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Tetramethylpyrazine Analogue CXC195 Ameliorates Cerebral Ischemia–reperfusion Injury by Regulating Endothelial Nitric Oxide Synthase Phosphorylation Via PI3K/Akt Signaling

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Abstract

A novel tetramethylpyrazine derivative, CXC195, has been recently shown to protect against cerebral ischemia–reperfusion (I/R) injury. However, the detailed mechanisms underlying the neuroprotection of CXC195 are still unclear. The aim of the present study was to investigate the effects of CXC195 on the phosphorylation of endothelial nitric oxide synthase (eNOS) in response to cerebral I/R and to determine whether phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway might be involved. An in vitro model of oxygen glucose deprivation (OGD) which was performed on primary cultured human aortic endothelial cells (HAECs) and an in vivo middle cerebral artery occlusion (MCAO) model that was performed on Wistar rats were used in this study. CXC195 increased nitric oxide (NO) production and the phosphorylation but not the protein level of eNOS in HAECs subjected to 1 h OGD followed by reperfusion. In addition, CXC195 increased the phosphorylation of Akt; inhibition of PI3K/Akt pathway by a specific inhibitor, wortmannin, suppressed CXC195-induced NO release in HAECs. Consistently, CXC195 treatment significantly restored the phosphorylations of eNOS and Akt in the cortical penumbra of rats subjected to 2 h MCAO followed by reperfusion. Moreover, wortmannin abolished CXC195-induced eNOS phosphorylation and neuroprotection as evidenced by a reversal of the reduction in infarct volume and neurobehavioral outcomes. In conclusion, CXC195 induced phosphorylation of eNOS by activation of PI3K/Akt signaling under pathological cerebral I/R conditions, which provided a novel explanation for the neuroprotective effect of CXC195.

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Acknowledgments

This work was financially supported by National Natural Science Foundation of China (No. 81200904, No. 81100874) and Shandong Province Science and Technology Plan (No. 2014GSF118003).

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Wenhua West Road 107#, Jinan, 250012, Shandong, People’s Republic of China

    Shi Yan

  2. Department of Pharmacology, School of Medicine, Shandong University, Wenhua West Road 44#, Jinan, 250012, Shandong, People’s Republic of China

    Lin Chen, Xinbing Wei, Li Cheng, Lingjun Kong, Xiumei Zhang & Huiqing Liu

  3. School of Pharmaceutical Sciences, Shandong University, Wenhua West Road 44#, Jinan, 250012, Shandong, People’s Republic of China

    Xinyong Liu

  4. Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Qingquan Road 30#, Yantai, 264005, Shandong, People’s Republic of China

    Huiqing Liu

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  1. Shi Yan
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  2. Lin Chen
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  3. Xinbing Wei
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Correspondence to Huiqing Liu.

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Yan, S., Chen, L., Wei, X. et al. Tetramethylpyrazine Analogue CXC195 Ameliorates Cerebral Ischemia–reperfusion Injury by Regulating Endothelial Nitric Oxide Synthase Phosphorylation Via PI3K/Akt Signaling. Neurochem Res 40, 446–454 (2015). https://doi.org/10.1007/s11064-014-1485-x

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  • DOI: https://doi.org/10.1007/s11064-014-1485-x

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