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

Haiping Wei, Yun Li, Song Han, Shuiqiao Liu, Nan Zhang, Li Zhao, Shujuan Li, Junfa Li
Translational Stroke Research 2016, 7 (6): 497-511
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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