Yuhao Xu1,2,3,4,5  · Yi Tan1,2,3,4,5 · Zhi Zhang1,2,3,4,5 · Duo Chen1,2,3,4,5 · Chao Zhou1,2,3,4,5 · Liang Sun1,2,3,4,5 · Shengnan Xia1,2,3,4,5 · Xinyu Bao1,2,3,4,5 · Haiyan Yang1,2,3,4,5 · Yun Xu1,2,3,4,5

1 Department of Neurology, Nanjing Drum Tower Hospital, Afliated Hospital of Medical School, Nanjing University, Nanjing 212008, China 

2 Jiangsu Key Laboratory for Molecular Medicine and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing 212008, China 

3 Nanjing Neurology Clinical Medical Center, Nanjing 212008, China 

4 The Brain Disease and Brain Science Center of Nanjing Drum Tower Hospital, Nanjing 212008, China 5 Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Nanjing 212008, China

Abstract

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.

Keywords

13-Docosenamide; White matter injury; Oligodendrocyte precursor cell; Cannabinoid receptor 1; Ubiquitin-specifc peptidase 33

[SpringerLink]