Activation of Liver X receptors alleviates neuropathic pain-induced cognitive dysfunction by modulating PI3K/AKT-mediated microglia polarization

Background: ： Cognitive dysfunction is a prevalent comorbidity in patients with chronic pain. Evidence suggested that activation of Liver X receptors (LXRs) plays a potential role in improving cognitive disorders in multiple central nervous diseases by modulating neuroinflammation and synaptic plasticity. In this study, we mainly investigated whether LXRs could reverse cognitive deficits induced by neuropathic pain. Methods: ： We established the spared nerve injury (SNI) model to explore the roles of LXRs in neuropathic pain induced-cognitive dysfunction. Pharmacological activation of LXRs with T0901317 or inhibition with GSK2033 was applied. In addition, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was administered to examine the downstream mechanism of LXRs. Changes in neuroinflammation, microglia polarization, and synaptic plasticity were assessed using biochemical technologies. Results: ： We found that SNI induced mechanical allodynia and novel object recognition dysfunction in mice, accompanied by the reduced expression levels of LXRβ, synaptic proteins, and the PI3K/AKT pathway in the hippocampus. Microglia were activated in the hippocampus after SNI, with an increase in the M1 phenotype and a decrease in the M2 phenotype, as well as upregulation of pro-inflammatory cytokines. Activation of LXRs with T0901317 significantly ameliorated SNI-induced cognitive dysfunction including anxiety, learning and memory. T0901317 also reversed neuroinflammation and microglia M1-polarization induced by SNI, upregulated expression levels of synaptic proteins, and phosphorylation of PI3K and AKT. However, administration of the LXRs inhibitor GSK2033 or PI3K inhibitor LY294002 abolished the protective effects of T0901317 on cognitive dysfunction in SNI mice. Conclusion: ： Our data indicate that activation of LXRs can alleviate neuropathic pain-induced cognitive dysfunction by modulating microglia polarization, neuroinflammation, and synaptic plasticity through the PI3K/AKT signaling pathway, and thus, LXRs may be identified as potential new targets for pain-related cognitive deficits.