The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats

Sun, Bo; Chen, Lin; Wei, Xinbing; Xiang, Yuzhi; Liu, Xiaoqian; Zhang, Xiumei

doi:10.1016/j.bbrc.2011.05.095

Cited by 44 publications

(19 citation statements)

References 33 publications

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“…Thus, the ratio of Bcl-2/Bax regulates apoptotic cell death in response to I/R injury. Our results proved that cerebral I/R injury decreased Bcl-2 levels, increased Bax levels, and consequently decreased the Bcl-2/Bax ratio in the penumbra cortex, which was consistent with the previous reports (20,30). We also studied the participation of Bax and Bcl-2 in the neuroprotective effects of 4-MCPC in I/R injury.…”

Section: Discussionsupporting

confidence: 92%

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Neuroprotective Effect of 4-Methylcyclopentadecanone on Focal Cerebral Ischemia/Reperfusion Injury in Rats

Zhang³

et al. 2014

J Pharmacol Sci

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Abstract. The present study aimed to investigate the effect of 4-methylcyclopentadecanone (4-MCPC) on local cerebral ischemia-reperfusion and the possible mechanisms involved. For this purpose, the focal cerebral ischemia rat model was induced by middle cerebral artery occlusion (MCAO) for 2 h, and the rats were treated with 4-MCPC (4 or 8 mg·kg −1 , p.o.) just 0.5 h before reperfusion. The neurological deficit scores and the ischemic infarct volume were recorded 24 h after the MCAO. In addition, the number of apoptotic cells was measured by TUNEL assay, and the expression of apoptosis-regulatory proteins and the PI3K/Akt neuroprotective signaling pathway were investigated by western blotting. Our results indicated that 4-MCPC (4 or 8 mg·kg −1 ) remarkably alleviated cerebral I/R injury by decreasing infarct volume and neurological deficit scores. 4-MCPC also decreased the number of apoptotic cells, regulated the expression of Bcl-2 and Bax, and increased the ratio of Bcl-2/Bax. Further study revealed that 4-MCPC treatment also increased the level of p-Akt and p-GSK-3b. Wortmannin (PI3K inhibitor) markedly abolished the effects of 4-MCPC. Taken together, our results suggest that 4-MCPC protects against cerebral I/R injury through the inhibition of apoptosis, and this neuroprotective effect may be partly related to the activation of the PI3K/Akt signal pathway.

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Section: Discussionsupporting

confidence: 92%

“…Western blotting was performed as described previously (20). Briefly, rats from each group (n = 4) were anesthetized and sacrificed 24 h after reperfusion.…”

Section: Western Blot Analysismentioning

confidence: 99%

Neuroprotective Effect of 4-Methylcyclopentadecanone on Focal Cerebral Ischemia/Reperfusion Injury in Rats

Zhang³

et al. 2014

J Pharmacol Sci

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“…Vascular endothelial growth factor (VEGF), which can promote endothelial cell proliferation and angiogenesis, is important in nerve cell protection (6,7). Moreover, some studies have suggested that PI3K/AkT/GSK3β could affect neuronal death in rat cerebral ischemia models of ischemia reperfusion, but the mechanisms of how to improve the ischemic injury remains unclear (8,14,18). In the present study, we aimed to investigate the therapeutic potential of the VEGF-BMSCs in cerebral ischemia of the rats.…”

Section: █ Introductionmentioning

confidence: 94%

Protective effect of ad-vegf-bone mesenchymal stem cells on cerebral infarction

Chen¹,

Zhang²,

Li³

et al. 2015

Turkish Neurosurgery

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AIM:To understand the mechanism of intracerebroventricular transplantation of vascular endothelial growth factor (VEGF) genemodified bone mesenchymal stem cells (BMSCs) in rats after cerebral infarction. MATERIAl and METhODS:The middle cerebral artery occlusion ischemia/reperfusion (MCAO I/R) model was established in rats using the Zea-Longa suture method. A recombinant adenovirus (Ad-VEGF) was engineered to express VEGF. The rats were divided into 3 groups. Control BMSC infected with control adenovirus (BMSC-Ad), BMSC infected by Ad-VEGF (BMSC-Ad-VEGF), and phosphate buffered saline (PBS) suspension were injected into the intracerebroventricular system of the rats in groups 1, 2 and 3 respectively, 24 hours after middle cerebral artery occlusion (MCAO). The neurological function of rats was evaluated with the modified Neurological Severity Scores (mNSS). The infarct volume of brain in rats was determined using 2,3,5-triphenyltetrazolium chloride (TTC) stain at 14 days. GFAP and pGSK3β expression of ischemic penumbra was determined using immunohistochemical method. GFAP, pAKT, AKT, and pGSK3β expressions were determined with Western blot. RESulTS:Functional improvement was accelerated in animals receiving BMSC-Ad, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with BMSC-Ad-VEGF than for other treated animals. The number of GFAP-labeled cells was prevented by post-ischemic BMSC-Ad-VEGF treatment; pMCAO activate the PI3K/AKT/GSK3β pathway to reduce reactive gliosis.COnCluSIOn: Our findings demonstrate that PI3K/AKT/GSK3β pathway could reduce reactive gliosis, ameliorate neurological deficit, diminish the percentage of cerebral infarction volume in rats, and facilitate angiogenesis.

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“…Thus, β-catenin is important in cell proliferation, embryonic development and tumor formation (20)(21)(22). Akt contains serine/threonine protein kinase and, following phosphorylation, Akt phosphorylates numerous intercellular substrate proteins and regulates their activities (23,24). Therefore, Akt is involved in regulating a number of intercellular signal pathways, promoting cell survival and proliferation, preventing cellular apoptosis and regulating glycometabolism and protein synthesis (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Akt regulates β-catenin in a rat model of focal cerebral ischemia-reperfusion injury

Xue-song

Liu

2014

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the effects of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway on the Wnt/β-catenin signaling pathway in rats with focal cerebral ischemia-reperfusion injury. A total of 96 rat focal cerebral ischemia-reperfusion models, established according to a modified version of Longa's method, were randomly divided into four groups: Sham-operated (S), cerebral ischemia-reperfusion injury (I), cerebral ischemia-reperfusion + basic fibroblast growth factor (bFGF) post-processing and, finally, cerebral ischemia-reperfusion + bFGF post-processing + PI3K inhibitor LY294002 (LY). Each group consisted of 24 rats and each group was divided into four subgroups according to the indicated reperfusion times of 12, 24, 48 and 72 h. The morphological changes of the cortical tissue and the cellular apoptosis were determined using hematoxylin and eosin staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling method, respectively. The expression levels of phosphorylated (p-)Akt, glycogen synthase kinase-3β (GSK-3β) mRNA and β-catenin in the cortical tissue were detected at different time-points. The number of apoptotic cells and the expression levels of p-Akt, GSK-3β mRNA and β-catenin in the I and LY groups were significantly higher compared with those in the S group (P<0.05). In the bFGF group, the number of apoptotic cells and the mRNA expression levels of GSK-3β were significantly decreased, whereas the expression levels of p-Akt and β-catenin were significantly increased compared with those in the I and LY groups (P<0.05). In cerebral ischemia-reperfusion injury, the PI3K/Akt signaling pathway regulated β-catenin, the main member of the Wnt signaling pathway, via GSK-3β, providing information to assist in further investigation of the mechanism of β-catenin in ischemia-reperfusion injury.

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The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats

Cited by 44 publications

References 33 publications

Neuroprotective Effect of 4-Methylcyclopentadecanone on Focal Cerebral Ischemia/Reperfusion Injury in Rats

Neuroprotective Effect of 4-Methylcyclopentadecanone on Focal Cerebral Ischemia/Reperfusion Injury in Rats

Protective effect of ad-vegf-bone mesenchymal stem cells on cerebral infarction

Akt regulates β-catenin in a rat model of focal cerebral ischemia-reperfusion injury

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