The antidepressant effect of resveratrol may correlate with the anti-inflammatory pathways mediated by Tas2r123 in hippocampus

Abstract

Background

Bitter substances, such as resveratrol, alleviate depression by curbing inflammation, yet the mechanisms involved are obscure, not to mention a unified mechanism. Our previous research implies that the type 2 bitter taste receptors (Tas2rs) signaling pathway is crucial for the anti-inflammatory effect of resveratrol, potentially driving its antidepressant action. This study aims to illustrate the possible antidepressant mechanism of resveratrol via Tas2rs-mediated anti-inflammatory pathways which may reveal a common thread in therapeutic action of the bitter.

Method

Firstly, resveratrol, a typical bitter polyphenol, was selected as a representative of bitter compounds. Then, a phylogenetic analysis and agarose gel electrophoresis of 35 Tas2rs in rats' brain was performed. Subsequently, we established a chronic unpredictable mild stress (CUMS) model with administering resveratrol to evaluate impact of this polyphenol on depressive-like behaviors and the expression of Tas2rs. Meanwhile, inflammation-related proteins were measured within the hippocampus and prefrontal cortex (PFC) using qPCR and western blotting (WB). Further, we utilized qPCR, WB, and calcium (Ca²⁺) assay kit to scrutinize the expression of Tas2rs downstream signaling pathway in the aforementioned brain areas. Ultimately, proteomics analysis of hippocampus has been employed to speculated the holistic changes post-resveratrol intervention.

Result

Our investigation has unveiled the considerable heterogeneity and pronounced cerebral expression of Tas2rs. It shows that depressive-like behaviors are induced by CUMS, with 2 Tas2rs in hippocampus and 1 Tas2r in PFC decreasing. Nevertheless, resveratrol exerts its antidepressant effect with 14 Tas2rs increasing in hippocampus but only 1 Tas2r in the PFC. During this process, among the Tas2rs that declined in the hippocampus and PFC following CUMS, only Tas2r123 in hippocampus exhibited a notable increase after resveratrol treatment. Meanwhile, we observe that resveratrol ameliorates the hippocampal inflammation incited by CUMS, an effect not observed in the PFC. Additionally, the Tas2rs downstream signaling pathway is highly involved in the anti-inflammatory property of resveratrol with the context of its antidepressant effect and our previous proteomics have supported these findings.

Conclusion

The Tas2rs-mediated anti-inflammatory pathway in the hippocampus plays a pivotal role in the antidepressant effect of resveratrol. Concurrently, a Tas2rs mediated anti-inflammatory pathway paradigm has been provide for exploring the common mechanisms underlying the antidepressant and anti-inflammatory properties of bitter substances, offering a novel perspective on the pathophysiology of depression and promising avenues for innovative antidepressant therapies.