<scp>AKT</scp>/<scp>GSK</scp>3β‐Dependent Autophagy Contributes to the Neuroprotection of Limb Remote Ischemic Postconditioning in the Transient Cerebral Ischemic Rat Model

Qi, Zhifeng; Luo, Yumin; Liu, Xiangrong; Wang, Rong‐Liang; Zhao, Haiping; Yan, Feng; Song, Zhao-Jing; Luo, Mei; Ji, Xunming

doi:10.1111/cns.12016

Cited by 72 publications

(61 citation statements)

References 35 publications

(51 reference statements)

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“…For the middle cerebral artery occlusion (MCAO) model, ischemia and reperfusion (I/R) was established as described previously [6]. MCA occlusion was conducted by a nylon suture with a diameter of 0.38 mm and maintained in position for 2 h. Successful MCAO was confirmed by laser Doppler flowmetry (PeriFlux System 5000, Perimed, Stockholm, Sweden).…”

Section: Mcao Modelmentioning

confidence: 99%

“…After MCAO onset, RIC was performed by bilateral clamping of the femoral artery in three cycles of 10-min occlusion/10-min release, as described in our previous study [6]. All rats were subjected to 2 h of MCAO followed by 22 h of reperfusion (I/R).…”

Section: Ric Treatment and Experimental Designmentioning

confidence: 99%

“…Twenty-four rats were divided into six groups: DMSO+I/R, AKTi+ I/R, DMSO+I-30, AKTi+I-30, DMSO+R-0, and AKTi+R-0, with four animals in each group. LY294002 (15 μM in 10 μl, Sigma, St. Louis, MO, USA) or DMSO (vehicle control) was microinjected into the lateral ventricle 30 min prior to MCAO surgery [6]. The stereotaxic coordinates for injection were bregma posterior (P) −1 mm, lateral (L) ±1.5 mm, and ventral (V) −4.0 mm from the dura, with the tooth bar set at 0 mm.…”

Section: Ric Treatment and Experimental Designmentioning

confidence: 99%

“…A number of studies have been shown that RIC during ischemia or post reperfusion plays a protective role in animal models of stroke [4][5][6][7]. Furthermore, a recent clinical study showed that prehospital RIC therapy after stroke confers protective effects on reducing the risk of tissue infarction, based on voxelwise analysis for baseline perfusion and diffusion lesion severity [8].…”

Section: Introductionmentioning

confidence: 99%

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Bcl-2 Phosphorylation Triggers Autophagy Switch and Reduces Mitochondrial Damage in Limb Remote Ischemic Conditioned Rats After Ischemic Stroke

Dong

Shi

et al. 2015

Transl. Stroke Res.

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Autophagy, an important intracellular degradation pathway, has been reported to clear impaired mitochondria and reduce mitochondria-mediated injury in ischemic disease. Our study and other recent investigations have shown that AKT-dependent autophagy contributes to the neuroprotection afforded by limb remote ischemic conditioning (RIC) in experimental stroke. However, how AKT triggers RIC-based autophagy and whether RIC-afforded autophagy is beneficial for mitochondrial function after cerebral ischemia remains unclear. The disruption of the Bcl-2/Beclin1 complex has been reported to trigger autophagy formation in the condition of Bcl-2 phosphorylation at Ser70. We investigated whether Bcl-2 phosphorylation triggers RIC-based autophagy and thereby confers RIC-induced neuroprotection against mitochondrial injury, using a transient cerebral ischemic rat model. We demonstrated that rats undergoing RIC treatment 30 min after the onset of ischemia (I-30) and at reperfusion (R-0) significantly upregulated Bcl-2 phosphorylation. Immunoprecipitation revealed that RIC increased dissociation of the Bcl-2/Beclin1 complex, leading to a higher level of autophagy than in ischemia/reperfusion rats. Furthermore, AKT activation was shown to play a critical role in regulating Bcl-2-mediated autophagy, as an AKT inhibitor (LY294002, AKTi) administered 30 min prior to ischemia significantly suppressed Bcl-2 phosphorylation and Bcl-2/Beclin1 complex dissociation, thereby reducing autophagy in RIC rats. Blocking Bcl-2 phosphorylation-dependent autophagy with AKTi suppressed RIC-afforded protection on mitochondrial potential and mitochondrial-dependent cell death effector pathway. These findings indicate that Bcl-2 phosphorylation and thereby Bcl-2/Beclin1 complex disruption play a crucial role in triggering autophagy and reducing mitochondrial damage in RIC rats after cerebral ischemia and require the involvement of the AKT activation.

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Section: Mcao Modelmentioning

confidence: 99%

Section: Ric Treatment and Experimental Designmentioning

confidence: 99%

Section: Ric Treatment and Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bcl-2 Phosphorylation Triggers Autophagy Switch and Reduces Mitochondrial Damage in Limb Remote Ischemic Conditioned Rats After Ischemic Stroke

Dong

Shi

et al. 2015

Transl. Stroke Res.

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“…Autophagy was also reported to be involved in cerebral ischemia [13,14], but the role of autophagy in neuroprotection was still controversial. Some reports have indicated that autophagy activation offer neuroprotective effects by IPC [15,16] and RIPost [17] treatment. However, Gao et al [18] reported that inhibition of autophagy could induce neuroprotection in ischemic postconditioning treatment.…”

Section: Introductionmentioning

confidence: 99%

Autophagy Activation Contributes to the Neuroprotection of Remote Ischemic Perconditioning Against Focal Cerebral Ischemia in Rats

Zhang

Wang

et al. 2014

Neurochem Res

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Remote ischemic perconditioning (RIPer) has been proved to provide potent cardioprotection. However, there are few studies on neuroprotection of RIPer. This study aims to clarify the neuroprotective effect of RIPer and the role of autophagy induced by RIPer against cerebral ischemia reperfusion injury in rats. Using a transient middle cerebral artery occlusion (MCAO) model in rats to imitate focal cerebral ischemia. RIPer was carried out 4 cycles of 10 min ischemia and 10 min reperfusion, with a thin elastic band tourniquet encircled on the bilateral femoral arteries at the start of 10 min after MCAO. Autophagy inhibitor 3-methyladenine (3-MA) and autophagy inducer rapamycin were administered respectively to determine the contribution of autophagy in RIPer. Neurologic deficit scores, infarct volume, brain edema, Nissl staining, TUNEL assay, immunohistochemistry and western blot was performed to analyze the neuroprotection of RIPer and the contribution of autophagy in RIPer. RIPer significantly exerted neuroprotective effects against cerebral ischemia reperfusion injury in rats, and the autophagy-lysosome pathway was activated by RIPer treatment. 3-MA reversed the neuroprotective effects induced by RIPer, whereas rapamycin ameliorated the brain ischemic injury. Autophagy activation contributes to the neuroprotection by RIPer against focal cerebral ischemia in rats.

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The regulation of GSK‐3β in nervous system

Tan¹,

Chen²,

Zhu³

2017

Ibrain

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Glycogen synthase kinase‐3β (GSK‐3β) is a multifunctional serine‐threonine kinase, which is expressesed in all eukaryotic cells. Many diseases, such as metabolic diseases, cancer, digestive diseases and lung diseases, have been confirmed to be associated with the changes of expression level of GSK‐3β. At present, studies have found that it is also involved in the development of nervous system diseases such as traumatic brain injury, Alzheimer's psychosis, etc. This article summarizes the regulatory mechanism of GSK‐3β in the development of nerve diseases and intends to clarify the mechanisms of nervous system disease to guide its application in future clinic trial.

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AKT/GSK3β‐Dependent Autophagy Contributes to the Neuroprotection of Limb Remote Ischemic Postconditioning in the Transient Cerebral Ischemic Rat Model

Abstract: These results aid optimization of the time window for RIPostC use and offer novel insight into, and a better understanding of, the protective mechanism of autophagy in limb RIPostC.

Cited by 72 publications

References 35 publications

Bcl-2 Phosphorylation Triggers Autophagy Switch and Reduces Mitochondrial Damage in Limb Remote Ischemic Conditioned Rats After Ischemic Stroke

Bcl-2 Phosphorylation Triggers Autophagy Switch and Reduces Mitochondrial Damage in Limb Remote Ischemic Conditioned Rats After Ischemic Stroke

Autophagy Activation Contributes to the Neuroprotection of Remote Ischemic Perconditioning Against Focal Cerebral Ischemia in Rats

The regulation of GSK‐3β in nervous system

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