Protective effects of β-hydroxybutyrate against N-methyl-D-aspartic acid-induced excitotoxic retinal injury in rats.

β-Hydroxybutyrate, a metabolic substrate and signaling molecule, exerts neuroprotective effects against various neurodegenerative diseases, including retinal diseases. However, mechanisms underlying these neuroprotective effects are currently not fully understood. In this study, we examined the effects of β-hydroxybutyrate against N-methyl-D-aspartic acid (NMDA)-induced retinal injury in rats and the underlying mechanisms. The intravitreal injection of NMDA (200 nmol) resulted in a decrease in neuronal cells, an increase in apoptotic cells, and activation of microglial cells. Simultaneous intravitreal injection of β-hydroxybutyrate (50 nmol) and NMDA significantly attenuated these NMDA-induced responses. The protective effects of β-hydroxybutyrate against NMDA-induced retinal injury were suppressed by Compound C (an inhibitor of AMPK), but not AR-C155858 (an inhibitor of monocarboxylate transporters). These findings suggest that β-hydroxybutyrate exerts protective effects against NMDA-induced retinal excitotoxicity through inhibition of neuronal cell apoptosis and microglial cell activation. β-Hydroxybutyrate is transported across the plasma membrane via monocarboxylate transporters; however, the mechanisms associated with these transporters are unlikely to be involved in its protective effect. Instead, activation of AMPK pathway may contribute to β-hydroxybutyrate-mediated protection.