【摘 要】
：
Blood-brain barrier(BBB)damage after ischemia significantly influences stroke outcome.Com-pound LFHP-1c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of BBB disruption after stroke remains un
【机 构】
：
State Key Laboratory of Natural Medicines,Jiangsu Key Laboratory of Drug Screening,Jiangsu Key Labor
论文部分内容阅读
Blood-brain barrier(BBB)damage after ischemia significantly influences stroke outcome.Com-pound 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 ac-tivity,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 Ma-cacafascicularis model with tMCAO.Thus,our study identifies compound LFHP-1c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a poten-tially therapeutics for brain ischemic stroke.
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