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Pharmacological Activation of GPR55 Improved Cognitive Impairment Induced by Lipopolysaccharide in Mice

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Abstract

Our previous research found that activation of GPR55 can alleviate cognitive impairment induced by amyloid-beta 1–42 (Aβ1-42) and streptozotocin in mice, but the role of GPR55 in the pathogenesis of cognitive impairment remains unknown. Here, we used a lipopolysaccharide (LPS) mouse model to further investigate the role and mechanism of O-1602, a GPR55 agonist, on cognitive dysfunction. ICR mice were treated with an intracerebroventricular (i.c.v.) injection of LPS, followed by cognitive function tests. The expression of GPR55, NF-κB p65, caspase-3, Bax, and Bcl-2 in the hippocampus was examined by Western blotting. Inflammatory cytokines and microglia were detected by ELISA kit and immunohistochemical analyses, respectively. The levels of MDA, GSH, SOD, and CAT were examined by assay kits. Furthermore, TUNEL-staining was used to detect neuronal apoptosis. Our results showed that i.c.v. injection of LPS in mice exhibited impaired performance in the behavior tests, which were ameliorated by O-1602 treatment (2.0 or 4.0 μg/mouse, i.c.v.). Importantly, we found that O-1602 treatment reversed GPR55 downregulation, decreased the expression of NF-κB p65, suppressed the accumulation of proinflammatory cytokines and microglia activation, increased the anti-inflammatory cytokines, and reduced the levels of MDA, increased the levels of GSH, SOD, and CAT in the hippocampus. In addition, O-1602 treatment also significantly reduced Bax and increased Bcl-2 expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus. These observations indicate that O-1602 may ameliorate LPS-induced cognition deficits via inhibiting neuroinflammation, oxidative stress, and apoptosis mediated by the NF-κB pathway in mice.

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Data Availability

We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality.

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Funding

This project was supported by the Natural Science Foundation of Anhui Province (2108085QH385), Doctor Foundation of Anhui Medical University (0601086201), Anhui Medical University School Funding Project (2020xkj012), and National undergraduate innovation and entrepreneurship training program (202010366022).

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Authors and Affiliations

  1. Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    **aoTong **ang, Jie Hu, YuMei Wu, YueYue Li, ShiYu ** & **an Wu

  2. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China

    **aoTong **ang, Jie Hu, YuMei Wu, YueYue Li, ShiYu ** & **an Wu

  3. West Anhui Health Vocational College, Luan, 237000, China

    **n Wang

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  1. **n Wang
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  2. **aoTong **ang
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Contributions

XW conceived and designed the study. XTX, JH, YMW, YYL, and SYJ performed the experiments and collected the data. XW analyzed the data, and drafted this article. All authors read and approved the final manuscript.

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Correspondence to **an Wu.

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The studies involving animals were approved and performed in accordance with the ethical standards of the institutional animal ethics committee in Anhui Medical University.

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The authors declare no competing interests.

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**n Wang, **aoTong **ang, and Jie Hu contributed equally to this work.

Highlights

• Activation of GPR55 ameliorates cognitive impairment induced by LPS in mice.

• Activation of GPR55 protects against LPS-induced neuroinflammation, oxidative stress, and apoptosis via inhibition of the NF-κB pathway in mice.

• The central GPR55 may play an important role in cognitive dysfunction.

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Wang, X., **ang, X., Hu, J. et al. Pharmacological Activation of GPR55 Improved Cognitive Impairment Induced by Lipopolysaccharide in Mice. J Mol Neurosci 72, 1656–1669 (2022). https://doi.org/10.1007/s12031-022-02020-y

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  • DOI: https://doi.org/10.1007/s12031-022-02020-y

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