Background:
When neonatal rats suffer hypoxic-ischemic brain injury (HIBI), autophagy is over-activated in the hippocampus, and inhibition of autophagy provides neuroprotection. The aim of this study was to investigate the possible roles of autophagy and Ezh2-regulated Pten/Akt/mTOR pathway in sevoflurane post-conditioning (SPC)-mediated neuroprotection against HIBI in neonatal rats.
Methods:
Seven-day-old Sprague–Dawley rats underwent left common artery ligation followed by 2 h hypoxia as described in the Rice–Vannucci model. The roles of autophagy and the Ezh2-regulated Pten/Akt/mTOR signaling pathway in the neuroprotection conferred by SPC were examined by left-side intracerebroventricular injection with the autophagy activator rapamycin and the Ezh2 inhibitor GSK126.
Results:
SPC was neuroprotective against HIBI through the inhibition of over-activated autophagy in the hippocampus as characterized by the rapamycin-induced reversal of neuronal density, neuronal morphology, cerebral morphology, and the expression of the autophagy markers, LC3B-II and Beclin1. SPC significantly increased the expression of Ezh2, H3K27me3, pAkt, and mTOR and decreased the expression of Pten induced by HI. The Ezh2 inhibitor, GSK126, significantly reversed the SPC-induced changes in expression of H3K27me3, Pten, pAkt, mTOR, LC3B-II, and Beclin1. Ezh2 inhibition also reversed SPC-mediated attenuation of neuronal loss and behavioral improvement in the Morris water maze.
Conclusion:
These results indicate that SPC inhibits excessive autophagy via the regulation of Pten/Akt/mTOR signaling by Ezh2 to confer neuroprotection against HIBI in neonatal rats.
Neonatal hypoxic-ischemic (HI) brain injury is associated with long-term neurological disorders, and protective strategies are presently scarce. Sodium 4-phenylbutyrate (4-PBA) reportedly acts as a chemical chaperone that alleviates endoplasmic reticulum (ER) stress, which plays a critical role in neurological diseases. The present study aimed to evaluate the neuroprotective effects of 4-PBA on HI-induced neonatal brain injury in a rat model, and to characterize possible underlying mechanisms. The HI brain injury model was established by ligating the left common carotid artery in 7-day-old rats, followed by exposure to 8% oxygen for 2 h. The 4-PBA or vehicle was administered by an intracerebroventricular injection 30 min before HI. The protein expression levels of ER stress markers (GRP78, ATF6, and CHOP) were detected by western blotting at 24 h after HI insult. The activation of cAMP-response element-binding protein (CREB) was evaluated by western blotting and immunofluorescence. TUNEL and Nissl staining were performed to detect the histomorphological changes in the hippocampal neurons at 24 h and 7 days, respectively, after HI injury. From days 29 to 34 after brain HI, rats underwent Morris water maze tests to assess cognitive functioning. The results showed that pretreatment with 4-PBA decreased HI-induced excessive ER stress and neuronal injury. Moreover, CREB activation might be involved in the beneficial effects of 4-PBA on HI-induced learning and memory deficits in rats. In conclusion, the present study suggested a potential therapeutic approach of ER stress inhibition in the treatment of neonatal HI brain injury.
Post-conditioning with sevo urane, 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 sevo urane 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 sevo urane post-conditioning groups were treated with 2.4% sevo urane 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 sevo urane 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 signi cantly aggravated by tunicamycin but blocked by 4-PBA; however, HIBI-induced ER stress was not affected by 3-MA. Sevo urane post-conditioning signi cantly alleviated ER stress, autophagy, cell apoptosis, and cognitive impairments, which were remarkably abolished by tunicamycin. Also, tunicamycin blocked sevo urane-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, sevo urane post-conditioning signi cantly protects against HIBI in neonatal rats by inhibiting ER stress-mediated autophagy via IRE1/JNK/beclin1 signaling pathway.
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