Metformin attenuated depressive-like behaviors by suppressing TRPV1/NLRP3 mediated neuroinflammation in the hypothalamus of allergic rhinitis mice.

Abstract

Background: In addition to nasal symptoms, allergic rhinitis (AR) has increasingly been reported to be associated with depression-like behaviors. Recent evidence suggests that neuroinflammation in the hypothalamus may cause these depressive symptoms in AR. However, the precise mechanisms and effective treatments remain to be elucidated.

Objective: This study investigated the ameliorative effects of metformin on neuroinflammation in the hypothalamus, depressive-like behavior and the underlying molecular mechanisms of AR mice.

Methods: Mice were administered ovalbumin (OVA) intranasally to induce allergic rhinitis and subsequently subjected to behavioral experiments to detect depressive-like behavior. The roles of the TRPV1/NLRP3 pathway in depression-like behaviors in AR were examined in vivo. Additionally, the mechanism of TRPV1/NLRP3-mediated neuroinflammation was investigated in vitro. Finally, metformin was utilized to explore its possible mechanisms and efficacy in treating depressive-like behavior in AR.

Results: AR mice exhibited significant depressive-like behavior, which was attenuated by metformin. The number of Iba-1⁺ microglia significantly increased in the hypothalamus of AR mice. The expression of NLRP3 was significantly upregulated in the hypothalamus, activating microglia. Metformin ameliorated the neuropsychiatric symptoms by reducing NLRP3 expression in the hypothalamus. Moreover, metformin inhibited LPS-induced upregulation of the TRPV1/NLRP3 signaling pathway in microglial cell line, an effect that can be reversed by the TRPV1-specific agonist capsaicin.

Conclusion: Increased TRPV1 expression activates the NLRP3 inflammasome in hypothalamic microglia, promoting the pathological process of depressive-like behavior in AR mice. Metformin could effectively treat neuroinflammation by regulating microglia via TRPV1 downregulation, indicating its potential as a treatment for depressive-like behaviors in AR.