Edaravone-dexborneol improves neurological function after cerebral ischemia-reperfusion injury by activating NRF2/p62 and suppressing NF-κB/NLRP3 signaling.

Edaravone-dexborneol (EDB) is a prospective neuroprotective agent for ischemic stroke. However, its integrated mechanisms of action remain to be elucidated. Here, we investigated the multiple effects of EDB in a rat model of cerebral ischemia-reperfusion injury induced by transient middle cerebral artery occlusion (MCAO). Rats received intraperitoneal EDB (4 mL/kg, once daily). Acute infarct volume and biochemical parameters were assessed 24 h after reperfusion. Longitudinal behavioral and histological outcomes were evaluated after a 7-day treatment course. EDB significantly reduced neurological deficit scores and infarct size. EDB ameliorated deficits in affective-like behaviors, social cognition, learning and memory, and motor coordination. EDB markedly attenuated neuroinflammation by decreasing interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, concomitant with reduced nuclear factor-κB (NF-κB) signaling and NLR family pyrin domain-containing 3 (NLRP3) abundance. In addition, EDB mitigated oxidative stress, as demonstrated by decreased malondialdehyde (MDA) and restoration of glutathione (GSH) and total antioxidant capacity(T-AOC). At the molecular level, EDB increased nuclear factor erythroid 2-related factor 2 (NRF2) and sequestosome-1 (p62/SQSTM1) protein expression and modulated autophagy-associated markers, including Beclin-1 and microtubule-associated protein 1 light chain 3B (LC3B). Histological analyses demonstrated that EDB alleviated tissue injury and reduced glial activation, including attenuation of reactive astrocyte hypertrophy and microglial amoeboid transformation. To summarize, EDB promotes functional recovery, mediated by enhanced NRF2/p62-dependent cytoprotection and NF-κB/NLRP3-driven suppression of neuroinflammation.