Isoginkgetin attenuates endoplasmic reticulum stress-induced autophagy of brain after ischemic reperfusion injury

Isoginkgetin is characterized by properties of potent anticancer and anti-inflammation. To explore its effect on ischemic stroke, a rat model of ischemia/reperfusion (I/R) injury was established and induced by transient middle cerebral artery occlusion/reperfusion (MCAO/R). Different doses of isoginkgetin were intraperitoneally injected into each rat. Expressions of ER stress activation related makers including phosphorylated inositol-requiring enzyme 1 (IRE1), phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), activating transcription factor-6 (ATF6), and two autophagy markers (ratio of LC3II/I and Beclin-1) were detected by western blot. Infarct volume, neurological deficits, and brain water content were detected. The results showed that ER stress and autophagy were activated by cerebral (I/R) injury, which could be effectively attenuated following pre-ischemia isoginkgetin administration. Moreover, autophagy induced by ER stress was triggered by the activation of PERK and IRE1 pathways. ER stress inhibitor (4-PBA) and ER-related signaling inhibitors including PERK, GSK, IRE1, and DBSA markedly inhibited ER stress and autophagy induced by I/R. In addition, isoginkgetin markedly mitigated cerebral infarction, edema, neuronal apoptosis as well as neurological impairment induced by I/R injury, while tunicamycin (ER stress activator TM) and rapamycin (autophagy activator RAPA) could eliminate these lesions. This research identified a novel therapeutic agent isoginkgetin, which could effectively attenuate I/R injury by blocking autophagy induced by ER stress.

Automated summary

Isoginkgetin effectively attenuates ischemia/reperfusion injury by blocking autophagy induced by endoplasmic reticulum stress. It also mitigates cerebral infarction, edema, neuronal apoptosis, and neurological impairment.