Asano Takashi, Matsuzaki Hirokazu, Xuan Meiyan, Yuan Bo, Takayama Jun, Sakamoto Takeshi, Okazaki Mari
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan.
Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan.
Int J Mol Sci. 2025 Apr 1;26(7):3277. doi: 10.3390/ijms26073277.
Dysphagia is a serious complication of stroke, yet effective pharmacological treatments remain limited. This study investigated the effects of FAD012 (3,5-dimethyl-4-hydroxy cinnamic acid), a synthetic derivative of ferulic acid (FA), on cerebral damage and swallowing dysfunction in a rat model of bilateral common carotid artery occlusion (2VO). Sprague-Dawley rats were orally administered FAD012 (3 or 10 mg/kg), FA (10 mg/kg), or 0.5% carboxymethyl cellulose (CMC, suspension vehicle) starting one week before 2VO. Two weeks after 2VO surgery, which was performed under isoflurane anesthesia, reflex swallowing was assessed by electromyographic recordings of the mylohyoid muscle under urethane anesthesia. Two weeks after 2VO, cerebral blood flow (CBF) declined to approximately 40% of baseline, and the number of reflex swallowing responses was significantly reduced in the CMC group. Additionally, 2VO induced O production, apoptotic cell death in the striatum, and a reduction in tyrosine hydroxylase expression. Substance P (SP) levels in the laryngopharyngeal mucosa, positively regulated by dopaminergic signaling in the basal ganglia, also decreased. FAD012 (10 mg/kg) effectively prevented the 2VO-induced reduction in CBF, enhanced the reflex swallowing, and preserved the dopamine-SP system. Notably, FAD012 exerted significantly stronger effects than FA at the same dose. These findings suggest that FAD012 maintains CBF under cerebral hypoperfusion and enhances the swallowing reflex by maintaining neuronal function in the striatal and laryngopharyngeal regions of 2VO rats.
吞咽困难是中风的一种严重并发症，但有效的药物治疗仍然有限。本研究调查了阿魏酸（FA）的合成衍生物FAD012（3,5 - 二甲基 - 4 - 羟基肉桂酸）对双侧颈总动脉闭塞（2VO）大鼠模型脑损伤和吞咽功能障碍的影响。在2VO手术前一周开始，对Sprague - Dawley大鼠口服给予FAD012（3或10 mg/kg）、FA（10 mg/kg）或0.5%羧甲基纤维素（CMC，悬浮载体）。在异氟烷麻醉下进行2VO手术后两周，在乌拉坦麻醉下通过下颌舌骨肌的肌电图记录评估反射性吞咽。2VO手术后两周，脑血流量（CBF）降至基线的约40%，CMC组的反射性吞咽反应次数显著减少。此外，2VO诱导了超氧阴离子产生、纹状体中的凋亡细胞死亡以及酪氨酸羟化酶表达的降低。基底节中多巴胺能信号正向调节的喉咽黏膜中P物质（SP）水平也降低。FAD012（10 mg/kg）有效预防了2VO诱导的CBF降低，增强了反射性吞咽，并保留了多巴胺 - SP系统。值得注意的是，相同剂量下FAD012的作用明显强于FA。这些发现表明，FAD012在脑灌注不足时维持CBF，并通过维持2VO大鼠纹状体和喉咽区域的神经元功能来增强吞咽反射。
