Gao Chenglong, Xu Yazhou, Liang Zhuangzhuang, Wang Yunjie, Shang Qinghong, Zhang Shengbin, Wang Cunfang, Ni Mingmin, Wu Dalei, Huang Zhangjian, Pang Tao
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.
Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
Acta Pharm Sin B. 2021 Jul;11(7):1867-1884. doi: 10.1016/j.apsb.2021.01.008. Epub 2021 Jan 7.
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 model with tMCAO. Thus, our study identifies compound LFHP-1c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption and , and provides a potentially therapeutics for brain ischemic stroke.
缺血后血脑屏障（BBB）损伤对中风预后有显著影响。化合物LFHP-1c先前在中风模型中被发现具有神经保护作用，但其对中风后血脑屏障破坏的保护作用机制仍不清楚。在此，我们表明，LFHP-1c作为一种直接的PGAM5抑制剂，可预防大鼠短暂性大脑中动脉闭塞（tMCAO）后血脑屏障的破坏。从机制上讲，LFHP-1c与内皮细胞PGAM5结合不仅抑制了PGAM5磷酸酶活性，还减少了PGAM5与NRF2的相互作用，这促进了NRF2的核转位，以防止缺血导致的血脑屏障破坏。此外，在非人灵长类tMCAO模型中，通过靶向PGAM5给予LFHP-1c显示出梗死体积、脑水肿和神经功能缺损减少的趋势。因此，我们的研究确定化合物LFHP-1c是首个显示出改善缺血诱导的血脑屏障破坏作用的直接PGAM5抑制剂，并为脑缺血性中风提供了一种潜在的治疗方法。
