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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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Abstract

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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Abbreviations

AQP:

Aquaporin

BWC:

Brain water content

CaMK II:

Ca2+/calmodulin-dependent protein kinase II

MCAO:

Middle cerebral artery occlusion

NMDARs:

N-methyl-d-aspartate receptors

Ser:

Serine

Sim:

Simvastatin

T2WI:

T2-weighted imaging

Thr:

Threonine

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Acknowledgments

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

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Medical College of Tibet University for Nationalities, Xianyang, Shaanxi, China

    Min-xia Zhu

  2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Min-xia Zhu, Chao Lu, Chun-mei Xia & Da-nian Zhu

  3. Department of Radiology, Children’s Hospital, Fudan University, Shanghai, China

    Zhong-wei Qiao

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  1. Min-xia Zhu
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  2. Chao Lu
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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). https://doi.org/10.1007/s12031-014-0307-6

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