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Anxiolytic effects of corilagin by targeting Htr2c through activation of the TrkB/CREB/BDNF pathway

Xiaoyun Yun,Jianhui Wu,Jie Zhou,Linlin Song,Yongpei Tang,Hanghong Lo,Jerome P.L. Ng,Menghan Liu,Zhikang Wang,Liqun Qu,Huimiao Wang,Ruilong Zhang,Cairen Wang,Linna Wang,Jiujie Yang,Sookja Kim Chung,Vincent Kam Wai Wong,Betty Yuen Kwan Law

Background Anxiety disorders rank among the most ubiquitous neuropsychiatric disease classifications. Despite their substantial disease burden, the persistent lack of innovative, mechanistically grounded therapeutic interventions over the past two decades highlights an urgent need for novel pharmacological strategies. Purpose The aim of this study is to investigate the neuroprotective and anxiolytic effects of corilagin derived from plant sources, offering novel perspectives for the development of therapeutic strategies targeting anxiety disorders. Methods In this study, high-performance liquid chromatography-mass spectrometry analysis was performed on the crude extract of Phyllanthus emblica Linn. A glutamine-induced cell model and a scopolamine-induced anxiety model were established for in vitro and in vivo investigations, respectively. Anxiety-like behaviors were evaluated using Y-maze, open field tests, and fear conditioning experiments. Laser speckle contrast imaging was employed for relative and qualitative assessment of cerebral blood flow and perfusion in mice. Western blotting, quantitative real-time PCR, and flow cytometry were utilized to elucidate the underlying pathway mechanisms. Finally, RNA sequencing and recombinant adeno-associated virus (AAV)-mediated gene silencing experiments were conducted for target prediction and validation. Results Phyllanthus emblica Linn. derived corilagin showed a strong antioxidant activity in a glutamate-induced cell model. It also inhibited neuronal cell apoptosis caused by oxidative damage, rescued apoptosis from the late stage to the early stage and restored cellular viability. Corilagin alleviated anxiety as reflected by the improvement in scopolamine-induced mice’s behavior such as hyperlocomotion, working memory and emotion memory damage. By applying recombinant AAV-mediated Htr2c silencing shRNA, our findings indicate that corilagin targets the serotonergic system, producing anxiolytic effects by modulating Htr2c to influence 5-HT levels and activate the TrkB/CREB/BDNF pathway in the prefrontal cortex. Compared with the existing fluoxetine anxiolytic drug, this compound demonstrates unique liver-protective properties by downregulating the ALT and AST level. Conclusion This study revealed that corilagin, a bioactive hydrolysable tannin isolated from natural plants, has multiple efficacy in mitigating oxidative and apoptotic damage, alleviating anxiety. The superiority of corilagin as an Htr2c agonist lies in its lower risk of side effects, representing its potential as a novel therapeutic candidate through Htr2c-BDNF signaling modulation, offering a mechanistically innovative approach for both the prevention and clinical management of anxiety disorders.