Alpha‑Asarone Ameliorates Neuronal Injury After Ischemic Stroke and Hemorrhagic Transformation by Attenuating Blood-Brain Barrier Destruction, Promoting Neurogenesis, and Inhibiting Neuroinflammation.

Abstract

Recombinant tissue-type plasminogen activator (rt-PA), the primary drug for acute ischemic stroke (IS), has a narrow therapeutic window and carries a potential risk of hemorrhagic transformation (HT). Without rt-PA administration, patients may suffer permanent cerebral ischemia. Alpha-asarone (ASA), a natural compound derived from Acorus tatarinowii Schott, exhibits diverse neuropharmacological effects. This study aims to investigate whether ASA could improve outcomes in IS and be used to mitigate HT induced by rt-PA. We employed models of permanent middle cerebral artery occlusion (pMCAO) and photothrombotic cortical injury (PCI) to investigate both the therapeutic efficacy and underlying mechanisms of ASA during the acute and recovery periods following IS, respectively. Additionally, Sprague-Dawley rats were subjected to rt-PA treatment at 6-h post-PCI to mimic HT (rt-PA-HT). Our results revealed three key findings: (1) ASA demonstrated therapeutic effects in the acute phase of pMCAO rats by alleviating blood-brain barrier damage through inhibition of glial cell-mediated neuroinflammation; (2) administration of ASA 24 h after stroke ameliorated the neurological damage during the recovery phase in PCI mice by promoting neurogenesis via activation of the BDNF/ERK/CREB signaling pathway; (3) ASA attenuated rt-PA-HT injury by modulating the NLRP3/Caspase1/IL-1β and IL-18 pathways. Overall, our findings suggest that ASA mitigates neuronal injury following IS and HT, positioning it as a promising candidate for treating these conditions.