Muscone enhances synaptic function in vascular dementia through activating BDNF-TrkB-NP2 signaling pathway

Objective: The objective of this study is to explore the mechanism by which Muscone treats VD. Methods: Cognitive function was evaluated by behavioral tests, cerebral blood flow(CBF) was detected with laser speckle imaging(LSI) on rat model induced by bilateral common carotid artery ligation(2-VO). To further elucidate the mechanism of Muscone acts on synaptic function, Mendelian randomization test was employed to identify neuronal pentraxin receptor (NPTXR) as a risk factor for VD. Subsequently, Oxygen and Glucose-Deprivation/Reoxygenation (OGD/R) model was established in HT22 cells. BDNF transfection, protein docking, and co-immunoprecipitation were utilized to validate whether the protective effect of Muscone is mediated through regulation of the BDNF-TrkB-NP2 pathway. Results: Muscone significantly enhanced the cognitive performance, memory capacity in rats, promoted axonal growth and increased dendritic spine density. Muscone effectively improved cell survival rates, mitigated the accumulation of ROS and Ca2+ following OGD/R treatment. Furthermore, Muscone led to a significant upregulation of synapse-associated proteins expression. Importantly, Muscone exhibited a notable ability to elevate BDNF levels, with subsequent binding with its downstream molecule TrkB to NP2. Conclusion: The activation of the BDNF-TrkB-NP2 pathway and synaptic function enhancement by Muscone contribute to its protective effect against VD injury. Therefore, our study uncovers a novel mechanism underlying the anti-VD properties of Muscone.