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Glycogen Synthase Kinase-3β Is Involved in Electroacupuncture Pretreatment via the Cannabinoid CB1 Receptor in Ischemic Stroke

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Abstract

We have previously shown that electroacupuncture (EA) pretreatment produces neuroprotective effects, which were mediated through an endocannabinoid signal transduction mechanism. Herein, we have studied the possible contribution of the phosphorylated form of glycogen synthase kinase-3β (GSK-3β) in EA pretreatment-induced neuroprotection via the cannabinoid CB1 receptor (CB1R). Focal transient cerebral ischemia was induced by middle cerebral artery occlusion in rats. Phosphorylation of GSK-3β at Ser-9 [p-GSK-3β (Ser-9)] was evaluated in the penumbra tissue following reperfusion. Infarct size and neurological score were assessed in the presence of either PI3K inhibitors or a GSK-3β inhibitor 72 h after reperfusion. Cellular apoptosis was evidenced by TUNEL staining and determination of the Bax/Bcl-2 ratio 24 h after reperfusion. The present study showed that EA pretreatment increased p-GSK-3β(Ser-9) 2 h after reperfusion in the ipsilateral penumbra. Augmented phosphorylation of GSK-3β induced similar neuroprotective effects as did EA pretreatment. By contrast, inhibition of PI3K dampened the levels of p-GSK-3β(Ser-9), and reversed not only the neuroprotective effect but also the anti-apoptotic effect following EA pretreatment. Regulation of GSK-3β by EA pretreatment was abolished following treatment with a CB1R antagonist and CB1R knockdown, whereas two CB1R agonists enhanced the phosphorylation of GSK-3β. Therefore we conclude that EA pretreatment protects against cerebral ischemia/reperfusion injury through CB1R-mediated phosphorylation of GSK-3β.

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Acknowledgments

This work was supported by the Major Program of National Natural Science Foundation of China (grant 30930091), the Program for Changjiang Scholars and Innovative Research Team in University (grant 2010 CXTD01), National Natural Science Foundation of China (grant 81072888, 81035375), and the Overseas, Hong Kong and Macao Scholars Collaborated Researching Fund (grant 81228022).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, Shaanxi, China

    Haidong Wei, Lifang Yang, Shiquan Wang, Fan Guo, Heng Zhou, Qiang Wang & Lize Xiong

  2. Department of anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Xi Yao

  3. NeuroCentre Magendie, INSERM U862, 33076, Bordeaux, France

    Giovanni Marsicano

  4. Key Laboratory of the Critical Care Medicine of PLA, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi, China

    Lize Xiong

  5. Department of Anesthesiology, Northwestern Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, 710004, Shaanxi, China

    Haidong Wei

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  1. Haidong Wei
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  2. Xi Yao
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Correspondence to Qiang Wang or Lize Xiong.

Additional information

Haidong Wei, Xi Yao, and Lifang Yang contributed equally to this work.

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Wei, H., Yao, X., Yang, L. et al. Glycogen Synthase Kinase-3β Is Involved in Electroacupuncture Pretreatment via the Cannabinoid CB1 Receptor in Ischemic Stroke. Mol Neurobiol 49, 326–336 (2014). https://doi.org/10.1007/s12035-013-8524-5

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  • DOI: https://doi.org/10.1007/s12035-013-8524-5

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