Prevention of retinal ganglion cell death by GPR81 agonist treatment

Abstract

PurposeRetinal ganglion cell (RGC) death is a common characteristic for ocular neurodegenerative diseases such as glaucoma and optic neuropathies. Recently, GPR81 agonist treatment has been identified as a key modulator of mitochondrial function and cell survival. Thus, we aimed to test whether GPR81 agonist treatment likewise promotes RGC survival and energy metabolism in retinal explants and wholemounts from mice.MethodsRetinal explants were treated with 5 mM of the GPR81 agonist, 3,5‐DHBA, for two, four, 24 & 72 hours, and compared to conditions with no treatment. Additionally, explants were also treated with 15 mM of L‐glutamate to induce toxicity and simultaneously treated with GPR81 agonist. Tissue survival was assessed through lactate dehydrogenase (LDH) viability assays. Retinal ganglion cell survival was measured in murine wholemount retinas through immunohistochemical staining (IHC). Total ATP levels were quantified through bioluminescence assays.ResultsGPR81 agonist treatment increased retinal explant survival after 24 and 72 hours of exposure. No significant effect was seen in retinal explants survival after GPR81 agonist treatment alone for two hours. However, during glutamate‐induced death, supplemented GPR81 agonist treatment increased survival compared to conditions with glutamate toxicity. IHC analysis revealed that GPR81 agonist treatment for two hours promoted RGC survival in retinal wholemounts compared with no treatment. GPR81 agonist treatment also enhanced ATP levels in retinal explants after two, 24, and 72 hr of exposure.ConclusionsThe present study reveals that GPR81 agonist treatment has a neuroprotective effect on specifically RGCs and on glutamate‐induced retinal degeneration. Hence, GPR81 agonist administration may be a potential new strategy to sustain RGCs, ultimately preventing visual disability as a consequence of RGC death.