Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Microglia mediate neuroinflammation and neuropathic pain in the central nervous system (CNS).
• FKBP5 facilitates IκB kinase (IKK) complex assembly, activating NF-κB, a target for neuropathic pain treatment.

Purpose of the Study:

• To investigate cannabidiol (CBD) as an antagonist of FKBP5.
• To elucidate the mechanism by which CBD affects FKBP5, IKK complex, and NF-κB activation.
• To evaluate CBD's efficacy in reducing neuroinflammation and neuropathic pain.

Main Methods:

• In vitro protein intrinsic fluorescence titration and cellular thermal shift assay (CETSA) to confirm direct binding and target engagement.
• Biochemical assays to assess IKK complex assembly and NF-κB activation.
• Stern-Volmer analysis, protein thermal shift assay, and molecular docking to identify critical interaction sites (FKBP5 Y113).
• In vivo studies using chronic constriction injury (CCI) model to assess CBD's effect on microglia activation and FKBP5 expression.

Main Results:

• CBD directly binds to FKBP5, increasing its stability, indicating FKBP5 as an endogenous target.
• CBD inhibits IKK complex assembly and NF-κB activation, reducing pro-inflammatory factors (NO, IL-1β, IL-6, TNF-α).
• FKBP5 tyrosine 113 (Y113) is critical for CBD interaction; Y113A mutation reduced CBD's inhibitory effects.
• CBD administration inhibited CCI-induced microglia activation and FKBP5 overexpression in the spinal cord.

Conclusions:

• FKBP5 is identified as a direct endogenous target of CBD.
• CBD exhibits therapeutic potential for neuropathic pain by inhibiting FKBP5-mediated neuroinflammation.
• Targeting the FKBP5-CBD interaction offers a novel strategy for managing neuropathic pain.