Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c was previously discovered with neuroprotective role in stroke model,but its mechanism of action on protection of ...Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c 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-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in rats.Mechanistically,LFHP-1 c 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-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t MCAO.Thus,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.展开更多
基金supported by the National Natural Science Foundation of China(81973512,81822041,21977116,and 81673305)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(No.2018ZX09711002006-013,China)+7 种基金Science&Technology Major Project of Zhongshan City(No.2019A4020,China)Double First-Class Project of China Pharmaceutical University(CPU2018GY06,CPU2018GY18,and CPU2018GY20,China)the Open Project of State Key Laboratory of Natural Medicines(SKLNMZZCX 201824 and SKLNMZZ202029,China)the Open Project Program of the State Key Laboratory of Drug Research(SIMM2004KF-08,China)the Open Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University(Traditional Chinese Pharmacology,China)Zhejiang Chinese Medical University(No.ZYAOX2018001,China)State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(SKL-HIDCA-2018-1,China)supported by the Six Talent Peaks Project of Jiangsu Province to Tao Pang
文摘Bloodebrain barrier(BBB)damage after ischemia significantly influences stroke outcome.Compound LFHP-1 c 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-1 c,as a direct PGAM5 inhibitor,prevented BBB disruption after transient middle cerebral artery occlusion(tMCAO)in rats.Mechanistically,LFHP-1 c 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-1 c administration by targeting PGAM5 shows a trend toward reduced infarct volume,brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with t MCAO.Thus,our study identifies compound LFHP-1 c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo,and provides a potentially therapeutics for brain ischemic stroke.
