Abstract：
Cerebral ischemia-reperfusion injury (CIRI) can induce massive death of ischemic penumbra neurons via oxygen burst, exacerbating brain damage. Parthanatos is a form of caspase-independent cell death involving excessive activation of PARP-1, closely associated with intense oxidative stress following CIRI. 4\'-O-methylbavachalcone (MeBavaC), an isoprenylated chalcone component in Fructus Psoraleae, has potential neuroprotective effects. This study primarily investigates whether MeBavaC can act on SIRT3 to alleviate parthanatos of ischemic penumbra neurons induced by CIRI. MeBavaC was oral gavaged to the middle cerebral artery occlusion-reperfusion (MCAO/R) rats after occlusion. The effects of MeBavaC on cerebral injury were detected by the neurological deficit score and cerebral infarct volume. In vitro, PC-12 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R), and assessed cell viability and cell injury. Also, the levels of ROS, mitochondrial membrane potential (MMP), and intracellular Ca2+ levels were detected to reflect mitochondrial function. We conducted western blotting analyses of proteins involved in parthanatos and related signaling pathways. Finally, the exact mechanism between the neuroprotection of MeBavaC and parthanatos was explored. Our results indicate that MeBavaC reduces the cerebral infarct volume and neurological deficit scores in MCAO/R rats, and inhibits the decreased viability of PC-12 cells induced by OGD/R. MeBavaC also downregulates the expression of parthanatos-related death proteins PARP-1, PAR, and AIF. However, this inhibitory effect is weakened after the use of a SIRT3 inhibitor. In conclusion, the protective effect of MeBavaC against CIRI may be achieved by inhibiting parthanatos of ischemic penumbra neurons through the SIRT3-PARP-1 axis.
摘要：
脑缺血再灌注损伤(CIRI)可通过氧爆发诱导缺血半暗带神经元大量死亡,加重脑损伤.Parthanatos是一种不依赖caspase的细胞死亡，涉及PARP-1的过度激活，与CIRI后的强烈氧化应激密切相关。4'-O-甲基巴瓦卡酮（MeBavaC），补骨脂中的一种异戊二烯化查尔酮成分，具有潜在的神经保护作用。这项研究主要调查MeBavaC是否可以作用于SIRT3以减轻CIRI诱导的缺血半暗带神经元的parthanatos。闭塞后，将MeBavaC口服给大脑中动脉闭塞再灌注（MCAO/R）大鼠。通过神经功能缺损评分和脑梗死体积检测MeBavaC对脑损伤的影响。体外，PC-12细胞进行氧和葡萄糖剥夺/复氧（OGD/R），并评估细胞活力和细胞损伤。此外，ROS的水平，线粒体膜电位（MMP），检测细胞内Ca2+水平以反映线粒体功能。我们对参与parthanatos和相关信号通路的蛋白质进行了蛋白质印迹分析。最后,探讨了MeBavaC和parthanatos的神经保护之间的确切机制。我们的结果表明，MeBavaC降低了MCAO/R大鼠的脑梗死体积和神经功能缺损评分，并抑制OGD/R诱导的PC-12细胞活力下降。MeBavaC还下调parthanatos相关死亡蛋白PARP-1，PAR，AIF。然而,使用SIRT3抑制剂后，这种抑制作用减弱。总之,MeBavaC对CIRI的保护作用可能是通过SIRT3-PARP-1轴抑制缺血半暗带神经元的parthanatos来实现的。
