FAD012, a Ferulic Acid Derivative, Preserves Cerebral Blood Flow and Blood-Brain Barrier Integrity in the Rat...

Background/Objectives: The rapid progression of stroke often results in irreversible brain damage and poor outcomes when treatment is delayed. Prophylactic administration of FAD012 (3,5-dimethyl-4-hydroxycinnamic acid), a synthetic derivative of ferulic acid (FA), has demonstrated cerebroprotective effects in ischemic models through antioxidant and endothelial protective mechanisms. This study investigated the effects of FAD012 on cerebral infarction and blood-brain barrier (BBB) integrity using a photothrombotic stroke model in rats. Methods: Male Sprague Dawley rats received a single intraperitoneal injection of FAD012 or FA (100 or 300 mg/kg) 60 min prior to stroke induction. Under isoflurane anesthesia, the middle cerebral artery was exposed, and stroke was induced by intravenous administration of Rose Bengal followed by green laser irradiation. Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry. BBB disruption was evaluated by Evans Blue extravasation and immunohistochemistry for tight junction (TJ) proteins. Results: Control rats exhibited extensive infarction, BBB disruption, and reduced expression of claudin-5, occludin, and ZO-1, along with fragmented collagen IV. In contrast, FAD012 (300 mg/kg) significantly attenuated CBF reduction, reduced infarct size, preserved BBB integrity, and maintained TJ protein expression, with greater efficacy than an equivalent dose of FA. FAD012 also preserved the expression and phosphorylation of endothelial nitric oxide synthase (eNOS), a key marker of vascular integrity. The CBF-preserving effect of FAD012 was completely abolished by N^G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Conclusions: These findings suggest that FAD012 protects endothelial function, thereby contributing to the maintenance of CBF and BBB integrity, supporting its potential as a prophylactic therapeutic agent for ischemic stroke.