Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5

Xue Wang; Cong Lin; Sha Jin; Yibo Wang; Yinghua Peng; Xiaohui Wang

doi:10.1016/j.bbi.2023.05.008

Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5

Brain Behav Immun. 2023 Jul:111:365-375. doi: 10.1016/j.bbi.2023.05.008. Epub 2023 May 15.

Authors

Xue Wang¹, Cong Lin², Sha Jin³, Yibo Wang², Yinghua Peng⁴, Xiaohui Wang⁵

Affiliations

¹ Department of Anesthesiology, Lequn Branch, The First Hospital of Jilin University, Changchun 130021, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
² Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
³ Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China.
⁴ Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun 130112, China. Electronic address: pengyinghua@caas.cn.
⁵ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China; Beijing National Laboratory for Molecular Sciences, Beijing 100190, China. Electronic address: xiaohui.wang@ciac.ac.cn.

PMID: 37196785
DOI: 10.1016/j.bbi.2023.05.008

Abstract

Microglia is a heterogeneous population that mediates neuroinflammation in the central nervous system (CNS) and plays a crucial role in developing neuropathic pain. FKBP5 facilitates the assembly of the IκB kinase (IKK) complex for the activation of NF-κB, which arises as a novel target for treating neuropathic pain. In this study, cannabidiol (CBD), a main active component of Cannabis, was identified as an antagonist of FKBP5. In vitro protein intrinsic fluorescence titration showed that CBD directly bound to FKBP5. Cellular thermal shift assay (CETSA) indicated that CBD binding increased the FKBP5 stability, which implies that FKBP5 is the endogenous target of CBD. CBD was found to inhibit the assembly of the IKK complex and the activation of NF-κB, therefore blocking LPS-induced NF-κB downstream pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Stern-Volmer analysis and protein thermal shift assay revealed that tyrosine 113 (Y113) of FKBP5 was critical for FKBP5 interacting with CBD, which is consistent with in silico molecular docking simulation. FKBP5 Y113 mutation (Y113A) alleviated the effect of CBD inhibiting LPS-induced pro-inflammatory factors overproduction. Furthermore, systemic administration of CBD inhibited chronic constriction injury (CCI)-induced microglia activation and FKBP5 overexpression in lumbar spinal cord dorsal horn. These data imply that FKBP5 is an endogenous target of CBD.

Keywords: Cannabidiol; FKBP5; NF-κB; Neuroinflammation; Neuropathic pain.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cannabidiol* / pharmacology
Lipopolysaccharides / pharmacology
Molecular Docking Simulation
NF-kappa B / metabolism
Neuralgia* / drug therapy
Neuralgia* / metabolism
Neuroinflammatory Diseases
Rats
Rats, Sprague-Dawley
Tacrolimus Binding Proteins* / antagonists & inhibitors

Substances

Cannabidiol
Lipopolysaccharides
NF-kappa B
Tacrolimus Binding Proteins