-MSH. [13]
10. Several studies have shown a significant reduction of pro‐inflammatory substances such as IL1 β, IL6, TNFα, IL8, Groα, and interferon γ (IFNγ) following KPV treatment. [14-15]
11. A cell study found that KPV produced antibodies against the inflammatory IL10. [16]
12. Studies also show that KPV reduces inflammation through inhibition of inflammatory cell adhesion and transmigration. [17-18]
13. In murine models of colitis, KPV treatment showed significant anti-inflammatory effects which suggest that it can be an important therapeutic option in treating inflammatory bowel disease. [19]
14. In a mice model of ulcerative colitis, oral administration of KPV loaded into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs) was effective in alleviating intestinal inflammation. [20]
15. In mice, topical administration of KPV in chemotherapy-induced oral mucositis resulted in improved healing due to its anti-inflammatory and antibacterial properties. [21]
16. In an imiquimod-induced psoriasis mouse model, the application of a gel containing alpha-MSH resulted in a reduction in psoriasis-associated inflammation. [22]
17. Studies reported that most of the anti-inflammatory activities of alpha-MSH can be attributed to its C-terminal tripeptide KPV. [23-24]

Improves Wound Healing

The potent anti-inflammatory properties of KPV may play a role in speeding up the wound healing process. In addition, since KPV does not cause skin pigmentation, this makes it a good candidate for improving wound healing while avoiding unpleasant skin changes. Another mechanism that is thought to contribute to faster wound healing is the immune-boosting effects of KPV, which helps lower the risk of infection during the regeneration process.

The beneficial effects of KPV on wound healing are backed by a number of studies:

1. Studies found that alpha-MSH peptides can speed up wound healing by enhancing the antimicrobial activity of human neutrophils and through their antifungal effects. [25-26]
2. In young adult mice with two circular through-and-through holes (6.5 mm diameter), the injection of 1 mg/kg of α-MSH reduced the scar area and improved the organization of the collagen fibers. [27]
3. In rats with liver injury caused by surgery, a single intravenous injection of α-MSH increased the replication of liver cells. [28]
4. In rats that had undergone heart transplantation, α-MSH preserved heart function and prolonged the survival of tissue graft. [29]
5. In rats with acute bleomycin-induced lung injury, α-MSH peptide treatment reduced inflammation and prevented alterations in genes involved in lung fluid homeostasis. [30]

Improves Skin Health

The anti-inflammatory effects of KPV make it an ideal treatment for various inflammatory skin conditions. Furthermore, the immune-boosting effects as well as antimicrobial and antifungal properties of this peptide may play a role in improving skin health.

Evidence suggests that KPV has the potential to treat unpleasant skin conditions:

1. In mice with experimental contact dermatitis, KPV suppressed the skin inflammatory response. [31-34]
2. In human subjects, the application of KPV cream reduced nickel‐induced contact eczema. [35]
3. KPV also suppresses antigen-induced lymphocyte proliferation in humans, resulting in healthier and smoother skin. [36]
4. A 2012 study published in the Journal of Allergy and Clinical Immunology found that KPV acts as a natural anti-allergic basophil-response modifier. [37]
5. A study published in the Archives of Dermatological Research reported that KPV regulates interleukin-10 production by human keratinocytes (skin cells), a mechanism that prevents skin inflammation. [38]
6. In mice, application of KPV on the skin suppressed contact hypersensitivity responses. [39]
7. Several studies also found that KPV is capable of suppressing the production of intercellular adhesion molecule-1 (ICAM-1) induced by pro-inflammatory stimuli such as TNF-α, IFN-γ, or LPS in the skin. [40-45]

Strengthens the Immune System

Aside from its potent anti-inflammatory properties, studies show that KPV may help boost immune function by positively affecting the production of immune system cells and other mechanisms:

1. Studies found that alpha-MSH peptides can enhance the antimicrobial activity of human neutrophils and can help fight fungi such as Cryptococcus neoformans. [25-26]
2. As a C-terminal tripeptide of α-MSH, studies found that KPV has potent antipyretic activity (lowers body temperature) in experimental fever. [46-55]
3. Studies show that KPV prevents fever by targeting the hypothalamus, the brain region that controls temperature, and by reducing pyrogens (substances that cause fever). [56-62]
4. A 2007 study published in Gene Therapy found that KPV treatment was associated with a high frequency of CD4+CD25+ regulatory T cells. [63]
5. In rats, KPV injections twice daily significantly reduced the clinical and histological signs of adjuvant-induced arthritis. [64]
6. In animal models of human autoimmune inflammatory eye diseases such as uveitis or retinitis, KPV significantly reduced symptoms and inflammatory substances. [65-69]
7. In an animal model of experimentally induced acute pancreatitis, KPV treatment reduced pancreas islet cell apoptosis (programmed cell death. [70-72]
8. In rabbits with fever induced by intravenous administration of leukocytic pyrogen, central (0.5-2.0 mg) and peripheral (2-200 mg) administration of KPV reduced fever. [73]

Protects Against Nerve Damage

As a C-terminal tripeptide of α-MSH, KPV exerts protective effects against various forms of nerve damage, suggesting that it can help combat the effect of aging and other medical conditions on nerve health:

1. In neonatal rats with nerve injury, KPV effectively induced sciatic nerve regeneration. [74-75]
2. A cell study found that KPV stimulated the growth of the long threadlike part of a nerve cell called an axon. [76]
3. In a rat model of spinal cord injury, application of α-MSH cream shortly after trauma in high doses induced nerve protection. [77]
4. In cultured rat brain cells, treatment with 10 nM α-MSH protected against cisplatin-induced neurotoxicity. [78-79]
5. A cell study also found that α-MSHprotects against nerve damage by blocking signals involved in programmed cell death. [80 -81]
6. Studies found that α-MSH protects nerve cells against ultraviolet radiation-induced apoptosis and DNA damage. [82-83]
7. Studies show that α-MSH may help protect nerve cells through its anti-scarring properties. [84-91]
8. In rats, local delivery of α-MSHcan increase postlesional repair of nerve. [92-93]
9. Rat studies also show that α-MSH treatment can significantly improve the neurological and electrophysiological function of the damaged spinal cord. [94-97]

Protects Against Stroke

Because KPV and α-MSH share similar properties, they may exert the same beneficial effects. There’s increasing evidence that supports that these peptides may be a therapeutic option in stroke:

1. α-MSH (1 mg/kg) was shown to improve the recovery of animals with stroke, especially when given before and during the 20-minute ischemia (reduced blood flow to the brain). [98]
2. When given before the start of the ischemia and again 1 hour after reperfusion (restoration of blood flow), α-MSH prevents further occlusion and inflammation of the artery. [99]
3. Several studies suggest that α-MSH exerts its protective mechanism against ischemic brain damage by reducing the brain levels of pro-inflammatory cytokines. [100-104]
4. A 2003 study published in the European Journal of Pharmacology reported that subcutaneous injection of α-MSH appears to significantly reduce the size of infarct (dead tissue caused by reduced blood flow). [105]
5. Several studies also found that α-MSH can help protect against heart and kidney problems associated with stroke. [106-111]

Associated Side Effects of KPV

KPV side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on KPV. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of KPV. Despite this, it was listed as a side effect associated with KPV even though these associated side effects are very uncommon.

Side effects associated with KPV may include the following:

• Diarrhea
• Headache
• Nausea
• Vomiting

References

1. Brzoska, T., Luger, T. A., Maaser, C., Abels, C., & Böhm, M. (2008). Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocrine reviews, 29(5), 581–602. https://doi.org/10.1210/er.2007-0027.
2. Dalmasso G, Charrier-Hisamuddin L, Nguyen HT, Yan Y, Sitaraman S, Merlin D. PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology. 2008;134(1):166–178. doi:10.1053/j.gastro.2007.10.026.
3. Mandrika I, Muceniece R, Wikberg JE. Effects of melanocortin peptides on lipopolysaccharide/interferon-gamma-induced NF-kappaB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. BiochemPharmacol. 2001;61(5):613-21.
4. Haddad JJ, Lauterbach R, Saadé NE, Safieh-garabedian B, Land SC. Alpha-melanocyte-related tripeptide, Lys-d-Pro-Val, ameliorates endotoxin-induced nuclear factor kappaB translocation and activation: evidence for involvement of an interleukin-1beta193-195 receptor antagonism in the alveolar epithelium. Biochem J. 2001;355(Pt 1):29-38.
5. Rajora N, Boccoli G, Catania A, et al. α-MSH modulates experimental inflammatory bowel disease. Peptides. 1997;18:381–385.
6. Oktar BK, Ercan F, Ye en BC, et al. The effect of α-melanocyte stimulating hormone on colonic inflammation in the rat. Peptides. 2000;21:1271–1277.
7. Kelly JM, Moir AJ, Carlson K, et al. Immobilized α-melanocyte stimulating hormone 10–13 (GKPV) inhibits tumor necrosis factor-α stimulated NF-κB activity. Peptide. 2006;27:431–437.
8. Cooper A, Robinson SJ, Pickard C, et al. α-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status. J Immunol. 2005;175:4806–4813.
9. Hiltz ME, Lipton JM. Antiinflammatory activity of a COOH-terminal fragment of the neuropeptide alpha-MSH. FASEB J. 1989;3(11):2282-4.
10. Getting SJ, Schioth HB, Perretti M. Dissection of the anti-inflammatory effect of the core and C-terminal (KPV) alpha-melanocyte-stimulating hormone peptides. J PharmacolExpTher. 2003;306(2):631-7.
11. Schiöth HB, Muceniece R, Mutule I, Wikberg JE. New melanocortin 1 receptor binding motif based on the C-terminal sequence of alpha-melanocyte-stimulating hormone. Basic ClinPharmacolToxicol. 2006;99(4):287-93.
12. Kelly JM, Moir AJ, Carlson K, Yang Y, Macneil S, Haycock JW. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity. Peptides. 2006;27(2):431-7.
13. Brzoska T, Böhm M, Lügering A, Loser K, Luger TA. Terminal signal: anti-inflammatory effects of α-melanocyte-stimulating hormone related peptides beyond the pharmacophore. AdvExp Med Biol. 2010;681:107-16.
14. Luger T A, Scholzen T, Grabbe S. The role of α‐melanocyte stimulating hormone in cutaneous biology. J Invest DermatolSympProc 1997287–93.
15. Brzoska T, Luger TA, Maaser C, Abels C, Böhm M. Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocr Rev. 2008;29(5):581-602.
16. Grabbe S, Bhardwaj R S, Steinert M, Mahnke K, Simon M M, Schwarz T. et al Alpha‐melanocyte stimulating hormone induces hapten‐specific tolerance in mice. J Immunol 1996156473–478.
17. Bohm M, Eickelmann M, Li Z, Schneider S W, Oji V, Diederichs S. et al Detection of functionally active melanocortin receptors and evidence for an immunoregulatory activity of alpha‐melanocyte‐stimulating hormone in human dermal papilla cells. Endocrinology 20051464635–4646.
18. Scholzen T E, Sunderkotter C, Kalden D H, Brzoska T, Fastrich M, Fisbeck T. et al Alpha‐melanocyte stimulating hormone prevents lipopolysaccharide‐induced vasculitis by down‐regulating endothelial cell adhesion molecule expression. Endocrinology 2003144360–370.
19. Klaus Kannengiesser, MD, Christian Maaser, MD, Jan Heidemann, MD, Andreas Luegering, MD, Matthias Ross, MD, Thomas Brzoska, PhD, Markus Bohm, MD, Thomas A. Luger, MD, Wolfram Domschke, MD, Torsten Kucharzik, MD, Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease, Inflammatory Bowel Diseases, Volume 14, Issue 3, 1 March 2008, Pages 324–331, https://doi.org/10.1002/ibd.20334.
20. Xiao B, Xu Z, Viennois E, Zhang Y, Zhang Z, Zhang M, Han MK, Kang Y, Merlin D. Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis. Mol Ther. 2017 Jul 5;25(7):1628-1640. doi: 10.1016/j.ymthe.2016.11.020. Epub 2017 Jan 28. PMID: 28143741; PMCID: PMC5498804.
21. Available from https://pubs.rsc.org/en/content/articlehtml/2022/bm/d1bm01466h.
22. Available from https://www.researchgate.net/publication/284175171_Percutaneous_delivery_of_a_-melanocyte-stimulating_hormone_for_the_treatment_of_imiquimod-induced_psoriasis.
23. Luger, T. A., & Brzoska, T. (2007). alpha-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs. Annals of the rheumatic diseases, 66 Suppl 3(Suppl 3), iii52–iii55. https://doi.org/10.1136/ard.2007.079780.
24. Available from https://www.researchgate.net/publication/7277622_Dissection_of_the_Anti-Inflammatory_Effect_of_the_Core_and_C-Terminal_KPV_-Melanocyte-Stimulating_Hormone_Peptides.
25. Cutuli, M., Cristiani, S., Lipton, J. M., & Catania, A. (2000). Antimicrobial effects of alpha-MSH peptides. Journal of leukocyte biology, 67(2), 233–239. https://doi.org/10.1002/jlb.67.2.233.
26. Masman, M. F., Rodríguez, A. M., Svetaz, L., Zacchino, S. A., Somlai, C., Csizmadia, I. G., Penke, B., & Enriz, R. D. (2006). Synthesis and conformational analysis of His-Phe-Arg-Trp-NH2 and analogues with antifungal properties. Bioorganic & medicinal chemistry, 14(22), 7604–7614. https://doi.org/10.1016/j.bmc.2006.07.007.
27. de Souza, K. S., Cantaruti, T. A., Azevedo, G. M., Jr, Galdino, D. A., Rodrigues, C. M., Costa, R. A., Vaz, N. M., & Carvalho, C. R. (2015). Improved cutaneous wound healing after intraperitoneal injection of alpha-melanocyte-stimulating hormone. Experimental dermatology, 24(3), 198–203. https://doi.org/10.1111/exd.12609.
28. Lonati, C., Carlin, A., Leonardi, P., Valenza, F., Bosari, S., Catania, A., & Gatti, S. (2013). Modulatory effects of NDP-MSH in the regenerating liver after partial hepatectomy in rats. Peptides, 50, 145–152.
29. Colombo, G., Gatti, S., Turcatti, F., Sordi, A., Fassati, L. R., Bonino, F., Lipton, J. M., & Catania, A. (2005). Gene expression profiling reveals multiple protective influences of the peptide alpha-melanocyte-stimulating hormone in experimental heart transplantation. Journal of immunology (Baltimore, Md. : 1950), 175(5), 3391–3401. https://doi.org/10.4049/jimmunol.175.5.3391.
30. Colombo, G., Gatti, S., Sordi, A., Turcatti, F., Carlin, A., Rossi, C., Lonati, C., & Catania, A. (2007). Production and effects of alpha-melanocyte-stimulating hormone during acute lung injury. Shock (Augusta, Ga.), 27(3), 326–333. https://doi.org/10.1097/01.shk.0000239764.80033.7e.
31. Rheins L A, Cotleur A L, Kleier R S, Hoppenjans W B, Sauder D N, Nordlund J J. Alpha‐melanocyte stimulating hormone modulates contact hypersensitivity responsiveness in C57/BL6 mice. J Invest Dermatol 198993511–517.
32. Elliott R J, Szabo M, Wagner M J, Kemp E H, MacNeil S, Haycock J W. alpha‐Melanocyte‐stimulating hormone, MSH 11‐13 KPV and adrenocorticotropic hormone signalling in human keratinocyte cells. J Invest Dermatol 20041221010–1019.
33. Getting S J, Schioth H B, Perretti M. Dissection of the anti‐inflammatory effect of the core and C‐terminal (KPV) alpha‐melanocyte‐stimulating hormone peptides. J PharmacolExpTher 2003306631–637.
34. Luger T A, Scholzen T E, Brzoska T, Bohm M. New insights into the functions of alpha‐MSH and related peptides in the immune system. Ann N Y AcadSci 2003994133–140.
35. Slominski A, Wortsman J, Luger T, Paus R, Solomon S. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev 200080979–1020.
36. Cooper A, Robinson SJ, Pickard C, Jackson CL, Friedmann PS, Healy E. Alpha-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status. J Immunol. 2005;175(7):4806-13.
37. Bohm M, Apel M, Sugawara K, et al. Modulation of basophil activity: a novel function of the neuropeptide α-melanocyte-stimulating hormone. J Allergy ClinImmunol. 2012;129(4):1085-93.
38. Redondo P, García-foncillas J, Okroujnov I, Bandrés E. Alpha-MSH regulates interleukin-10 expression by human keratinocytes. Arch Dermatol Res. 1998;290(8):425-8.
39. Rheins LA, Cotleur AL, Kleier RS, Hoppenjans WB, Saunder DN, Nordlund JJ. Alpha-melanocyte stimulating hormone modulates contact hypersensitivity responsiveness in C57/BL6 mice. J Invest Dermatol. 1989;93(4):511-7.
40. Morandini R, Boeynaems JM, Hedley SJ, MacNeil S , Ghanem G 1998 Modulation of ICAM-1 expression by α-MSH in human melanoma cells and melanocytes. J Cell Physiol175:276–282.
41. Kalden DH, Scholzen T, Brzoska T, Luger TA 1999 Mechanisms of the antiinflammatory effects of α-MSH. Role of transcription factor NF-κB and adhesion molecule expression. Ann NY AcadSci 885:254–261.
42. Scholzen TE, Sunderkötter C, Kalden DH, Brzoska T, Fastrich M, Fisbeck T, Armstrong CA, Ansel JC, Luger TA 2003 α-Melanocyte stimulating hormone prevents lipopolysaccharide-induced vasculitis by down-regulating endothelial cell adhesion molecule expression. Endocrinology 144:360–370.
43. Bohm M, Eickelmann M, Li Z, Schneider SW, Oji V, Diederichs S, Barsh GS, Vogt A, Stieler K, Blume-Peytavi U, Luger TA 2005 Detection of functionally active melanocortin receptors and evidence for an immunoregulatory activity of α-melanocyte-stimulating hormone in human dermal papilla cells. Endocrinology 146:4635–4646.
44. Hill RP, MacNeil S, Haycock JW 2006 Melanocyte stimulating hormone peptides inhibit TNF-α signaling in human dermal fibroblast cells. Peptides 27:421–430.
45. Sarkar A, Sreenivasan Y, Manna SK 2003 α-Melanocyte-stimulating hormone induces cell death in mast cells: involvement of NF-κB. FEBS Lett 549:87–93.
46. Glyn JR, Lipton JM. Hypothermic and antipyretic effects of centrally administered ACTH (1–24) and alpha-melanotropin. Peptides. 1981;2(2):177-87.
47. Glyn-ballinger JR, Bernardini GL, Lipton JM. alpha-MSH injected into the septal region reduces fever in rabbits. Peptides. 1983;4(2):199-203.
48. Murphy MT, Lipton JM. Peripheral administration of alpha-MSH reduces fever in older and younger rabbits. Peptides. 1982;3(5):775-9.
49. Murphy MT, Richards DB, Lipton JM. Antipyretic potency of centrally administered alpha-melanocyte stimulating hormone. Science. 1983;221(4606):192-3.
50. Kandasamy SB, Williams BA. Hypothermic and antipyretic effects of ACTH (1-24) and alpha-melanotropin in guinea-pigs. Neuropharmacology. 1984;23(1):49-53.
51. Shih ST, Lipton JM. Intravenous alpha-MSH reduces fever in the squirrel monkey. Peptides. 1985;6(4):685-7.
52. Daynes RA, Robertson BA, Cho BH, Burnham DK, Newton R. Alpha-melanocyte-stimulating hormone exhibits target cell selectivity in its capacity to affect interleukin 1-inducible responses in vivo and in vitro. J Immunol. 1987;139(1):103-9.
53. Deeter LB, Martin LW, Lipton JM. Antipyretic effect of central alpha-MSH summates with that of acetaminophen or ibuprofen. Brain Res Bull. 1989;23(6):573-5.
54. Martin LW, Lipton JM. Acute phase response to endotoxin: rise in plasma alpha-MSH and effects of alpha-MSH injection. Am J Physiol. 1990;259(4 Pt 2):R768-72.
55. Feng JD, Dao T, Lipton JM. Effects of preoptic microinjections of alpha-MSH on fever and normal temperature control in rabbits. Brain Res Bull. 1987;18(4):473-7.
56. Tatro JB 2000 Melanocortin receptor expression and function in the nervous system. In: Cone RD , ed. The melanocortin receptors. Totowa, NJ: Humana Press; 173–207.
57. Tatro JB 2000 Endogenous antipyretics. Clin Infect Dis 21:S190–S201.
58. Rezvani AH, Denbow DM, Myers RD. alpha-Melanocyte-stimulating hormone infused ICV fails to affect body temperature or endotoxin fever in the cat. Brain Res Bull. 1986;16(1):99-105.
59. Greenberg R, Whalley CE, Jourdikian F, Mendelson IS, Walter R, Nikolics K, Coy DH, Schally AV, Kastin AJ 1976 Peptides readily penetrate the blood-brain barrier: uptake of peptides by synaptosomes is passive. PharmacolBiochemBehav 5(Suppl 1):151–158.
60. Tatro JB, Sinha PS. The central melanocortin system and fever. Ann N Y Acad Sci. 2003;994:246-57.
61. Sinha PS, Schiöth HB, Tatro JB. Roles of the melanocortin-4 receptor in antipyretic and hyperthermic actions of centrally administered alpha-MSH. Brain Res. 2004;1001(1-2):150-8.
62. Huang QH, Entwistle ML, Alvaro JD, Duman RS, Hruby VJ, Tatro JB. Antipyretic role of endogenous melanocortins mediated by central melanocortin receptors during endotoxin-induced fever. J Neurosci. 1997;17(9):3343-51.
63. Han D, Tian Y, Zhang M, Zhou Z, Lu J. Prevention and treatment of experimental autoimmune encephalomyelitis with recombinant adeno-associated virus-mediated alpha-melanocyte-stimulating hormone-transduced PLP139-151-specific T cells. Gene Ther. 2007;14(5):383-95.
64. Ceriani G, Diaz J, Murphree S, Catania A, Lipton JM. The neuropeptide alpha-melanocyte-stimulating hormone inhibits experimental arthritis in rats. Neuroimmunomodulation. 1994;1(1):28-32.
65. Taylor AW, Yee DG, Nishida T, Namba K. Neuropeptide regulation of immunity. The immunosuppressive activity of alpha-melanocyte-stimulating hormone (alpha-MSH). Ann N Y Acad Sci. 2000;917:239-47.
66. Nishida T, Miyata S, Itoh Y, et al. Anti-inflammatory effects of alpha-melanocyte-stimulating hormone against rat endotoxin-induced uveitis and the time course of inflammatory agents in aqueous humor. IntImmunopharmacol. 2004;4(8):1059-66.
67. Namba K, Kitaichi N, Nishida T, Taylor AW. Induction of regulatory T cells by the immunomodulating cytokines alpha-melanocyte-stimulating hormone and transforming growth factor-beta2. J Leukoc Biol. 2002;72(5):946-52.
68. Taylor AW, Streilein JW, Cousins SW. Identification of alpha-melanocyte stimulating hormone as a potential immunosuppressive factor in aqueous humor. Curr Eye Res. 1992;11(12):1199-206.
69. Naveh N, Marshall J. Melanocortins are comparable to corticosteroids as inhibitors of traumatic ocular inflammation in rabbits. Graefes Arch ClinExpOphthalmol. 2001;239(11):840-4.
70. Jahovic N, Arbak S, Tekeli O, Alican I. Alpha-melanocyte stimulating hormone has beneficial effects on cerulein-induced acute pancreatitis. Peptides. 2004;25(1):129-32.
71. Al-majed HT, Jones PM, Persaud SJ, et al. ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans. J Endocrinol. 2004;180(1):155-66.
72. Jung EJ, Han DJ, Chang SH, et al. Protective effect of alpha-melanocyte-stimulating hormone on pancreas islet cell against peripheral blood mononuclear cell-mediated cytotoxicity in vitro. Transplant Proc. 2007;39(5):1604-6.
73. Richards, D. B., & Lipton, J. M. (1984). Effect of alpha-MSH 11-13 (lysine-proline-valine) on fever in the rabbit. Peptides, 5(4), 815–817. https://doi.org/10.1016/0196-9781(84)90027-5.
74. Strand FL, Zuccarelli LA, Williams KA, et al. Melanotropins as growth factors. Ann N Y Acad Sci. 1993;680:29-50.
75. Gispen WH. The potential of melanotropins in the treatment of nervous system diseases. Ann N Y Acad Sci. 1993;680:401-11.
76. Gispen WH, Adan RA. Melanocortins and the treatment of nervous system disease. Potential relevance to the skin?. Ann N Y Acad Sci. 1999;885:342-9.
77. Sharma HS. Neuroprotective effects of neurotrophins and melanocortins in spinal cord injury: an experimental study in the rat using pharmacological and morphological approaches. Ann N Y Acad Sci. 2005;1053:407-21.
78. Bar PR, Mandys V, Turecek R, Gispen WH. Alpha-melanocyte-stimulating hormone has protective properties against the toxic effect of cisplatin on cultured dorsal root ganglia. Ann N Y Acad Sci. 1993;680:649-51.
79. Windebank AJ, Smith AG, Russell JW. The effect of nerve growth factor, ciliaryneurotrophic factor, and ACTH analogs on cisplatin neurotoxicity in vitro. Neurology. 1994;44(3 Pt 1):488-94.
80. Chai B, Li JY, Zhang W, Newman E, Ammori J, Mulholland MW. Melanocortin-4 receptor-mediated inhibition of apoptosis in immortalized hypothalamic neurons via mitogen-activated protein kinase. Peptides. 2006;27(11):2846-57.
81. Caruso C, Durand D, Schiöth HB, Rey R, Seilicovich A, Lasaga M. Activation of melanocortin 4 receptors reduces the inflammatory response and prevents apoptosis induced by lipopolysaccharide and interferon-gamma in astrocytes. Endocrinology. 2007;148(10):4918-26.
82. Bohm M, Wolff I, Scholzen TE, et al. alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage. J Biol Chem. 2005;280(7):5795-802.
83. Kadekaro AL, Kavanagh R, Kanto H, et al. alpha-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res. 2005;65(10):4292-9.
84. Abdel-malek ZA, Kadekaro AL, Kavanagh RJ, et al. Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASEB J. 2006;20(9):1561-3.
85. Hill RP, Wheeler P, Macneil S, Haycock JW. Alpha-melanocyte stimulating hormone cytoprotective biology in human dermal fibroblast cells. Peptides. 2005;26(7):1150-8.
86. Kokot A , Sindrilaru A , Schiller S , Sunderkötter C , Kerkhoff C , Scharffetter-Kochanek K , Luger TA , Böhm M 2008 α-Melanocyte-stimulating hormone is a powerful agent in the bleomycin model of collagen synthesis and fibrosis. ExpDermatol 17:286.
87. Yamamoto T, Nishioka K. Cellular and molecular mechanisms of bleomycin-induced murine scleroderma: current update and future perspective. ExpDermatol. 2005;14(2):81-95.
88. Bohm M, Raghunath M, Sunderkötter C, et al. Collagen metabolism is a novel target of the neuropeptide alpha-melanocyte-stimulating hormone. J Biol Chem. 2004;279(8):6959-66.
89. Lee TH, Jawan B, Chou WY, et al. Alpha-melanocyte-stimulating hormone gene therapy reverses carbon tetrachloride induced liver fibrosis in mice. J Gene Med. 2006;8(6):764-72.
90. Edwards PM, Van der zee CE, Verhaagen J, Schotman P, Jennekens FG, Gispen WH. Evidence that the neurotrophic actions of alpha-MSH may derive from its ability to mimick the actions of a peptide formed in degenerating nerve stumps. J Neurol Sci. 1984;64(3):333-40.
91. Vadoudseyedi J, Liénard D, Lespagnard L, Ghanem G, Van wijck R, Lejeune F. Local administration of alpha-MSH exerts a trophic effect on the 200-kDa neurofilament in sciatic rat nerve. Ann N Y Acad Sci. 1993;680:655-9.
92. Van de meent H, Hamers FP, Lankhorst AJ, Joosten EA, Gispen WH. Beneficial effects of the melanocortin alpha-melanocyte-stimulating hormone on clinical and neurophysiological recovery after experimental spinal cord injury. Neurosurgery. 1997;40(1):122-30.
93. Lankhorst AJ, Duis SE, Terlaak MP, Joosten EA, Hamers FP, Gispen WH. Functional recovery after central infusion of alpha-melanocyte-stimulating hormone in rats with spinal cord contusion injury. J Neurotrauma. 1999;16(4):323-31.
94. Joosten EA, Majewska B, Houweling DA, Bär PR, Gispen WH. Alpha-melanocyte stimulating hormone promotes regrowth of injured axons in the adult rat spinal cord. J Neurotrauma. 1999;16(6):543-53.
95. Sharma HS, Skottner A, Lundstedt T, Flärdh M, Wiklund L. Neuroprotective effects of melanocortins in experimental spinal cord injury. An experimental study in the rat using topical application of compounds with varying affinity to melanocortin receptors. J Neural Transm (Vienna). 2006;113(4):463-76.
96. Huh SK, Lipton JM, Batjer HH. The protective effects of alpha-melanocyte stimulating hormone on canine brain stem ischemia. Neurosurgery. 1997;40(1):132-9.
97. Huang Q, Tatro JB. Alpha-melanocyte stimulating hormone suppresses intracerebral tumor necrosis factor-alpha and interleukin-1beta gene expression following transient cerebral ischemia in mice. NeurosciLett. 2002;334(3):186-90.
98. Spulber S, Moldovan M, Oprica M, et al. Alpha-MSH decreases core and brain temperature during global cerebral ischemia in rats. Neuroreport. 2005;16(1):69-72.
99. Forslinaronsson S, Spulber S, Popescu LM, et al. alpha-Melanocyte-stimulating hormone is neuroprotective in rat global cerebral ischemia. Neuropeptides. 2006;40(1):65-75.
100. Giuliani D, Leone S, Mioni C, et al. Broad therapeutic treatment window of [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone for long-lasting protection against ischemic stroke, in Mongolian gerbils. Eur J Pharmacol. 2006;538(1-3):48-56.
101. Giuliani D, Ottani A, Mioni C, et al. Neuroprotection in focal cerebral ischemia owing to delayed treatment with melanocortins. Eur J Pharmacol. 2007;570(1-3):57-65.
102. Giuliani D, Mioni C, Altavilla D, et al. Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology. 2006;147(3):1126-35.
103. Vecsernyes M, Juhasz B, Der P, et al. The administration of alpha-melanocyte-stimulating hormone protects the ischemic/reperfused myocardium. Eur J Pharmacol. 2003;470(3):177-83.
104. Mioni C, Giuliani D , Cainazzo MM, Leone S, Bazzani C, Grieco P, Novellino E, Tomasi A, Bertolini A, Guarini S 2004 Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors. Eur J Pharmacol 477:227–234.
105. Bertolini A, Guarini S, Rompianesi E, Ferrari W. Alpha-MSH and other ACTH fragments improve cardiovascular function and survival in experimental hemorrhagic shock. Eur J Pharmacol. 1986;130(1-2):19-26.
106. Guarini S, Schiöth HB, Mioni C, et al. MC(3) receptors are involved in the protective effect of melanocortins in myocardial ischemia/reperfusion-induced arrhythmias. NaunynSchmiedebergs Arch Pharmacol. 2002;366(2):177-82.
107. Yamaoka-tojo M, Tojo T, Shioi T, Masuda T, Inomata T, Izumi T. Central neurotranspeptide, alpha-melanocyte-stimulating hormone (alpha-MSH) is upregulated in patients with congestive heart failure. Intern Med. 2006;45(7):429-34.
108. Chiao H, Kohda Y, Mcleroy P, Craig L, Housini I, Star RA. Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest. 1997;99(6):1165-72.
109. Jo SK, Yun SY, Chang KH, et al. alpha-MSH decreases apoptosis in ischaemic acute renal failure in rats: possible mechanism of this beneficial effect. Nephrol Dial Transplant. 2001;16(8):1583-91.
110. Kwon TH, Frøkiaer J, Fernández-llama P, Knepper MA, Nielsen S. Reduced abundance of aquaporins in rats with bilateral ischemia-induced acute renal failure: prevention by alpha-MSH. Am J Physiol. 1999;277(3):F413-27.
111. Gong H, Wang W, Kwon TH, et al. EPO and alpha-MSH prevent ischemia/reperfusion-induced down-regulation of AQPs and sodium transporters in rat kidney. Kidney Int. 2004;66(2):683-95.