Capsazepine Treatment Alleviates Depression-Like Behaviors via TRPV1-Mediated Modulation of Neuroinflammation and Neurogenesis

Abstract Depression is a common mental disorder with a currently unclear pathogenesis, and it often fails to repond to treatment. Transient receptor potential vanilloid 1 (TRPV1) is known to regulate glial activation and inflammatory responses, yet its specific role in stress-related depressive pathophysiology remains incompletely understood. In this study, we explored the effects of modulating TRPV1 in neuroinflammation and neurogenesis underlying depression-like behaviors. A chronic social defeat stress (CSDS) mice model, followed by behavioral tests, was used to evaluate the antidepressant potential of capsaicin (CAP) and capsazepine (CPZ). Then, western blotting, elisa, and immunofluorescence were employed to assess microglial activation, the pro-inflammatory cytokine levels, neurogenesis, and JAK2/STAT3 signaling pathway in hippocampus tissues. The JAK2 agonist coumarin A1 (CA1) was used to verify the involvement of the JAK2/STAT3 pathway. In CSDS-susceptible mice, the protein expression of TRPV1 and the levels of p-CaMKIIα were elevated, and CPZ downregulated the expression of these indicators. Also, CSDS reduced the migcroglial numbers and altered microglial morphology in the subregions of the hippocampus; these results were accompanied by proinflammatory cytokine production. In parallel, TRPV1 inhibition by CPZ suppressed promoted neurogenesis, which was testified by increased BrdU + and DCX + cells. Further, CPZ exerts its regulatory effects through inhibition of the JAK2/STAT3 signaling pathway. CA1 reversed the neuroprotective effects of CPZ, confirming the involvement of the JAK2/STAT3 pathway. The discovered microglia-mediated mechanism provides novel insight into how TRPV1 modulation ameliorate stress-induced neuroinflammation and impaired neurogenesis These findings identify microglial TRPV1 as a potential therapeutic target for depression.