Clemastine alleviates cognitive dysfunction after SAH by targeting neuronal CNTN1 to regulate the ADA-adenosine pathway

作者：Li Li, Bo-yang Wei, Lei Jin, Yan Wu, Ze-yu Yang, Can Li, Jia-ming Zhou, Yu Song, Wen-zhi Gong, Yuan-hao Ou-Yang, H Huang, X H Feng, Guo Shen-quan, Wen-ping Cheng, Ran Li, Shu-yin LIANG, Shi-xing Su, Fa Jin, Xin Zhang, Yan-chao Liu, Chuan-zhi Duan, Wen-chao Liu, X Li · 发表于：Acta Pharmacologica Sinica · 年份：2026 · DOI：10.1038/s41401-026-01852-3 · 研究领域：Intracranial Aneurysms: Treatment and Complications、Intracerebral and Subarachnoid Hemorrhage Research、Neurogenesis and neuroplasticity mechanisms

Demyelination following subarachnoid hemorrhage (SAH) is an important cause of cognitive impairment in patients. However, its underlying mechanisms remain unclear. This study aimed to elucidate the molecular basis of SAH-related demyelination and identify potential treatments. Contactin-1 (CNTN1) levels in the cerebrospinal fluid were significantly decreased in patients following SAH. Higher levels of CNTN1 expression correlated positively with Montreal Cognitive Assessment (MoCA) scores. However, whether and in which specific cell types CNTN1 expression is downregulated in the SAH brain parenchyma remains unknown. Our single-cell RNA sequencing revealed that Cntn1 was downregulated specifically in neurons, but not in oligodendrocytes. Then knockdown of Cntn1 in neurons via adeno-associated virus (AAV) significantly exacerbated cognitive impairment in mice with SAH. To investigate the mechanisms by which CNTN1 downregulation contributes to cognitive impairment, we performed transcriptome sequencing. This analysis revealed a significant decline in Ada, Plp1, and Mbp following CNTN1 knockdown in neurons. We therefore hypothesized that CNTN1 regulates neuronal ADA and existence of CNTN1-ADA-ADORA2B signaling axis. Through this axis, downregulation of CNTN1 after SAH might lead to demyelination. To validate our hypothesis, we overexpressed Cntn1 in murine neurons using AAV. Results demonstrated that Cntn1 overexpression effectively improved SAH-induced cognitive dysfunction, whic...