Covalent organic framework based cytoprotective therapy after ischemic stroke
Yuqin Peng,
Qingfan Ren,
Huanrong Ma,
Chuman Lin,
Mingjia Yu,
Yongchuan Li,
Jiancong Chen,
Haihao Xu,
Peng Zhao,
Suyue Pan,
Jia Tao,
Kaibin Huang
Affiliations
Yuqin Peng
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Qingfan Ren
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, China
Huanrong Ma
Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Chuman Lin
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Mingjia Yu
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Yongchuan Li
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Jiancong Chen
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Haihao Xu
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Peng Zhao
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangzhou, 510515, China
Suyue Pan
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Corresponding author.
Jia Tao
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, China; Corresponding author.
Kaibin Huang
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Neurology, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, China; Corresponding author. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Cytoprotection has emerged as an effective therapeutic strategy for mitigating brain injury following acute ischemic stroke (AIS). The sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel plays a pivotal role in brain edema and neuroinflammation. However, the practical use of the inhibitor glyburide (GLB) is hindered by its low bioavailability. Additionally, the elevated reactive oxygen species (ROS) after AIS exacerbate SUR1-TRPM4 activation, contributing to irreversible brain damage. To overcome these challenges, GLB and superoxide dismutase (SOD) were embedded in a covalent organic framework (COF) with a porous structure and great stability. The resulting S/G@COF demonstrated significant improvements in survival and neurological functions. This was achieved by eliminating ROS, preventing neuronal loss and apoptosis, suppressing neuroinflammation, modulating microglia activation, and ameliorating blood-brain barrier (BBB) disruption. Mechanistic investigations revealed that S/G@COF concurrently activated the Wnt/β-catenin signaling pathway while suppressing the upregulation of SUR1-TRPM4. This study underscores the potential of employing multi-target therapy and drug modification in cytoprotective strategies for ischemic stroke.
