Docosahexaenoic acid prevents apoptosis of retina photoreceptors by activating the ERK/MAPK pathway

GERMAN OL; INSUA MF; GENTILI C; ROTSTEIN NP; POLITI LP

JOURNAL OF NEUROCHEMISTRY

Año: 2006 vol. 98 p. 1507 - 1520

0022-3042

Abstract   Identifying the trophic factors for retina photoreceptors and the intracellular pathways  activated to promote cell survival is crucial for treating retina neurodegenerative diseases. Docosahexaenoic acid (DHA), the major retina polyunsaturated fatty acid, prevents photoreceptor apoptosis during early development in vitro and upon oxidative stress, promoting differentiaton. However, the signaling mechanisms activated by DHA are still unclear. We investigated whether the extracellular signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) or the phosphatidylinositol-3- kinase (PI3K) pathway participated in DHA protection. U0126, a specific MEK inhibitor, completely blocked DHA antiapoptotic effect. DHA rapidly increased ERK phosphorylation in photoreceptors, while U0126 blocked this increase. U0126 hindered DHA prevention of mitochondrial depolarization, and blocked DHA-induced increase in opsin expression. On the contrary, PI3K inhibitors did not diminish DHA protective effect. DHA promoted early expression of Bcl-2, decreased Bax expression and reduced caspase-3 activation in photoreceptors. These results suggest that DHA exclusively activates the ERK/MAPK pathway to promote photoreceptor survival during early development in vitro and upon oxidative stress. This leads to the regulation of Bcl-2 and Bax expression, thus preserving mitochondrial membrane potential and inhibiting caspase activation. Hence, DHA, a lipid trophic factor, promotes photoreceptor survival and differentiation by activating the same signaling pathways triggered by peptidic trophic factors.