A novel PGAM5 inhibitor LFHP-1c protects blood-brain barrier integrity in ischemic stroke.
10.1016/j.apsb.2021.01.008
- Author:
Chenglong GAO
1
;
Yazhou XU
1
;
Zhuangzhuang LIANG
1
;
Yunjie WANG
1
;
Qinghong SHANG
2
;
Shengbin ZHANG
3
;
Cunfang WANG
3
;
Mingmin NI
3
;
Dalei WU
2
;
Zhangjian HUANG
1
;
Tao PANG
1
Author Information
1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
2. Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
3. Guangdong Long Fu Pharmaceutical Co., Ltd., Zhongshan 528451, China.
- Publication Type:Journal Article
- Keywords:
Blood–brain barrier;
Brain microvascular endothelial cells;
Ischemic stroke;
LFHP-1c;
NRF2;
PGAM5;
Surface plasmon resonance;
Target identification
- From:
Acta Pharmaceutica Sinica B
2021;11(7):1867-1884
- CountryChina
- Language:English
-
Abstract:
Blood-brain barrier (BBB) damage after ischemia significantly influences stroke outcome. Compound LFHP-1c was previously discovered with neuroprotective role in stroke model, but its mechanism of action on protection of BBB disruption after stroke remains unknown. Here, we show that LFHP-1c, as a direct PGAM5 inhibitor, prevented BBB disruption after transient middle cerebral artery occlusion (tMCAO) in rats. Mechanistically, LFHP-1c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity, but also reduced the interaction of PGAM5 with NRF2, which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia. Furthermore, LFHP-1c administration by targeting PGAM5 shows a trend toward reduced infarct volume, brain edema and neurological deficits in nonhuman primate
