Sevoflurane Postconditioning Inhibits Autophagy To Alleviate Hypoxic-Ischemic Brain Injury Through Activating ERK/TSC2/mTOR In Neonatal Rats

Objective: Hypoxic-ischemic brain injury(HIBI)in neonates is the significant cause of newborn death.Numerous animal studies have demonstrated autophagy and apoptosis substantially increase and share common mediators in HIBI and sevoflurane postconditioning(SPC)can attenuate HIBI by inhibiting apoptosis.However,the specific relationship between autophagy and apoptosis and whether autophagy participates in SPC-induced neuroprotection remains elusive.The primary objectives of this study were to(1)clarify the relationship between autophagy and apoptosis in HIBI.(2)explore the underlying mechanism of cerebral protection induced by SPC-HIBI.Methods:(1)Rats at postnatal day 7(P7)were subjected to ligate left common carotid artery,followed by 2h hypoxia.Rats were assigned to Sham,HIBI,HIBI + autophagic agonist,HIBI + autophagic inhibitor,HIBI + apoptotic inhibitor.Then,markers of autophagy and apoptosis were measured in brains at the 24 th hour.(2)Rats at postnatal day 7(P7)were subjected to ligate left common carotid artery,followed by 2h hypoxia.SPC was performed with 1MAC(2.4%)30min after HIBI.Rats were assigned to Sham,HIBI,SPC-HIBI,SPC-HIBI + rapamycin,HIBI + p-ERK inhibitor,SPC-HIBI + p-ERK inhibitor.Then,markers of autophagy and expression of ERK cascade components were measured in brains at the 24 th hour and spatial learning and memory function were examined after administration of an autophagy agonist or a p-ERK inhibitor.Results:(1)Compared with HIBI group,Rapamycin,an autophagic agonist,significantly enhanced the activation of autophagy and apoptosis in HIBI;3-methyladenine(3-MA),an autophagic inhibitor,significantly attenuated the activation of autophagy and apoptosis in HIBI;Quinoline-val-asp(OMe)-Ch2-O-phenoxy(Q-VDOPH),an apoptotic inhibitor,significantly attenuated the activation of apoptosis,but had no effect on the activation of autophagy in HIBI.(2)Compared with HIBI group,SPCHIBI significantly attenuated the activation of autophagy and enhanced ERK cascade.SCH772984,an inhibitor of p-ERK,which reduced the increased expression of ERK cascade in SPC-HIBI group and rapamycin,an agonist of autophagy,significantly attenuated the decreased expression of autophagy,decreased cross platform times,and increased escape latency in SPC-HIBI.Conclusions: Our results demonstrated that(1)autophagy overactivation involved in hypoxic-ischemic brain injury triggers apoptosis in P7 rats.(2)30min 2.4% SPC-HIBI at P7 inhibited excessive autophagy through activating ERK cascade.