['To investigate whether activation of liver X receptors (LXRs) protects N-methyl-D-aspartic (NMDA)-induced retinal neurotoxicity in mice and to explore the underlying mechanism.', 'Inner retinal damage was induced by intravitreal injection of NMDA. A synthetic LXR ligand TO901317 (TO90, 50 mg/kg/d) or vehicle was intragastrically administrated from 3 days before to 1 day or 7 days after NMDA injection. The severity of retinal damage was evaluated with histological analysis and TUNEL staining, and retinal functions were evaluated by ERG. The expressions of caspase-3, bax, bcl-2, TNF-α, and BACE1, the rate-limiting enzyme in the formation of amyloid β (Aβ), in the retina were examined by real-time PCR and ELISA. The levels of LXRs, NF-κB subunit p65, p-p38 mitogen-activated protein kinase (MAPK), and an LXR target gene ABCA1 were detected with real-time PCR and Western blotting. The localization and protein expression of Aβ in the retina was assessed by immunohistochemistry and Western blotting.', 'The NMDA enhanced the expression of LXRβ but not LXRα and ABCA1 in mouse retina. Nevertheless, administration of TO90 after NMDA injection not only enhanced the expression of LXRβ but also upregulated the level of ABCA1, suggesting retinal LXRs were activated in a ligand-dependent manner. The LXRα expression was unchanged in the vehicle and the TO90-treated groups. Activation of LXRβ with TO90 inhibited cell death in the ganglion cell layer (GCL) and inner nuclear layer (INL), preserved ERG b- and a-wave amplitudes, and the b/a ratio in the NMDA-treated mice. Meanwhile, TO90 suppressed the elevation of apoptosis factors caspase-3 and bax induced by NMDA and upregulated the level of an antiapoptotic factor bcl-2. The TO90 also inhibited the increase of p-p38 MAPK and proinflammatory cytokine TNF-α after NMDA injection. Furthermore, activation of LXR attenuated the activation of NF-κB, and reduced gene expression of BACE1 and accumulation of Aβ induced by NMDA.'] Does activation of liver X receptor protect inner retinal damage induced by N-methyl-D-aspartate?