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Simvastatin Pretreatment Protects Cerebrum from Neuronal Injury by Decreasing the Expressions of Phosphor-CaMK II and AQP4 in Ischemic Stroke Rats

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Excitotoxicity and cytotoxic edema are the two major factors resulting in neuronal injury during brain ischemia and reperfusion. Ca2+/calmodulin-dependent protein kinase II (CaMK II), the downstream signal molecular of N-methyl-d-aspartate receptors (NMDARs), is a mediator in the excitotoxicity. Aquaporin 4 (AQP4), expressed mainly in the brain, is an important aquaporin to control the flux of water. In a previous study, we had reported that pretreatment of simvastatin protected the cerebrum from ischemia and reperfusion injury by decreasing neurological deficit score and infarct area (Zhu et al. PLoS One 7:e51552, 2012). The present study used a middle cerebral artery occlusion (MCAO) model to further explore the pleiotropic effect of simvastatin via CaMK II and AQP4. The results showed that simvastatin reduced degenerated cells and brain edema while decreasing the protein expressions of phosphor-CaMK II and AQP4, and increasing the ratios of Bcl-2/Bax, which was independent of cholesterol-lowering effect. Immunocomplexes formed between the subunit of NMDARs-NR3A and AQP4 were detected for the first time. It was concluded that simvastatin could protect the cerebrum from neuronal excitotoxicity and cytotoxic edema by downregulating the expressions of phosphor-CaMK II and AQP4, and that the interaction between NR3A and AQP4 might provide the base for AQP4 involving in the signaling pathways mediated by NMDARs.

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Brain water content


Ca2+/calmodulin-dependent protein kinase II


Middle cerebral artery occlusion


N-methyl-d-aspartate receptors






T2-weighted imaging




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This work was supported by grant from the Second Major Projects of Science and Technology Department in Tibet Autonomous Region.

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Correspondence to Min-xia Zhu.

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Zhu, Mx., Lu, C., Xia, Cm. et al. Simvastatin Pretreatment Protects Cerebrum from Neuronal Injury by Decreasing the Expressions of Phosphor-CaMK II and AQP4 in Ischemic Stroke Rats. J Mol Neurosci 54, 591–601 (2014).

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