Dataset Information

EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway.

ABSTRACT: Stroke remains one of the leading reasons of mortality and physical disability worldwide. The treatment of cerebral ischemic stroke faces challenges, partly due to a lack of effective treatments. In this study, we demonstrated that autophagy was stimulated by transient middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R). Treatment with (-)-epigallocatechin-3-gallate (EGCG), a bioactive ingredient in green tea, was able to mitigate cerebral ischemia/reperfusion injury (CIRI), given the evidence that EGCG administration could reduce the infarct volume and protect poststroke neuronal loss in MCAO/R mice in vivo and attenuate cell loss in OGD/R-challenged HT22 cells in vitro through suppressing autophagy activity. Mechanistically, EGCG inhibited autophagy via modulating the AKT/AMPK/mTOR phosphorylation pathway both in vivo and in vitro models of stroke, which was further confirmed by the results that the administration of GSK690693, an AKT/AMPK inhibitor, and rapamycin, an inhibitor of mTOR, reversed aforementioned changes in autophagy and AKT/AMPK/mTOR signaling pathway. Overall, the application of EGCG relieved CIRI by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway.

SUBMITTER: Wang L

PROVIDER: S-EPMC9489224 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy <i>via</i> the AKT/AMPK/mTOR phosphorylation pathway.

Wang Li L Dai Maosha M Ge Yangyang Y Chen Jiayi J Wang Chenchen C Yao Chengye C Lin Yun Y

Frontiers in pharmacology 20220906

Stroke remains one of the leading reasons of mortality and physical disability worldwide. The treatment of cerebral ischemic stroke faces challenges, partly due to a lack of effective treatments. In this study, we demonstrated that autophagy was stimulated by transient middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R). Treatment with (-)-epigallocatechin-3-gallate (EGCG), a bioactive ingredient in green tea, was able to mitigate cerebral i ...[more]

PMID: 36147330

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Project description:BackgroundIschemia stroke is the leading cause of disability, which is a consequence of vascular occlusion. The purpose of this study is to investigate the effect of cornin which is isolated from the fruit of Verbena officinalis L, against astrocytes autophagy induced by cerebral ischemia/reperfusion (CI/R) injury in vitro and in vivo and its potential mechanism.MethodsCornin at dose of 2.5, 5 and 10 mg/kg were intravenously injected to MCAO rats at 15 min after reperfusion. The infarction volume, blood-brain barrier (BBB), neurological severity score (mNSS), and autophagy related protein were used to evaluated the protective effects and potential mechanism of cornin in autophagy with or without phosphoinositide-3 kinase (PI3K)inhibitor LY294002 and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) at 24 h after CI/R injury. The potential protective effects and mechanism of cornin at concention of 10 ~ 1000 nM were also evaluated in oxygen glucose deprivation/reperfusion (OGD/R) in U87 cells.ResultsThe results suggest that cornin at dose of 5 or 10 mg/kg significantly reduce the cerebral infarction volume and blood-brain barrier (BBB) leakage, and improve neurological recovery in MCAO rats. Cleaved caspase-3 and Bax levels were significantly decreased, while B-cell lymphoma-2 (Bcl-2) and the apoptosis regulator ratio (Bcl-2/Bax) were markedly increased when treated with 2.5-10 mg/kg cornin. The obvious decreased expressions of glial fibrillary acidic protein (GFAP), myosin-like BCL2 interacting protein (Beclin-1) and microtubule-associated protein light chain 3 II (LC3-II) and increased of neuronal nuclei (NeuN), sequestosome-1 (p62), phosphorylated mTOR (p-mTOR), and phosphorylated Akt (p-Akt) were observed in MCAO rats treated with 10 mg/kg cornin, which was counteracted by LY294002. The expression of autophagy-related proteins with or without LY294002 and mTOR siRNA presented the similar results as in vitro in OGD/R in U87 cells.ConclusionsThese results indicate that cornin improved neurological recovery after cerebral ischemia injury by preventing astrocytes autophagy induced by CI/R via the PI3K/Akt/mTOR signaling pathway.

Project description:BackgroundCerebral ischemia-reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated.MethodsWe retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization.ResultsThe baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2-3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood-brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments.ConclusionsAc2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT.

Project description:BackgroundElectroacupuncture (EA) has been shown to promote functional recovery after cerebral ischemia-reperfusion (I/R) injury. However, the contribution of mitochondrial dynamics to recovery remains unclear. The aim of this study was to investigate whether mitochondrial dynamics are involved in the effects of EA on cerebral I/R injury.MethodsThe rats with cerebral I/R injury were established by the middle cerebral artery occlusion/reperfusion. Subsequently, EA was applied to Baihui (GV20) and Dazhui (GV14) acupoints, with 2 Hz/5 Hz in frequency, 1.0 mA in intensity, 20 min each time, once a day for seven consecutive days. The therapeutic outcomes were assessed by modified neurological severity score (mNSS), 2,3,5-Triphenyte-trazolium chloride (TTC) staining, and hematoxylin-eosin (HE) staining. Mitochondrial morphology was observed under transmission electron microscopy. Adenosine triphosphate (ATP) content and ATP synthases (ATPases) activity were evaluated to measure mitochondrial function using ELISA. Finally, mitochondrial dynamics-related molecules, including dynamin-related protein 1 (Drp1), fission 1 (Fis1), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (OPA1), were detected by Western blot and immunofluorescence staining.ResultsCerebral I/R injury induced neurological dysfunction, cerebral infarction and neuronal injury, all of which were ameliorated by EA. And EA improved mitochondrial morphology and function. Moreover, EA altered the balance of mitochondrial dynamics. Specifically, the data showed a significant decrease in the expression of Drp1 and Fis1, leading to the inhibition of mitochondrial fission. Additionally, Mfn1, Mfn2 and Opa1, which are related to mitochondrial fusion, were effectively promoted after EA treatment. However, sham EA did not show any neuroprotective effects in rats with cerebral I/R injury.ConclusionsIn summary, our study indicates that the balance of mitochondrial dynamics is crucial for EA therapy to treat cerebral I/R injury.

Dataset Information

EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway.

Publications

EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy <i>via</i> the AKT/AMPK/mTOR phosphorylation pathway.

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