Han, S, Yuan, X, Zhao, F, Manyande, Anne ORCID: https://orcid.org/0000-0002-8257-0722, Gao, F, Wang, J, Zhang, W and Tian, X (2024) Activation of LXRs alleviates neuropathic pain-induced cognitive dysfunction by modulation 2 of microglia polarization and synaptic plasticity via PI3K/AKT pathway. Inflammation Research, 73. pp. 157-174. ISSN 1023-3830

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Abstract

Background
Cognitive dysfunction is one of the most common comorbidities in patients with chronic pain. It has been shown 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
The spared nerve injury (SNI) model was established to explore the roles of LXRs in neuropathic pain induced-cognitive dysfunction. Pharmacological activation of LXRs by T0901317 or inhibition by 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 reduction in 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 M1 phenotype and decrease in 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. Neuroinflammation and microglia M1-polarization also induced by SNI were reversed after using T0901317. Moreover, T0901317 upregulated expression levels of synaptic proteins and phosphorylation of PI3K and AKT. However, administration of the LXRs inhibitor GSK2033 or PI3K inhibitor LY294002 abolished all the protective effects of T0901317 on cognitive dysfunction in SNI mice.
Conclusion
Our data indicate that LXRs activation alleviated neuropathic pain-induced cognitive dysfunction by modulating microglia polarization, neuroinflammation, and synaptic plasticity via the PI3K/AKT signaling pathway, and thus, LXRs may be identified as potential new targets for pain-related cognitive deficits.
Keywords
Liver X receptors; Neuropathic pain; Microglia polarization; Cognitive dysfunction; Neuroinflammation

Item Type:	Article
Identifier:	10.1007/s00011-023-01826-9
Keywords:	Liver X receptors; Neuropathic pain; Microglia polarization; Cognitive dysfunction; Neuroinflammation ; Synaptic plasticity
Subjects:	Medicine and health
Depositing User:	Anne Manyande
Date Deposited:	11 Dec 2023 10:41
Last Modified:	18 Mar 2024 11:11
URI:	https://repository.uwl.ac.uk/id/eprint/10531

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