Ferulic acid attenuates acute ischemic cerebral injury by enhancing antioxidant capacity and modulating autophagy via the Nrf2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferulic acid (FA), a key bioactive compound extracted from Angelica sinensis- traditionally used in herbal medicine, is now widely used as nutritional supplements and therapeutic agent for the management of cardiovascular diseases in which oxidative stress and autophagy dysregulation contribute significantly to disease progression. AIM OF THE STUDY: This study aimed to investigate the protective effects and underlying mechanisms of FA against oxidative stress using both an in vivo transient middle cerebral artery occlusion (MCAO) rat model and an in vitro oxygen-glucose deprivation (OGD) model in PC12 cells. MATERIALS AND METHODS: Male Sprague-Dawley rats (180-220 g) subjected to transient MCAO received intraperitoneal FA (25, 50, or 100 mg/kg) once daily for five consecutive days. 50 mg/kg was identified as the lowest effective dose and used for subsequent mechanistic studies. Neurological function, infarct volume, oxidative stress, and autophagy-related markers were assessed in FA-treated and untreated animals. In OGD-exposed PC12 cells, RNA interference and Western blotting were used to investigate the molecular mechanisms underlying FA-mediated regulation of oxidative stress and autophagy. RESULTS: FA significantly reduced cerebral infarct volume, brain edema, and neurological deficit scores in MCAO rats. FA attenuated oxidative stress by decreasing reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) levels and enhancing the expression of key antioxidant mediators, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), and glutathione (GSH). FA also modulated autophagic markers in ischemic brain tissue, as evidenced by a reduced LC3-II/LC3-I ratio and increased p62 expression. FA significantly improved cell viability, increased GSH levels, reduced intracellular ROS accumulation, upregulated antioxidant protein expression, and inhibited autophagy in OGD-induced PC12 cells. siRNA-mediated knockdown of Nrf2 partially abolished the antioxidative and autophagy-modulating effects of FA. CONCLUSIONS: FA may protect against ischemic brain injury through Nrf2-dependent enhancement of antioxidant defenses and modulation of autophagy, highlighting its potential as a promising therapeutic candidate for the development of novel neuroprotective interventions.