α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways.

Yusha Ru,Yan Zhang,Shaozhen Zhao,Juan Du,Zexia Dou,Huijuan Liu,Yue Huang,Zhu Meng,Rui Hua Wei,Xun Liu

doi:10.1038/srep18619

Yusha Ru, Yan Zhang + Show 8 more

Open Access

https://doi.org/10.1038/srep18619

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Abstract

Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied α-Melanocyte-stimulating hormone (α-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that α-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-α, IL-1β, and IFN-γ, in ocular surface of the dry eye rats. Moreover, α-MSH, at 10−4 μg/μl, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, α-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished α-MSH’s protective effects, suggesting that both pathways are necessary for α-MSH’s protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of α-MSH warrant translation of the α-MSH-containing eye drop into a novel and effective intervention to DED.

Highlights

Α -Melanocyte-stimulating hormone (α -MSH) is a 13-amino acid peptide derived from proteolysis of Proopiomelanocortin[11]
We found that topical administrations of this peptide at different doses ameliorated the corneal dysfunctions and corrected the overexpression of proinflammatory factors in the scopolamine-induced dry eye rats (Figs 1 and 2). α -Melanocyte-stimulating hormone (α -MSH), at the optimal dosage of 10−4 mg/ml, maintained normal morphology and inhibited apoptosis in epithelium and stroma of the dry eye corneas (Figs 4 and 5)
As for the mechanisms, α -MSH activated PKA and Erk pathways in the dry eye ocular surface tissues (Fig. 7), and blockade of either pathway by the specific pharmacological blocker abolished the beneficial effects of α -MSH (Figs 3–6), suggesting that α -MSH exerts its protection via both pathways

Summary

Introduction

Α -Melanocyte-stimulating hormone (α -MSH) is a 13-amino acid peptide derived from proteolysis of Proopiomelanocortin[11]. We have shown that intravitreal injections of α -MSH protect neuroretina and retinal vessels from apoptotic cell death in a rat model of streptozotocin-induced diabetes[23] These studies indicate that α -MSH may have the potential to antagonize the pathogenic factors of the DED, the aqueous-deficient subtype of the disease, without incurring undesired complications, it would be interesting to examine the protective effects of this peptide in a dry eye model. We hypothesize that α -MSH may exert its protective effects against the pathogenic factors of dry eye through both PKA-CREB and MEK-Erk[1] or 2 pathways. Our results clearly showed that these previously undescribed protective effects were mediated by both PKA-CREB and MEK-Erk pathways

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