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cPKCγ-Modulated Autophagy in Neurons Alleviates Ischemic Injury in Brain of Mice with Ischemic Stroke Through Akt-mTOR Pathway

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Abstract

We have reported that neuron-specific conventional protein kinase C (cPKC)γ is involved in the development of cerebral hypoxic preconditioning (HPC) and the neuroprotection against ischemic injuries, but its molecular mechanism is unclear. In this study, the adult and postnatal 24 h C57BL/6J wild-type (cPKCγ+/+) and cPKCγ knockout (cPKCγ−/−) mice were respectively used to establish the models of middle cerebral artery occlusion (MCAO)-induced ischemic stroke in vivo and oxygen-glucose deprivation (OGD)-treated primarily cultured cortical neurons as cell ischemia in vitro. The results showed that cPKCγ knockout could increase the infarct volume and neuronal cell loss in the peri-infarct region, and enhance the neurological deficits, the impaired coordination, and the reduced muscle strength of mice following 1 h MCAO/1–7 days reperfusion. Meanwhile, cPKCγ knockout significantly increased the conversion of LC3-I to LC3-II and beclin-1 protein expression, and resulted in more reductions in P-Akt, P-mTOR, and P-S6 phosphorylation levels in the peri-infarct region of mice with ischemic stroke. The autophagy inhibitor BafA1 could enhance or reduce neuronal cell loss in the peri-infarct region of cPKCγ+/+ and cPKCγ−/− mice after ischemic stroke. In addition, cPKCγ knockout and restoration could aggravate or alleviate OGD-induced neuronal ischemic injury in vitro through Akt-mTOR pathway-mediated autophagy. These results suggested that cPKCγ-modulated neuron-specific autophagy improves the neurological outcome of mice following ischemic stroke through the Akt-mTOR pathway, providing a potential therapeutic target for ischemic stroke.

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Acknowledgments

This work was supported by grants from the Seed Grant of International Alliance of Translational Neuroscience (PXM2014-014226-000006), Beijing Municipal Program for Hundred-Thousand-Ten Thousand Excellent Talents of New Century (Li J), Beijing Natural Science Foundation (7144188, 7132070, and 7141001), and National Natural Science Foundation of China (81301015, 81400948, and 31471142).

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Authors and Affiliations

  1. Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, Capital Medical University, #10 You An Men Wai Xi Tou Tiao, Beijing, 100069, People’s Republic of China

    Haiping Wei, Yun Li, Song Han, Shuiqiao Liu, Nan Zhang, Li Zhao & Junfa Li

  2. Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China

    Shujuan Li

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  1. Haiping Wei
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  2. Yun Li
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Correspondence to Shujuan Li or Junfa Li.

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All animal procedures were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the Capital Medical University.

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Wei, H., Li, Y., Han, S. et al. cPKCγ-Modulated Autophagy in Neurons Alleviates Ischemic Injury in Brain of Mice with Ischemic Stroke Through Akt-mTOR Pathway. Transl. Stroke Res. 7, 497–511 (2016). https://doi.org/10.1007/s12975-016-0484-4

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