Patients with age related macular degeneration (AMD) will develop vision loss in the center of the visual field. Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is an important contributor of AMD. In this study, we explored the pro-survival effect of alpha-melanocyte stimulating hormone (alpha-MSH) on oxidative stressed RPE cells. We found that alpha-MSH receptor melanocortin I receptor (MC1R) was functionally expressed in primary and transformed RPE cells. RPE cells were response to alpha-MSH stimulation. alpha-MSH activated Akt/mammalian target of rapamycin (mTOR) and Erk1/2 signalings in RPE cells, which were inhibited by MC1R siRNA knockdown. alpha-MSH protected RPE cells from hydrogen peroxide (H2O2)-induced apoptosis, an effect that was almost abolished when MC1R was depleted by siRNA. alpha-MSH-mediated S6K1 activation and pro-survival effect against H2O2 was inhibited by Akt inhibitors (perifosine, MK-2206 and LY294002). Further, mTOR inhibition by rapamycin, or by mTOR siRNA knockdown, diminished alpha-MSH's pro-survival effect in RPE cells. Thus, Akt and its downstream mTOR signaling mediates alpha-MSH-induced survival in RPE cells. In summary, we have identified a new alpha-MSH-MC1R physiologic pathway that reduces H2O2-induced RPE cell damage, and might minimize the risk of developing AMD. (C) 2013 Elsevier Inc. All rights reserved.