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Atorvastatin Attenuates Ischemia/Reperfusion-Induced Hippocampal Neurons Injury Via Akt-nNOS-JNK Signaling Pathway

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Abstract

Ischemia-induced brain damage leads to apoptosis like delayed neuronal death in selectively vulnerable regions, which could further result in irreversible damages. Previous studies have demonstrated that neurons in the CA1 area of hippocampus are particularly sensitive to ischemic damage. Atorvastatin (ATV) has been reported to attenuate cognitive deficits after stroke, but precise mechanism for neuroprotection remains unknown. Therefore, the aims of this study were to investigate the neuroprotective mechanisms of ATV against ischemic brain injury induced by cerebral ischemia reperfusion. In this study, four-vessel occlusion model was established in rats with cerebral ischemia. Rats were divided into five groups: sham group, I/R group, I/R+ATV group, I/R+ATV+LY, and I/R+SP600125 group. Cresyl violet staining was carried out to examine the neuronal death of hippocampal CA1 region. Immunoblotting was used to detect the expression of the related proteins. Results showed that ATV significantly protected hippocampal CA1 pyramidal neurons against cerebral I/R. ATV could increase the phosphorylation of protein kinase B (Akt1) and nNOS, diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3. Whereas, all of the aforementioned effects of ATV were reversed by LY294002 (an inhibitor of Akt1). Furthermore, pretreatment with SP600125 (an inhibitor of JNK) diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3 after cerebral I/R. Taken together, our results implied that Akt-mediated phosphorylation of nNOS is involved in the neuroprotection of ATV against ischemic brain injury via suppressing JNK3 signaling pathway that provide a new experimental foundation for stroke therapy.

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Acknowledgments

This work was supported by Jiangsu Province Key Laboratory of Brain Disease Bioinformation (JSBL1505), Jiangsu Province Key Laboratory of Anesthesiology (KJS1502), and the National Natural Science Foundation of China (81271296).

Author Contributions

S.S. designed the study. M.X., J.Z., X.G., G.C., L.G., L.L., and K.L. performed the experiments and collected the data. S.S. and Z.Z. analyzed and interpreted the experimental data. S.S., M.X., and J.Z. prepared the manuscript.

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Authors and Affiliations

  1. The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310023, People’s Republic of China

    Sen Shao, Jiajun Zhou, Xiaoling Ge, Guanfeng Chen, Lili Guo, Lian Luo, Kun Li & Zhou Zhu

  2. The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, 310058, People’s Republic of China

    Mingwei Xu

  3. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China

    Sen Shao

  4. Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China

    Sen Shao

  5. Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University, Shanghai, 200040, People’s Republic of China

    Fayong Zhang

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  1. Sen Shao
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  2. Mingwei Xu
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Correspondence to Sen Shao or Fayong Zhang.

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Shao, S., Xu, M., Zhou, J. et al. Atorvastatin Attenuates Ischemia/Reperfusion-Induced Hippocampal Neurons Injury Via Akt-nNOS-JNK Signaling Pathway. Cell Mol Neurobiol 37, 753–762 (2017). https://doi.org/10.1007/s10571-016-0412-x

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