Affiliation:
1. Huazhong University of Science and Technology
2. University of West London
3. Chinese Academy of Sciences
Abstract
Abstract
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.
Publisher
Research Square Platform LLC
Reference63 articles.
1. Mills SEE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. British Journal of Anaesthesia [Internet]. 2019 [cited 2022 Oct 27];123:e273–83. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0007091219302272
2. Phelps CE, Navratilova E, Porreca F. Cognition in the Chronic Pain Experience: Preclinical Insights. Trends in Cognitive Sciences [Internet]. 2021 [cited 2022 Oct 27];25:365–76. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1364661321000036
3. The impact of pain upon cognition: what have rodent studies told us?;Low LA;Pain,2013
4. Saffarpour S, Janzadeh A, Rahimi B, Ramezani F, Nasirinezhad F. Chronic nanocurcumin treatment ameliorates pain-related behavior, improves spatial memory, and reduces hippocampal levels of IL-1β and TNFα in the chronic constriction injury model of neuropathic pain. Psychopharmacology [Internet]. 2021 [cited 2022 Oct 28];238:877–86. Available from: https://link.springer.com/10.1007/s00213-020-05739-x
5. Gui W-S, Wei X, Mai C-L, Murugan M, Wu L-J, Xin W-J, et al. Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain [Internet]. 2016 [cited 2022 Oct 28];12:174480691664678. Available from: http://journals.sagepub.com/doi/10.1177/1744806916646784