Oxymatrine alleviates cognitive dysfunction in mice caused by chronic cerebral hypoperfusion by promoting SIRT1/...

Oxymatrine (OMT) has been reported to exert neuroprotective effects in cerebral ischemia. Mitochondrial dysfunction is closely associated with the neurological deficits caused by chronic cerebral hypoperfusion (CCH). However, the potential role of mitochondrial protection in the neuroprotective effects of OMT, as well as the underlying mechanisms, remains to be fully elucidated. The present study aimed to investigate the mechanistic basis of OMT-mediated neuroprotection in vivo using a mouse model of CCH-induced cognitive impairment established by bilateral common carotid artery stenosis (BCAS), and in vitro using an HT22 cell injury model induced by oxygen-glucose deprivation/reperfusion (OGD/R). The in vivo results showed that OMT effectively alleviated CCH-induced cognitive impairment in mice. In addition, OMT treatment attenuated OGD/R-induced neuronal injury in HT22 cells. Mechanistically, OMT activated SIRT1 and promoted PINK1/Parkin-mediated mitophagy in neurons. Moreover, pharmacological inhibition of SIRT1 suppressed OMT-induced activation of PINK1/Parkin-mediated mitophagy, as well as the recovery of neuronal and cognitive function in both the cell and mouse models. These findings suggest that OMT enhances mitophagy through modulation of SIRT1, thereby ameliorating neuronal dysfunction and cognitive deficits associated with CCH and OGD/R. This study provides preclinical mechanistic evidence supporting further investigation of OMT in chronic cerebral hypoperfusion-related cognitive impairment.