Inhibition of Autophagy Contributes to Ischemic Postconditioning-Induced Neuroprotection against Focal Cerebral Ischemia in Rats

Abstract

BackgroundIschemic postconditioning (IPOC), or relief of ischemia in a stuttered manner, has emerged as an innovative treatment strategy to reduce programmed cell death, attenuate ischemic injuries, and improve neurological outcomes. However, the mechanisms involved have not been completely elucidated. Recent studies indicate that autophagy is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. This study aims to determine the role of autophagy in IPOC-induced neuroprotection against focal cerebral ischemia in rats.Methodology/Principal FindingsA focal cerebral ischemic model with permanent middle cerebral artery (MCA) occlusion plus transient common carotid artery (CCA) occlusion was established. The autophagosomes and the expressions of LC3/Beclin 1/p62 were evaluated for their contribution to the activation of autophagy. We found that autophagy was markedly induced with the upregulation of LC3/Beclin 1 and downregulation of p62 in the penumbra at various time intervals following ischemia. IPOC, performed at the onset of reperfusion, reduced infarct size, mitigated brain edema, inhibited the induction of LC3/Beclin 1 and reversed the reduction of p62 simultaneously. Rapamycin, an inducer of autophagy, partially reversed all the aforementioned effects induced by IPOC. Conversely, autophagy inhibitor 3-methyladenine (3-MA) attenuated the ischemic insults, inhibited the activation of autophagy, and elevated the expression of anti-apoptotic protein Bcl-2, to an extent comparable to IPOC.Conclusions/SignificanceThe present study suggests that inhibition of the autophagic pathway plays a key role in IPOC-induced neuroprotection against focal cerebral ischemia. Thus, pharmacological inhibition of autophagy may provide a novel therapeutic strategy for the treatment of stroke.

Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome

“…39 Using a rat stroke mode, a significant decrease of p62, indication of autophagy activation, was not observed until 6 h reperfusion. 30 In contrast, in our ATF6-KI mice, we showed that activation of the ATF6 UPR branch significantly reduces the protein levels of p62 in the post-ischemic brain at 1 h reperfusion, suggesting earlier onset of increased autophagic activity ( Figure 5(c)). This activation of autophagy was likely mediated through decreased levels of phosphorylated mTOR, a key inhibitory regulator of autophagy.…”

“…In agreement with a previous report, we found a significant decrease of p62 in the ipsilateral cortex of both wild-type and ATF6-KI mice ( Figure 5(c)). 30 Levels of p-mTOR continued to be significantly lower in ATF6-KI mice after stroke ( Figure 5(c)). Although a similar trend of decreased p-mTOR levels after stroke appeared in wild-type mice, differences did not reach statistical significance at both reperfusion times.…”

Ischemic Postconditioning Relieves Cerebral Ischemia and Reperfusion Injury Through Activating T-LAK Cell–Originated Protein Kinase/Protein Kinase B Pathway in Rats

“…To date, the neuroprotective mechanism underlying IPostC has been investigated widely and has been found to be related to the suppression of oxidative stress, 18 endoplasmic stress, 19 cell apoptosis and autophagy, 20 and the inflammatory response. 21 Among them, oxidative stress is a major cause of necrotic and apoptotic cell death after I/R, 22 and IPostC was reported to reduce protein oxidization by increasing the levels of antioxidants including SOD and catalase.…”

Shengmai injection attenuates the cerebral ischemia/reperfusion induced autophagy via modulation of the AMPK, mTOR and JNK pathways

“…Recent studies have shown that autophagy is involved in the neural death pathway that follows cerebral ischemia, and scientists have already monitored autophagic processes in vivo in live stroke patients (Tian et al 2010). The role of autophagy in ischemic stroke is still debated: it has both protective and detrimental effects (Sheng et al 2010;Yan et al 2011;Gao et al 2012). It has been reported that Ginsenoside Rb1, one of major compounds in SMI, could alleviate ischemia/reperfusion insults in rats and that an autophagic mechanism was involved in the benefits ); these findings indicated that SMI might have a similar mechanism against ischemic stroke.…”