Xu Yuhao, Tan Yi, Zhang Zhi, Chen Duo, Zhou Chao, Sun Liang, Xia Shengnan, Bao Xinyu, Yang Haiyan, Xu Yun
Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 212008, China.
Jiangsu Key Laboratory for Molecular Medicine and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, 212008, China.
Neurosci Bull. 2025 Jul 18. doi: 10.1007/s12264-025-01461-w.
Chronic cerebral hypoperfusion leads to white matter injury (WMI), which plays a significant role in contributing to vascular cognitive impairment. While 13-docosenamide is a type of fatty acid amide, it remains unclear whether it has therapeutic effects on chronic cerebral hypoperfusion. In this study, we conducted bilateral common carotid artery stenosis (BCAS) surgery to simulate chronic cerebral hypoperfusion-induced WMI and cognitive impairment. Our findings showed that 13-docosenamide alleviates WMI and cognitive impairment in BCAS mice. Mechanistically, 13-docosenamide specifically binds to cannabinoid receptor 1 (CNR1) in oligodendrocyte precursor cells (OPCs). This interaction results in an upregulation of ubiquitin-specific peptidase 33 (USP33)-mediated CNR1 deubiquitination, subsequently increasing CNR1 protein expression, activating the phosphorylation of the AKT/mTOR pathway, and promoting the differentiation of OPCs. In conclusion, our study suggests that 13-docosenamide can ameliorate chronic cerebral hypoperfusion-induced WMI and cognitive impairment by enhancing OPC differentiation and could serve as a potential therapeutic drug.
慢性脑灌注不足会导致白质损伤（WMI），这在导致血管性认知障碍中起重要作用。虽然13-二十二碳酰胺是一种脂肪酸酰胺，但它对慢性脑灌注不足是否具有治疗作用仍不清楚。在本研究中，我们进行了双侧颈总动脉狭窄（BCAS）手术，以模拟慢性脑灌注不足诱导的WMI和认知障碍。我们的研究结果表明，13-二十二碳酰胺可减轻BCAS小鼠的WMI和认知障碍。机制上，13-二十二碳酰胺特异性结合少突胶质前体细胞（OPC）中的大麻素受体1（CNR1）。这种相互作用导致泛素特异性肽酶33（USP33）介导的CNR1去泛素化上调，随后增加CNR1蛋白表达，激活AKT/mTOR途径的磷酸化，并促进OPC的分化。总之，我们的研究表明，13-二十二碳酰胺可通过增强OPC分化来改善慢性脑灌注不足诱导的WMI和认知障碍，并可作为一种潜在的治疗药物。
