The action of 7,8-dihydroxyflavone preserves retinal ganglion cell survival and visual function via the TrkB pathway in NMDA-induced retinal excitotoxicity.

Abstract

PURPOSE: To analyze the response of different retinal ganglion cell (RGC) populations to NMDA-induced retinal excitotoxicity and the effect of an intraperitoneal treatment with 7,8-Dihydroxyflavone (DHF), a potent selective TrkB agonist. METHODS: Adult albino rats were treated the day prior to NMDA injection and the three following days with intraperitoneal vehicle (1?%DMSO in 0.09?%NaCl) or DHF (5 mg/kg in vehicle) injections. DHF-afforded protection was studied in the population of Brn3a(+)RGCs, OPN(+)RGCs (?-RGCs), OPN(+) Tbr2(+)RGCs (?ONs-RGCs), OPN(+) Tbr2(-)Brn3a(-)RGCs (?ONt-RGCs) and OPN(+)Brn3a(+)RGCs (?OFF-RGCs) at 3,7,14, or 21 days. The functional response was analyzed longitudinally with full-field electroretinograms. The mechanisms underlying DHF-afforded neuroprotection were assessed by western blot (WB) analysis of the levels of phosphorylated and total TrkB, phosphatidylinositol 3 kinase (PIK3/AKT) and mitogen-activated protein kinase (MAPK). RESULTS: NMDA intravitreal injection resulted in a significant diminution of the mean amplitudes of the pSTR and b-waves, as well as in severe depletion of all RGCs studied except ?ONt-RGCs. DHF treatment resulted in rescued mean amplitudes of the pSTR and b-waves up to 21 days after NMDA. WB analysis revealed an increase in p-TrkB which correlates to the increase of TRKB protein and an increase in normalized pAKT/AKT. pMAPK/MAPK was upregulated earlier and significantly higher in DHF-treated retinas. DHF afforded survival of up to 49?% of the Brn3a(+)RGCs versus 25?% of the vehicle group at 21 days after NMDA, and improved survival of the ?-RGC and ?ONs-RGCs but did not rescue the ?OFF-RGCs. CONCLUSION: Different RGC types exhibit variable susceptibilities to NMDA injury, and DHF-mediated activation of TrkB affords neuroprotection.