Asiatic acid alleviates subarachnoid hemorrhage-induced brain injury in rats by inhibiting ferroptosis of neurons via targeting acyl-coenzyme a oxidase 1

Abstract

The occurrence of subarachnoid hemorrhage (SAH) can lead to brain injury, which is a fatal condition with limited effective clinical intervention strategies. The naturally occurring component Asiatic acid (AA), found in the tropical plant Centella asiatica, has been reported to possess neuroprotective properties. The objective of this study was to evaluate the neuroprotective effect of AA following SAH and investigate its potential mechanisms. The SAH model was established in male Sprague-Dawley (SD) rats through intravascular perforation, following a standardized protocol. The administration of AA was performed via gavage following SAH. A lentiviral vector was constructed and utilized for the knockdown of Acyl Coenzyme A Oxidase 1 (ACOX1) Firstly, AA treatment effectively improves brain neurological deficit, neuronal damage, and iron deposition induced by SAH. Furthermore, it has been demonstrated that AA directly interacts with ACOX1, which exhibits decreased expression in neurons following SAH. Additionally, our study reveals AA can reverse SAH-induced reduction in ACOX1 expression, concurrently ameliorating neuronal ferroptosis. This improvement is evidenced by reduced lipid peroxidation, including mitigated GSH depletion, decreased MDA production, and increased GPX4 content and activity. Also, AA enhances mitochondrial constriction while alleviating cristae disruption induced by SAH, providing crucial insights into its neuroprotective effects against neuronal ferroptosis in SAH. Moreover, when ACOX1 is knocked down, the neuroprotective effects of AA are weakened. Collectively, this study elucidated the neuroprotective effect of AA by inhibiting neuronal cell ferroptosis through targeting ACOX1. These findings suggest that AA holds promise as a potential therapeutic candidate for ameliorating SAH-induced brain injury.