Therapeutic Effects of Stimulating the Melanocortin Pathway in Regulating Ocular Inflammation and Cell Death

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Abstract

Alpha-melanocyte-stimulating hormone (α-MSH) and its binding receptors (the melanocortin receptors) play important roles in maintaining ocular tissue integrity and immune homeostasis. Particularly extensive studies have demonstrated the biological functions of α-MSH in both immunoregulation and cyto-protection. This review summarizes the current knowledge of both the physiological and pathological roles of α-MSH and its receptors in the eye. We focus on recent developments in the biology of α-MSH and the relevant clinical implications in treating ocular diseases.

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Corneal nerves: structure, contents and function

Linda J. Müller, Carl F Marfurt, Friedrich E Kruse … (2003)

Experimental Eye Research, 76(5), 521-542

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The significance of vasoactive intestinal peptide in immunomodulation.

Doina Ganea, David Pozo, José M. R. Delgado (2004)

First identified by Said and Mutt some 30 years ago, the vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator peptide. Subsequently, its biochemistry was elucidated, and within the 1st decade, their signature features as a neuropeptide became consolidated. It did not take long for these insights to permeate the field of immunology, out of which surprising new attributes for VIP were found in the last years. VIP is rapidly transforming into something more than a mere hormone. In evolving scientifically from a hormone to a novel agent for modifying immune function and possibly a cytokine-like molecule, VIP research has engaged many physiologists, molecular biologists, biochemists, endocrinologists, and pharmacologists and it is a paradigm to explore mutual interactions between neural and neuroendocrine links in health and disease. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as exciting new candidates for therapeutic intervention and drug development.

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alpha-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes.

Ana Luisa Kadekaro, Renny Kavanagh, Hiromi Kanto … (2005)

UV radiation is an important etiologic factor for skin cancer, including melanoma. Constitutive pigmentation and the ability to tan are considered the main photoprotective mechanism against sun-induced carcinogenesis. Pigmentation in the skin is conferred by epidermal melanocytes that synthesize and transfer melanin to keratinocytes. Therefore, insuring the survival and genomic stability of epidermal melanocytes is critical for inhibiting photocarcinogenesis, particularly melanoma, the most deadly form of skin cancer. The paracrine factors alpha-melanocortin and endothelin-1 are critical for the melanogenic response of cultured human melanocytes to UV radiation. We report that alpha-melanocortin and endothelin-1 rescued human melanocytes from UV radiation-induced apoptosis and reduced DNA photoproducts and oxidative stress. The survival effects of alpha-melanocortin and endothelin-1 were mediated by activation of the melanocortin 1 and endothelin receptors, respectively. Treatment of melanocytes with alpha-melanocortin and/or endothelin-1 before exposure to UV radiation activated the inositol triphosphate kinase-Akt pathway and increased the phosphorylation and expression of the microphthalmia-related transcription factor. Treatment with alpha-melanocortin and/or endothelin-1 enhanced the repair of cyclobutane pyrimidine dimers and reduced the levels of hydrogen peroxide induced by UV radiation. These effects are expected to reduce genomic instability and mutagenesis.