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Activation of LXRs alleviates neuropathic pain-induced cognitive dysfunction by modulation of microglia polarization and synaptic plasticity via PI3K/AKT pathway

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Abstract

Objective

Cognitive dysfunction is a common comorbidity in patients with chronic pain. Activation of Liver X receptors (LXRs) plays a potential role in improving cognitive disorders in central nervous diseases. In this study, we investigated the role of LXRs in cognitive deficits induced by neuropathic pain.

Methods

We established the spared nerve injury (SNI) model to investigate pain-induced memory dysfunction. Pharmacological activation of LXRs with T0901317 or inhibition with GSK2033 was applied. PI3K inhibitor LY294002 was administered to explore the underlying mechanism of LXRs. Changes in neuroinflammation, microglia polarization, and synaptic plasticity were assessed using biochemical technologies.

Results

We found that SNI-induced cognitive impairment was associated with reduced LXRβ expression, increased M1-phenotype microglia, decreased synaptic proteins, and inhibition of PI3K/AKT signaling pathway in the hippocampus. Activation of LXRs using T0901317 effectively alleviated SNI-induced cognitive impairment. Additionally, T0901317 promoted the polarization of microglia from M1 to M2, reduced pro-inflammatory cytokines, and upregulated synaptic proteins in the hippocampus. However, administration of GSK2033 or LY294002 abolished these protective effects of T0901317 in SNI mice.

Conclusions

LXRs activation alleviates neuropathic pain-induced cognitive impairment by modulating microglia polarization, neuroinflammation, and synaptic plasticity, at least partly via activation of PI3K/AKT signaling in the hippocampus. LXRs may be promising targets for addressing pain-related cognitive deficits.

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Data availability

All data relevant to the study are included in the article or uploaded as supplementary information. Data is available upon request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81974170) and the Natural Science Foundation of Hubei Province (2021CFB341).

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Authors and Affiliations

  1. Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei Province, China

    Siyi Han, Xiaoman Yuan, Fengtian Zhao, Feng Gao, Wen Zhang & Xuebi Tian

  2. School of Human and Social Sciences, University of West London, London, UK

    Anne Manyande

  3. Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei Province, China

    Jie Wang

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  1. Siyi Han
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Contributions

ZW, TXB, and HSY worked on the experiment design. HSY, YXM, and ZFT conducted behavioral tests and biochemical experiments. HSY, YXM, ZFT, and ZW worked on data collection/analysis. The manuscript was drafted by HSY, ZW, and TXB. AM, GF, and WJ participated in the revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wen Zhang or Xuebi Tian.

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Han, S., Yuan, X., Zhao, F. et al. Activation of LXRs alleviates neuropathic pain-induced cognitive dysfunction by modulation of microglia polarization and synaptic plasticity via PI3K/AKT pathway. Inflamm. Res. 73, 157–174 (2024). https://doi.org/10.1007/s00011-023-01826-9

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