State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China.
Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Exp Brain Res. 2022 Dec;240(12):3167-3182. doi: 10.1007/s00221-022-06474-9. Epub 2022 Oct 18.
In recent years, more attention has been given to novel patterns of cell death observed during ischemia/reperfusion (I/R). Necroptosis is a regulable secondary cell death pathway; necroptosis is different from traditional forms of cell death, and it is regulated by the RIPK1-RIPK3-MLKL signaling pathway. JLX001 is the double hydrochloride of the natural compound cyclovirobuxine D (CVB-D). Previous studies have confirmed that CVB-D exerts a significant effect on cardiovascular and cerebrovascular diseases and that JLX001 can reduce ischemic brain injury by inhibiting cell apoptosis. For the first time, this project explored the in vivo and in vitro inhibitory effects of the therapeutic administration of JLX001 on the neuronal necroptosis caused by cerebral ischemia-reperfusion injury (CIRI). The middle cerebral artery occlusion reperfusion (MCAO/R) model was used to simulate I/R injury in rats in vivo, and oxygen-glucose deprivation and reperfusion (OGD/R) was used to simulate I/R injury in vitro. After the administration of JLX001, the relative expression of necroptosis-related molecules was measured by ELISA, RT-PCR, HE staining, immunofluorescence and Western blotting. The results showed that JLX001 significantly reduced pathological damage and the cerebral infarction rate in rat brain tissues, and the expression of neuronal necroptosis-related molecules was reduced, suggesting that JLX001 may regulate CIRI through the classic RIPK1-RIPK3-MLKL necroptosis pathway.
近年来，人们越来越关注在缺血/再灌注（I/R）过程中观察到的新型细胞死亡模式。坏死性凋亡是一种可调节的细胞死亡途径；坏死性凋亡不同于传统的细胞死亡形式，它受 RIPK1-RIPK3-MLKL 信号通路的调节。JLX001 是天然化合物环维黄杨星 D（CVB-D）的双盐酸盐。先前的研究已经证实，CVB-D 对心血管和脑血管疾病有显著作用，而 JLX001 可以通过抑制细胞凋亡来减少缺血性脑损伤。该项目首次探讨了 JLX001 的治疗给药对脑缺血再灌注损伤（CIRI）引起的神经元坏死性凋亡的体内和体外抑制作用。采用大脑中动脉闭塞再灌注（MCAO/R）模型模拟体内 I/R 损伤，采用氧葡萄糖剥夺和再灌注（OGD/R）模拟体外 I/R 损伤。在给予 JLX001 后，通过 ELISA、RT-PCR、HE 染色、免疫荧光和 Western blot 测量与坏死性凋亡相关的分子的相对表达。结果表明，JLX001 显著减轻了大鼠脑组织的病理损伤和脑梗死率，同时降低了神经元坏死性凋亡相关分子的表达，提示 JLX001 可能通过经典的 RIPK1-RIPK3-MLKL 坏死性凋亡途径来调节 CIRI。
