Abstract
Post-conditioning with sevoflurane, a volatile anesthetic, has been proved to be neuroprotective against hypoxic-ischemic brain injury (HIBI). Our previous research showed that autophagy is over-activated in a rat model of neonatal HIBI, and inhibition of autophagy confers neuroprotection. There is increasing recognition that autophagy can be triggered by activating endoplasmic reticulum (ER) stress. This study aimed to explore: i) the relationship between ER stress and autophagy in the setting of neonatal HIBI; and ii) the possible roles of ER stress-mediated autophagy and IRE1 signalings in the neuroprotection of sevoflurane post-conditioning against neonatal HIBI. Seven-day-old rats underwent left common artery ligation followed by 2 h hypoxia (8% O2 / 92% N2). The relationship between ER stress and autophagy was examined by ER stress inducer (tunicamycin), ER stress inhibitor (4-PBA), or autophagy inhibitor (3-MA). Rats in the sevoflurane post-conditioning groups were treated with 2.4% sevoflurane for 30 min after HIBI induction. The roles of ER stress-mediated autophagy and the IRE1/JNK/beclin1 signaling pathway in the neuroprotection afforded by sevoflurane were examined by ER stress inducer (tunicamycin) and the IRE1 inhibitor (STF-083010). HIBI over‑activated ER stress and autophagy in neonatal rats. HIBI-induced autophagy was significantly aggravated by tunicamycin but blocked by 4-PBA; however, HIBI-induced ER stress was not affected by 3-MA. Sevoflurane post-conditioning significantly alleviated ER stress, autophagy, cell apoptosis, and cognitive impairments, which were remarkably abolished by tunicamycin. Also, tunicamycin blocked sevoflurane-induced downregulation of IRE1/JNK/beclin1 signaling pathway. Whereas, IRE1 inhibitor could reverse the effects of tunicamycin. ER stress contributes to autophagy induced by HIBI. Furthermore, sevoflurane post-conditioning significantly protects against HIBI in neonatal rats by inhibiting ER stress-mediated autophagy via IRE1/JNK/beclin1 signaling pathway.
Progesterone alleviates hypoxic-ischemic brain injury via the Akt/GSK-3β signaling pathway
