The Role of Alpha-MSH as a Modulator of Ocular Immunobiology Exemplifies Mechanistic Differences between Melanocortins and Steroids

REFERENCES

• Catania A, Gatti S, Colombo G, et al. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev. 2004:56(1):1–29.
   PubMed Web of Science ®Google Scholar
• Catania A, Lonati C, Sordi A, et al. The melanocortin system in control of inflammation. ScientificWorldJournal. 2010:10:1840-1853.
   Google Scholar
• Schioth HB, Haitina T, Ling MK, et al. Evolutionary conservation of the structural, pharmacological, and genomic characteristics of the melanocortin receptor subtypes. Peptides. 2005:26(10):1886–1900.
   PubMed Web of Science ®Google Scholar
• Ottaviani E, Franchini A, Genedani S. ACTH and its role in immune-neuroendocrine functions. A comparative study. Curr Pharm Des. 1999:5(9):673–681.
   PubMed Web of Science ®Google Scholar
• Cooray SN, Clark AJ. Melanocortin receptors and their accessory proteins. Mol Cell Endocrinol. 2011:331(2):215–221.
   PubMed Web of Science ®Google Scholar
• Cone RD, Mountjoy KG, Robbins LS, et al. Cloning and functional characterization of a family of receptors for the melanotropic peptides. Ann N Y Acad Sci. 1993:680:342-363.
   Web of Science ®Google Scholar
• Mountjoy KG, Robbins LS, Mortrud MT, et al. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992:257(5074):1248–1251.
   PubMed Web of Science ®Google Scholar
• Clark AJ, McLoughlin L, Grossman A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet. 1993:341(8843):461–462.
   PubMed Web of Science ®Google Scholar
• Chida D, Nakagawa S, Nagai S, et al. Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc Natl Acad Sci U S A. 2007:104(46):18205–18210.
   PubMed Web of Science ®Google Scholar
• Schioth HB, Muceniece R, Larsson M, et al. Binding of cyclic and linear MSH core peptides to the melanocortin receptor subtypes. Eur J Pharmacol. 1997:319(2-3):369-373.
   Web of Science ®Google Scholar
• Schioth HB, Chhajlani V, Muceniece R, et al. Major pharmacological distinction of the ACTH receptor from other melanocortin receptors. Life Sci. 1996:59(10):797–801.
   PubMed Web of Science ®Google Scholar
• Costa JL, Bui S, Reed P, et al. Mutational analysis of evolutionarily conserved ACTH residues. Gen Comp Endocrinol. 2004:136(1):12–16.
   PubMed Web of Science ®Google Scholar
• Nussdorfer GG, Mazzocchi G, Malendowicz LK. Acute effects of alpha-MSH on the rat zona glomerulosa in vivo. Biochem Biophys Res Commun. 1986:141(3):1279–1284.
   PubMed Web of Science ®Google Scholar
• Shenker Y, Villareal JZ, Sider RS, et al. Alpha-melanocyte-stimulating hormone stimulation of aldosterone secretion in hypophysectomized rats. Endocrinology. 1985:116(1):138–141.
   PubMed Web of Science ®Google Scholar
• Costa JL, Forbes S, Brennan MB, et al. Genetic modifications of mouse proopiomelanocortin peptide processing. Mol Cell Endocrinol. 2011:336(1-2):14-22.
   Web of Science ®Google Scholar
• Getting SJ, Christian HC, Flower RJ, et al. Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum. 2002:46(10):2765–2775.
   PubMed Web of Science ®Google Scholar
• Gubner R, Cote L, Hughes J, et al. Comparative effects of aminopterin, cortisone and ACTH in experimental formaldehyde arthritis and psoriatic arthritis. J Invest Dermatol. 1952:19(4):297–305.
   PubMed Web of Science ®Google Scholar
• Yeh JK, Evans JF, Niu QT, et al. A possible role for melanocortin peptides in longitudinal growth. J Endocrinol. 2006:191(3):677–686.
   PubMed Web of Science ®Google Scholar
• Auriemma M, Brzoska T, Klenner L, et al. alpha-MSH-stimulated tolerogenic dendritic cells induce functional regulatory T cells and ameliorate ongoing skin inflammation. J Invest Dermatol. 2012:132(7):1814–1824.
   PubMed Web of Science ®Google Scholar
• Montero-Melendez T, Patel HB, Seed M, et al. The melanocortin agonist AP214 exerts anti-inflammatory and proresolving properties. Am J Pathol. 2011:179(1):259–269.
   PubMed Web of Science ®Google Scholar
• Patel HB, Bombardieri M, Sampaio AL, et al. Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin receptor type 3 in experimental arthritis. FASEB J. 2010:24(12):4835–4843.
   PubMed Web of Science ®Google Scholar
• Lee DJ, Biros DJ, Taylor AW. Injection of an alpha-melanocyte stimulating hormone expression plasmid is effective in suppressing experimental autoimmune uveitis. Int Immunopharmacol. 2009:9(9):1079–1086.
   PubMed Web of Science ®Google Scholar
• Lee SN, Ryu JH, Joo JH, et al. Alpha-melanocyte-stimulating hormone inhibits tumor necrosis factor alpha-stimulated MUC5AC expression in human nasal epithelial cells. Am J Respir Cell Mol Biol. 2011:44(5):716–724.
   PubMed Web of Science ®Google Scholar
• Cooper A, Robinson SJ, Pickard C, et al. Alpha-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status. J Immunol. 2005:175(7):4806–4813.
   PubMed Web of Science ®Google Scholar
• Buggy JJ. Binding of alpha-melanocyte-stimulating hormone to its G-protein-coupled receptor on B-lymphocytes activates the Jak/STAT pathway. Biochem J. 1998:331 (Pt 1):211–216.
   PubMed Web of Science ®Google Scholar
• Taylor A, Namba K. In vitro induction of CD25+ CD4+ regulatory T cells by the neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH). Immunol Cell Biol. 2001:79(4):358–367.
   PubMed Web of Science ®Google Scholar
• Loser K, Brzoska T, Oji V, et al. The neuropeptide alpha-melanocyte-stimulating hormone is critically involved in the development of cytotoxic CD8+ T cells in mice and humans. PLoS One. 2010:5( 2):e8958.
   Google Scholar
• Brzoska T, Luger TA, Maaser C, et al. 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.
   PubMed Web of Science ®Google Scholar
• Ratman D, Vanden Berghe W, Dejager L, et al. How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering. Mol Cell Endocrinol. 2013:380(1-2):41-54.
   Web of Science ®Google Scholar
• Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015:22(1-2):20-32.
   Web of Science ®Google Scholar
• Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002:96(1):23–43.
   PubMed Web of Science ®Google Scholar
• Harris E, Tiganescu A, Tubeuf S, et al. The prediction and monitoring of toxicity associated with long-term systemic glucocorticoid therapy. Curr Rheumatol Rep. 2015:17(6):513.
   Web of Science ®Google Scholar
• Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991:109(8):1090–1095.
   PubMed Web of Science ®Google Scholar
• AGIS-Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Ophthalmol. 2000:130(4):429–440.
   Google Scholar
• Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002: 120(6): 714-720; discussion 829–730.
   PubMedGoogle Scholar
• Tan JC, Peters DM, Kaufman PL. Recent developments in understanding the pathophysiology of elevated intraocular pressure. Curr Opin Ophthalmol. 2006:17(2):168–174.
   PubMed Web of Science ®Google Scholar
• Wordinger RJ, Clark AF. Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. Prog Retin Eye Res. 1999:18(5):629–667.
   PubMed Web of Science ®Google Scholar
• Gu Y, Zeng S, Qiu P, et al. [Apoptosis of bovine trabecular meshwork cells induced by dexamethasone]. Zhonghua Yan Ke Za Zhi. 2002:38(5):302–304.
   PubMedGoogle Scholar
• Zhang X, Clark AF, Yorio T. Regulation of glucocorticoid responsiveness in glaucomatous trabecular meshwork cells by glucocorticoid receptor-beta. Invest Ophthalmol Vis Sci. 2005:46(12):4607–4616.
   PubMed Web of Science ®Google Scholar
• Jain A, Wordinger RJ, Yorio T, et al. Role of the alternatively spliced glucocorticoid receptor isoform GRbeta in steroid responsiveness and glaucoma. J Ocul Pharmacol Ther. 2014:30(2-3):121-127.
   Web of Science ®Google Scholar
• Clark AF, Wordinger RJ. The role of steroids in outflow resistance. Exp Eye Res. 2009:88(4):752–759.
   PubMed Web of Science ®Google Scholar
• Sharma A, Patil AJ, Mansoor S, et al. Effects of dexamethasone on human trabecular meshwork cells in vitro. Graefes Arch Clin Exp Ophthalmol. 2013:251(7):1741–1746.
   PubMed Web of Science ®Google Scholar
• Lewis JM, Priddy T, Judd J, et al. Intraocular pressure response to topical dexamethasone as a predictor for the development of primary open-angle glaucoma. Am J Ophthalmol. 1988:106(5):607–612.
   PubMed Web of Science ®Google Scholar
• Kempen JH, Altaweel MM, Holbrook JT, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011:118(10):1916–1926.
   PubMed Web of Science ®Google Scholar
• Friedman DS, Holbrook JT, Ansari H, et al. Risk of elevated intraocular pressure and glaucoma in patients with uveitis: results of the multicenter uveitis steroid treatment trial. Ophthalmology. 2013:120(8):1571–1579.
   PubMed Web of Science ®Google Scholar
• Sen HN, Vitale S, Gangaputra SS, et al. Periocular corticosteroid injections in uveitis: effects and complications. Ophthalmology. 2014:121(11):2275–2286.
   PubMed Web of Science ®Google Scholar
• Black RL, Oglesby RB, Von Sallmann L, et al. Posterior subcapsular cataracts induced by corticosteroids in patients with rheumatoid arthritis. JAMA. 1960:174:166-171.
   Web of Science ®Google Scholar
• Butcher JM, Austin M, McGalliard J, et al. Bilateral cataracts and glaucoma induced by long term use of steroid eye drops. BMJ. 1994:309(6946):43.
   Google Scholar
• Urban RC, Jr., Cotlier E. Corticosteroid-induced cataracts. Surv Ophthalmol. 1986:31(2):102–110.
   PubMed Web of Science ®Google Scholar
• Costagliola C, Cati-Giovannelli B, Piccirillo A, et al. Cataracts associated with long-term topical steroids. Br J Dermatol. 1989:120(3):472–473.
   PubMed Web of Science ®Google Scholar
• Klein BE, Klein R, Lee KE, et al. Drug use and five-year incidence of age-related cataracts: The Beaver Dam Eye Study. Ophthalmology. 2001:108(9):1670–1674.
   PubMed Web of Science ®Google Scholar
• James ER, Robertson L, Ehlert E, et al. Presence of a transcriptionally active glucocorticoid receptor alpha in lens epithelial cells. Invest Ophthalmol Vis Sci. 2003:44(12):5269–5276.
   PubMed Web of Science ®Google Scholar
• James ER, Fresco VM, Robertson LL. Glucocorticoid-induced changes in the global gene expression of lens epithelial cells. J Ocul Pharmacol Ther. 2005:21(1):11–27.
   PubMed Web of Science ®Google Scholar
• Gupta V, Galante A, Soteropoulos P, et al. Global gene profiling reveals novel glucocorticoid induced changes in gene expression of human lens epithelial cells. Mol Vis. 2005:11:1018-1040.
   Web of Science ®Google Scholar
• Petersen A, Carlsson T, Karlsson JO, et al. Effects of dexamethasone on human lens epithelial cells in culture. Mol Vis. 2008:14:1344-1352.
   Web of Science ®Google Scholar
• Sharma A, Pirouzmanesh A, Patil J, et al. Evaluation of the toxicity of triamcinolone acetonide and dexamethasone sodium phosphate on human lens epithelial cells (HLE B-3). J Ocul Pharmacol Ther. 2011:27(3):265–271.
   PubMed Web of Science ®Google Scholar
• James ER. The etiology of steroid cataract. J Ocul Pharmacol Ther. 2007:23(5):403–420.
   PubMed Web of Science ®Google Scholar
• 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):1199–1206.
   PubMed Web of Science ®Google Scholar
• Taylor AW, Alard P, Yee DG, et al. Aqueous humor induces transforming growth factor-beta (TGF-beta)-producing regulatory T-cells. Curr Eye Res. 1997:16(9):900–908.
   PubMed Web of Science ®Google Scholar
• Kawanaka N, Taylor AW. Localized retinal neuropeptide regulation of macrophage and microglial cell functionality. Journal of Neuroimmunology. 2011:232(1-2):17-25.
   Web of Science ®Google Scholar
• Kaiser CJ, Ksander BR, Streilein JW. Inhibition of lymphocyte proliferation by aqueous humor. Regional Immunology. 1989:2(1):42–49.
   PubMedGoogle Scholar
• Nishida T, Taylor A. Specific aqueous humor factors induce activation of regulatory T cells. Investigative Ophthalmology & Visual Science. 1999:40(10):2268–2274.
   PubMed Web of Science ®Google Scholar
• Cousins SW, McCabe MM, Danielpour D, et al. Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci. 1991:32:33-43.
   Web of Science ®Google Scholar
• Granstein R, Staszewski R, Knisely T, et al. Aqueous humor contains transforming growth factor-b and a small (<3500 daltons) inhibitor of thymocyte proliferation. Journal of Immunology. 1990:144:3021-3027.
   Web of Science ®Google Scholar
• Jampel HD, Roche N, Stark WJ, et al. Transforming growth factor-beta in human aqueous humor. Curr Eye Res. 1990:9(10):963–969.
   PubMed Web of Science ®Google Scholar
• Namba K, Kitaichi N, Nishida T, et al. Induction of regulatory T cells by the immunomodulating cytokines alpha-melanocyte-stimulating hormone and transforming growth factor-beta2. J Leukoc Biol. 2002:72(5):946–952.
   PubMed Web of Science ®Google Scholar
• Zmijewski MA, Sharma RK, Slominski AT. Expression of molecular equivalent of hypothalamic-pituitary-adrenal axis in adult retinal pigment epithelium. The Journal of endocrinology. 2007:193(1):157–169.
   PubMed Web of Science ®Google Scholar
• Ortego J, Coca-Prados M. Molecular characterization and differential gene induction of the neuroendocrine-specific genes neurotensin, neurotensin receptor, PC1, PC2, and 7B2 in the human ocular ciliary epithelium. J Neurochem. 1997:69(5):1829–1839.
   PubMed Web of Science ®Google Scholar
• Taylor AW, Lee DJ. The alpha-melanocyte stimulating hormone induces conversion of effector T cells into treg cells. J Transplant. 2011:2011:246856.
   PubMedGoogle Scholar
• 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. Int Immunopharmacol. 2004:4(8):1059–1066.
   PubMed Web of Science ®Google Scholar
• Shiratori K, Ohgami K, Ilieva IB, et al. Inhibition of endotoxin-induced uveitis and potentiation of cyclooxygenase-2 protein expression by alpha-melanocyte-stimulating hormone. Invest Ophthalmol Vis Sci. 2004:45(1):159–164.
   PubMed Web of Science ®Google Scholar
• Lee DJ, Taylor AW. Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice. J Immunol. 2013:191(8):4103–4111.
   PubMed Web of Science ®Google Scholar
• Lee DJ, Taylor AW. Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs. J Leukoc Biol. 2015:97(6):1101–1109.
   PubMed Web of Science ®Google Scholar
• Li D, Taylor AW. Diminishment of alpha-MSH anti-inflammatory activity in MC1r siRNA-transfected RAW264.7 macrophages. J Leukoc Biol. 2008:84(1):191–198.
   PubMed Web of Science ®Google Scholar
• Getting SJ, Christian HC, Lam CW, et al. Redundancy of a functional melanocortin 1 receptor in the anti-inflammatory actions of melanocortin peptides: studies in the recessive yellow (e/e) mouse suggest an important role for melanocortin 3 receptor. J Immunol. 2003:170(6):3323–3330.
   PubMed Web of Science ®Google Scholar
• Neumann Andersen G, Nagaeva O, Mandrika I, et al. MC(1) receptors are constitutively expressed on leucocyte subpopulations with antigen presenting and cytotoxic functions. Clin Exp Immunol. 2001:126(3):441–446.
   PubMed Web of Science ®Google Scholar
• Lee DJ, Taylor AW. Following EAU recovery there is an associated MC5r-dependent APC induction of regulatory immunity in the spleen. Invest Ophthalmol Vis Sci. 2011:52(12):8862–8867.
   PubMed Web of Science ®Google Scholar
• Robertson MJ, Erwig LP, Liversidge J, et al. Retinal microenvironment controls resident and infiltrating macrophage function during uveoretinitis. Invest Ophthalmol Vis Sci. 2002:43(7):2250–2257.
   PubMed Web of Science ®Google Scholar
• Dick AD, Carter D, Robertson M, et al. Control of myeloid activity during retinal inflammation. J Leukoc Biol. 2003:74(2):161–166.
   PubMed Web of Science ®Google Scholar
• Phan TA, Taylor AW. The neuropeptides alpha-MSH and NPY modulate phagocytosis and phagolysosome activation in RAW 264.7 cells. J Neuroimmunol. 2013:260(1-2):9-16.
   Web of Science ®Google Scholar
• Taylor AW, Dixit S, Yu J. Retinal Pigment Epithelial Cell Line Suppression of Phagolysosome Activation. Int J Ophthalmol Eye Sci. 2015:Suppl 2(1):1–6.
   PubMedGoogle Scholar
• Taylor AW. Alpha-melanocyte stimulating hormone (alpha-MSH) is a post-caspase suppressor of apoptosis in RAW 264.7 macrophages. PLoS One. 2013:8(8):e74488.
   PubMed Web of Science ®Google Scholar
• Caspi RR, Roberge FG, Chan CC, et al. A new model of autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J Immunol. 1988:140(5):1490–1495.
   PubMed Web of Science ®Google Scholar
• Kitaichi N, Namba K, Taylor A. Inducible immune regulation following autoimmune disease in the immune-privileged eye. Journal of Leukocyte Biology. 2005:77(4):496–502.
   PubMed Web of Science ®Google Scholar
• Taylor AW, Kitaichi N. The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) therapy. Brain Behav Immun. 2008:22(5):639–646.
   PubMed Web of Science ®Google Scholar
• Yin P, Luby TM, Chen H, et al. Generation of expression constructs that secrete bioactive alphaMSH and their use in the treatment of experimental autoimmune encephalomyelitis. Gene Ther. 2003:10(4):348–355.
   PubMed Web of Science ®Google Scholar
• Ng TF, Kitaichi N, Taylor AW. In vitro-generated autoimmune regulatory T cells enhance intravitreous allogeneic retinal graft survival. Investigative Ophthalmology & Visual Science. 2007:48(11):5112–5117.
   PubMed Web of Science ®Google Scholar
• Cheng LB, Cheng L, Bi HE, et al. Alpha-melanocyte stimulating hormone protects retinal pigment epithelium cells from oxidative stress through activation of melanocortin 1 receptor-Akt-mTOR signaling. Biochem Biophys Res Commun. 2014:443(2):447–452.
   PubMed Web of Science ®Google Scholar
• Naveh N. Melanocortins applied intravitreally delay retinal dystrophy in Royal College of Surgeons rats. Graefes Arch Clin Exp Ophthalmol. 2003:241(12):1044–1050.
   PubMed Web of Science ®Google Scholar
• Steffensen EH. Corticotropin, cortisone, and hydrocortisone in treatment of ocular disease. J Am Med Assoc. 1952:150(17):1660–1664.
   PubMed Web of Science ®Google Scholar
• Takakura A, Tessler HH, Goldstein DA, et al. Viral retinitis following intraocular or periocular corticosteroid administration: a case series and comprehensive review of the literature. Ocul Immunol Inflamm. 2014:22(3):175–182.
   PubMed Web of Science ®Google Scholar
• Bouzas EA, Karadimas P, Pournaras CJ. Central serous chorioretinopathy and glucocorticoids. Surv Ophthalmol. 2002:47(5):431–448.
   PubMed Web of Science ®Google Scholar
• Karadimas P, Bouzas EA. Glucocorticoid use represents a risk factor for central serous chorioretinopathy: a prospective, case-control study. Graefes Arch Clin Exp Ophthalmol. 2004:242(9):800–802.
   PubMed Web of Science ®Google Scholar
• Wang M, Munch IC, Hasler PW, et al. Central serous chorioretinopathy. Acta Ophthalmol. 2008:86(2):126–145.
   PubMed Web of Science ®Google Scholar
• Cunningham ET, Jr., Wender JD. Practical approach to the use of corticosteroids in patients with uveitis. Can J Ophthalmol. 2010:45(4):352–358.
   PubMed Web of Science ®Google Scholar
• McGhee CN, Dean S, Danesh-Meyer H. Locally administered ocular corticosteroids: benefits and risks. Drug Saf. 2002:25(1):33–55.
   PubMed Web of Science ®Google Scholar
• Taylor AW. Ocular immunosuppressive microenvironment. Chem Immunol Allergy. 2007:92:71-85.
   Google Scholar
• Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008:8(7):523–532.
   PubMed Web of Science ®Google Scholar
• Taylor AW, Streilein JW. Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation. 1996:3(2-3):112-118.
   Web of Science ®Google Scholar
• Wong KY, Rajora N, Boccoli G, et al. A potential mechanism of local anti-inflammatory action of alpha-melanocyte-stimulating hormone within the brain: modulation of tumor necrosis factor-alpha production by human astrocytic cells. Neuroimmunomodulation. 1997:4(1):37–41.
   PubMed Web of Science ®Google Scholar
• Bhardwaj RS, Schwarz A, Becher E, et al. Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes. J Immunol. 1996:156(7):2517–2521.
   PubMed Web of Science ®Google Scholar
• 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):5795–5802.
   PubMed Web of Science ®Google Scholar
• Chai B, Li JY, Zhang W, et al. Melanocortin-4 receptor-mediated inhibition of apoptosis in immortalized hypothalamic neurons via mitogen-activated protein kinase. Peptides. 2006:27(11):2846–2857.
   PubMed Web of Science ®Google Scholar
• Zhang L, Dong L, Liu X, et al. alpha-Melanocyte-stimulating hormone protects retinal vascular endothelial cells from oxidative stress and apoptosis in a rat model of diabetes. PLoS One. 2014:9(4):e93433.
   PubMed Web of Science ®Google Scholar
• Edling AE, Gomes D, Weeden T, et al. Immunosuppressive activity of a novel peptide analog of alpha-melanocyte stimulating hormone (alpha-MSH) in experimental autoimmune uveitis. J Neuroimmunol. 2011:236(1-2):1-9.
   Web of Science ®Google Scholar
• Naveh N, Kaplan-Messas A, Marshall J. Mechanism related to reduction of intraocular pressure by melanocortins in rabbits. Br J Ophthalmol. 2000:84(12):1411–1414.
   PubMed Web of Science ®Google Scholar
• Catania A. Neuroprotective actions of melanocortins: a therapeutic opportunity. Trends Neurosci. 2008:31(7):353–360.
   PubMed Web of Science ®Google Scholar
• Joosten EA, Majewska B, Houweling DA, et al. Alpha-melanocyte stimulating hormone promotes regrowth of injured axons in the adult rat spinal cord. J Neurotrauma. 1999:16(6):543–553.
   PubMed Web of Science ®Google Scholar
• Bharne AP, Upadhya MA, Kokare DM, et al. Effect of alpha-melanocyte stimulating hormone on locomotor recovery following spinal cord injury in mice: Role of serotonergic system. Neuropeptides. 2011:45(1):25–31.
   PubMed Web of Science ®Google Scholar
• Schaible EV, Steinstrasser A, Jahn-Eimermacher A, et al. Single administration of tripeptide alpha-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice. PLoS One. 2013:8(8):e71056.
   PubMed Web of Science ®Google Scholar
• Giuliani D, Galantucci M, Neri L, et al. Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimers disease. Eur J Pharmacol. 2014:740:144-150.
   Web of Science ®Google Scholar
• Giuliani D, Bitto A, Galantucci M, et al. Melanocortins protect against progression of Alzheimer’s disease in triple-transgenic mice by targeting multiple pathophysiological pathways. Neurobiol Aging. 2014:35(3):537–547.
   PubMed Web of Science ®Google Scholar
• Ma K, McLaurin J. alpha-Melanocyte stimulating hormone prevents GABAergic neuronal loss and improves cognitive function in Alzheimer’s disease. J Neurosci. 2014:34(20):6736–6745.
   PubMed Web of Science ®Google Scholar
• Fang J, Han D, Hong J, et al. SValpha-MSH, a novel alpha-melanocyte stimulating hormone analog, ameliorates autoimmune encephalomyelitis through inhibiting autoreactive CD4(+) T cells activation. J Neuroimmunol. 2014:269(1-2):9-19.
   Web of Science ®Google Scholar
• Diem R, Hobom M, Maier K, et al. Methylprednisolone increases neuronal apoptosis during autoimmune CNS inflammation by inhibition of an endogenous neuroprotective pathway. J Neurosci. 2003:23(18):6993–7000.
   PubMed Web of Science ®Google Scholar
• Miller H, Newell DJ, Ridley A. Multiple sclerosis. Treatment of acute exacerbations with corticotrophin (A.C.T.H.). Lancet. 1961:2(7212):1120–1122.
   PubMed Web of Science ®Google Scholar
• Arnason BG, Berkovich R, Catania A, et al. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 2013:19(2):130–136.
   PubMed Web of Science ®Google Scholar
• Weinstein RS. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med. 2011:365(1):62–70.
   PubMed Web of Science ®Google Scholar
• Besser GM, Butler PW, Plumpton FS. Adrenocorticotrophic action of long-acting tetracosactrin compared with corticotrophin-gel. Br Med J. 1967:4(5576):391–394.
   PubMed Web of Science ®Google Scholar
• Coburg AJ, Gray SH, Katz FH, et al. Disappearance rates and immunosuppression of intermittent intravenously administered prednisolone in rabbits and human beings. Surg Gynecol Obstet. 1970:131(5):933–942.
   PubMedGoogle Scholar
• Zaidi M, Sun L, Robinson LJ, et al. ACTH protects against glucocorticoid-induced osteonecrosis of bone. Proc Natl Acad Sci U S A. 2010:107(19):8782–8787.
   PubMed Web of Science ®Google Scholar
• Grieco P, Carotenuto A, Auriemma L, et al. Novel alpha-MSH peptide analogues with broad spectrum antimicrobial activity. PLoS One. 2013:8(4):e61614.
   PubMed Web of Science ®Google Scholar
• Singh M, Mukhopadhyay K. Alpha-melanocyte stimulating hormone: an emerging anti-inflammatory antimicrobial peptide. Biomed Res Int. 2014:2014:874610.
   Google Scholar
• Holdeman M, Lipton JM. Effects of massive doses of alpha-MSH on thermoregulation in the rabbit. Brain Res Bull. 1985:14(4):327–330.
   PubMed Web of Science ®Google Scholar
• Ugwu SO, Blanchard J, Dorr RT, et al. Skin pigmentation and pharmacokinetics of melanotan-I in humans. Biopharm Drug Dispos. 1997:18(3):259–269.
   PubMed Web of Science ®Google Scholar
• Dorr RT, Lines R, Levine N, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996:58(20):1777–1784.
   PubMed Web of Science ®Google Scholar
• Dorr RT, Dvorakova K, Brooks C, et al. Increased eumelanin expression and tanning is induced by a superpotent melanotropin [Nle4-D-Phe7]-alpha-MSH in humans. Photochem Photobiol. 2000:72(4):526–532.
   PubMed Web of Science ®Google Scholar
• Dorr RT, Ertl G, Levine N, et al. Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers. Arch Dermatol. 2004:140(7):827–835.
   PubMedGoogle Scholar
• Royalty JE, Konradsen G, Eskerod O, et al. Investigation of safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of a long-acting alpha-MSH analog in healthy overweight and obese subjects. J Clin Pharmacol. 2014:54(4):394–404.
   PubMed Web of Science ®Google Scholar
• Safarinejad MR. Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose, randomized study. J Sex Med. 2008:5(4):887–897.
   PubMed Web of Science ®Google Scholar
• Rosen RC, Diamond LE, Earle DC, et al. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res. 2004:16(2):135–142.
   PubMed Web of Science ®Google Scholar
• Ceriani G, Diaz J, Murphree S, et al. The neuropeptide alpha-melanocyte-stimulating hormone inhibits experimental arthritis in rats. Neuroimmunomodulation. 1994:1(1):28–32.
   PubMedGoogle Scholar
• Botte DA, Noronha IL, Malheiros DM, et al. Alpha-melanocyte stimulating hormone ameliorates disease activity in an induced murine lupus-like model. Clin Exp Immunol. 2014:177(2):381–390.
   PubMed Web of Science ®Google Scholar
• Rajora N, Boccoli G, Catania A, et al. alpha-MSH modulates experimental inflammatory bowel disease. Peptides. 1997:18(3):381–385.
   PubMed Web of Science ®Google Scholar
• Fiechtner J, Montroy T. Treatment of moderately to severely active systemic lupus erythematosus with adrenocorticotropic hormone: a single-site, open-label trial. Lupus. 2014:23(9):905–912.
   PubMed Web of Science ®Google Scholar
• Levine T. Treating refractory dermatomyositis or polymyositis with adrenocorticotropic hormone gel: a retrospective case series. Drug Des Devel Ther. 2012:6:133-139.
   Web of Science ®Google Scholar
• Bomback AS, Tumlin JA, Baranski J, et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther. 2011:5:147-153.
   Web of Science ®Google Scholar
• Bomback AS, Canetta PA, Beck LH, Jr., et al. Treatment of resistant glomerular diseases with adrenocorticotropic hormone gel: a prospective trial. Am J Nephrol. 2012:36(1):58–67.
   PubMed Web of Science ®Google Scholar
• Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics. 1996:97(3):375–379.
   PubMed Web of Science ®Google Scholar