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

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 alpha-Melanocyte-stimulating hormone (alpha-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that a-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-alpha, IL-1 beta, and IFN-gamma, in ocular surface of the dry eye rats. Moreover, alpha-MSH, at 10(-4) mu g/mu l, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, alpha-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished alpha-MSH's protective effects, suggesting that both pathways are necessary for alpha-MSH's protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of alpha-MSH warrant translation of the alpha-MSH-containing eye drop into a novel and effective intervention to DED.