Neuroprotective effects of SB203580 (p38 MAP kinase inhibitor) against Endothelin-1-induced retinal ganglion cell death

Purpose: Endothelin-1 (ET-1) is a vasoactive peptide contributing to neurodegeneration in glaucoma, however, the underlying mechanisms are not completely understood. The current study tested the involvement of the p38 MAP kinase in ET-1-induced cell death in primary rat retinal ganglion cells (RGCs). Methods: Primary RGCs were treated for 24 hours with 100nM ET-1 either in the presence or absence of the p38 MAP kinase inhibitor SB203580. A Live/Dead assay was used to determine cell viability and the number of surviving and dying/dead cells were quantitated. Results: ET-1 induced RGC death following a 24 hour treatment (as seen by an increase in the dead/live ratio from 0.446 to 0.621), compared to untreated controls. Interestingly, compared to the untreated controls, an appreciable decrease in cell death was found in cells treated with SB203580 alone (a decrease in the dead/live ratio from 0.446 to 0.243). Following treatment with a combination of ET-1 and SB203580, cell counts showed a decrease in cell death when compared with cells treated with ET-1 alone (a change in the dead/live ratio from 0.621 to 0.333). Conclusions: The p38 MAP kinase pathway is known to be involved in signaling mechanisms underlying numerous pathways related to cellular stress. The current study suggests that p38 MAP kinase contributes to ET-1-mediated RGC death. Elucidation of endothelin-mediated signaling pathways will help understand mechanisms by which endothelins promote neurodegeneration in glaucoma.