Activation of liver X receptor promotes hippocampal neurogenesis and improves long-term cognitive function recovery in acute cerebral ischemia-reperfusion mice

Cerebral ischemia (CI) leads to cognitive dysfunction due to the loss of hippocampal neurons. Liver X receptors (LXRs), including the LXR alpha and LXR beta isoforms, are critical for neurogenesis, synaptic plasticity, neurodegeneration, and cholesterol metabolism. However, the potential role of LXRs in the pathogenesis of CI-induced cognitive impairment is unclear. Therefore, we investigated the effects of LXR activation on hippocampal neurogenesis and cognitive function in mice with CI. C57 mice were randomized into four groups that included a sham group and three treatment groups with CI [Vehicle, TO901317 (TO90, an agonist of LXRs) and GSK2033 (an antagonist of LXRs)]. Mice were subjected to bilateral common carotid artery occlusion for 20 min to induce transient CI. The Morris water maze test was executed to detect spatial learning and memory. Proliferation, differentiation, and immature neurons in the subgranular zone (SGZ) were examined using Immunofluorescence. Western blot assay was used to detect the expression of the Wnt/beta-catenin signaling pathway-associated protein. TO90 significantly improved spatial learning and memory deficits induced by CI on 28 days. It enhanced the proliferation of neural stem cells, the number of immature neurons and the differentiation from nascent cells to neurons. The expression of the Wnt/beta-catenin signaling pathway-associated protein level was totally increased. The forenamed effects of TO90 were decreased in GSK2033 group. Thus, our findings suggest that LXRs activation can improve long-term cognitive dysfunction caused by CI by increasing neurogenesis, and LXRs may serve as a potential therapeutic target for cerebral ischemia.