Activation Of Liver X Receptor Protects Inner Retinal Damage Induced By N-Methyl-D-Aspartate In Mice

Purpose:To investigate whether activation of liver X receptors (LXRs) protects N-methyl-Daspartic (NMDA)-induced retinal neurotoxicity in mice and to explore the underlying mechanism.Methods:The C57/BJ mice were randomly divided into three groups: an NMDA plus vehicle-treated group, an NMDA plus TO90-treated group, and a control group. 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 and number of cells in GCL were evaluated with histological analysis, TUNEL staining and immunofluorescence. 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 amyloidβ (Aβ), in the retina were examined by real-time PCR and ELISA. The levels of LXRs, NF-κB subunit p65, 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.Results:The NMDA enhanced the expression of LXRP but not LXRa and ABCA1 in mouse retina. Nevertheless, TO90 not only enhanced the expression of LXRβ but also upregulated the level of ABCA1, suggesting retinal LXRs were activated in a ligand-dependent manner. Activation of LXRβ with TO90 prevented RGC loss induced by NMDA, and preserved ERG b-and a-wave amplitudes 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 proinflammatory cytokine TNF-a after NMDA injection. Furthermore, activation of LXRβ attenuated the activation of NF-κB, and reduced gene expression of BACE1 and accumulation of AP induced by NMDA.Conclusion:Activation of LXRβ with a synthetic LXR ligand TO90 protects the inner retinal damage induced by NMDA in mice. We speculate the protective effect is associated with inhibition of the NF-κB signaling pathway and reduction of AP formation in retina. The LXR agonists may become a new class of neuroprotective agent for retinal diseases.