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Gastrodin Ameliorates Post-Stroke Depressive-Like Behaviors Through Cannabinoid-1 Receptor-Dependent PKA/RhoA Signaling Pathway

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Abstract

Post-stroke depression (PSD) is a significant complication in stroke patients, increases long-term mortality, and exaggerates ischemia-induced brain injury. However, the underlying molecular mechanisms and effective therapeutic targets related to PSD have remained elusive. Here, we employed an animal behavioral model of PSD by combining the use of middle cerebral artery occlusion (MCAO) followed by spatial restraint stress to study the molecular underpinnings and potential therapies of PSD. Interestingly, we found that sub-chronic application of gastrodin (Gas), a traditional Chinese medicinal herb Gastrodia elata extraction, relieved depression-related behavioral deficits, increased the impaired expression of synaptic transmission-associated proteins, and restored the altered spine density in hippocampal CA1 of PSD animals. Furthermore, our results indicated that the anti-PSD effect of Gas was dependent on membrane cannabinoid-1 receptor (CB1R) expression. The contents of phosphorated protein kinase A (p-PKA) and phosphorated Ras homolog gene family member A (p(ser188)-RhoA) were decreased in the hippocampus of PSD-mice, which was reversed by Gas treatment, and CB1R depletion caused a diminished efficacy of Gas on p-PKA and p-RhoA expression. In addition, the anti-PSD effect of Gas was partially blocked by PKA inhibition or RhoA activation, indicating that the anti-PSD effect of Gas is associated with the CB1R-mediated PKA/RhoA signaling pathway. Together, our findings revealed that Gas treatment possesses protective effects against the post-stroke depressive-like state; the CB1R-involved PKA/RhoA signaling pathway is critical in mediating Gas’s anti-PSD potency, suggesting that Gas application may be beneficial in the prevention and adjunctive treatment of PSD.

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Acknowledgements

We thank Xufei Chen for his help with molecular docking simulation.

Funding

This research was supported by the National Natural Science Foundation of China (no. 82271549 to MW; no. 81971226 to WH; no. 81901079 to HG), the Xi’an Innovative Project for Strengthening Basic Disciplines - Clinical Research Program (no. 22YXYJ0154 to MW); the Shaanxi Provincial Natural Science Foundation for Distinguished Young Scholars (no. 2021JC-33 to WH), and the Shaanxi Provincial Natural Science Foundation (no. 2023-JC-YB-652 to SW).

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Shiquan Wang, Minghui Wang, Wugang Hou and Xia Li contributed to the study conception and experimental design, Shiquan Wang, Liang Yu, Haiyun Guo, Yaru Guo, Huiqing Liu, Jiajia Wang and Wenqiang Zuo performed experiments, and Shiquan Wang, Jin Wang, and Wenqiang Zuo performed data collection and analysis. Minghui Wang and Shiquan Wang prepared figures. Minghui Wang, Shiquan Wang wrote the paper. All authors reviewed and approved the paper.

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Correspondence to Xia Li, Wugang Hou or Minghui Wang.

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Wang, S., Yu, L., Guo, H. et al. Gastrodin Ameliorates Post-Stroke Depressive-Like Behaviors Through Cannabinoid-1 Receptor-Dependent PKA/RhoA Signaling Pathway. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04267-5

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