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The Neuroprotective Effects of Isoflurane Preconditioning in a Murine Transient Global Cerebral Ischemia–Reperfusion Model: The Role of the Notch Signaling Pathway

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Abstract

Inhalational anesthetic preconditioning can induce neuroprotective effects, and the notch signaling pathway plays an important role in neural progenitor cell differentiation and the inflammatory response after central nervous system injury. This study evaluated whether the neuroprotective effect of isoflurane preconditioning is mediated by the activation of the notch signaling pathway. Mice were divided into two groups consisting of those that did or did not receive preconditioning with isoflurane. The expression levels of notch-1, notch intracellular domain (NICD), and hairy and enhancer of split (HES-1) were measured in mice subjected to transient global cerebral ischemia–reperfusion injury. The notch signaling inhibitor DAPT and conditional notch-RBP-J knockout mice were used to investigate the mechanisms of isoflurane preconditioning-induced neuroprotection. Immunohistochemical staining, real-time polymerase chain reaction assays, and Western blotting were performed. Isoflurane preconditioning induced neuroprotection against global cerebral ischemia. Preconditioning up-regulated the expression of notch-1, HES-1, and NICD after ischemic–reperfusion. However, these molecules were down-regulated at 72 h after ischemic–reperfusion. The inhibition of notch signaling activity by DAPT significantly attenuated the isoflurane preconditioning-induced neuroprotection, and similar results were obtained using notch knockout mice. Our results demonstrate that the neuroprotective effects of isoflurane preconditioning are mediated by the pre-activation of the notch signaling pathway.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Beijing, China; Grants 30772059/30972853 and 81371510 to Hailong Dong; Grant 81171051 to Yanyan Sun; Grant 81100901 to Binxiao Su) and the National Science Foundation for Distinguished Young Scholars (Beijing, China; Grant 30725039 to Lize Xiong).

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Authors and Affiliations

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

    Hao-peng Zhang, Yan-yan Sun, Xiao-mei Chen, Bin-xiao Su, Rui Ma & Hai-long Dong

  2. Department of Anesthesiology, General Hospital of People’s Liberation Army Chengdu Military Region, Chengdu, Sichuan, China

    Li-bang Yuan

  3. Department of Emergency and General Dentistry, Stomatological College, Fourth Military Medical University, Xi’an, Shaanxi, China

    Rui-ni Zhao

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

    Lize Xiong

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  1. Hao-peng Zhang
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Correspondence to Hai-long Dong or Lize Xiong.

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Hao-peng Zhang, Yan-yan Sun, and Xiao-mei Chen have contributed equally to this work.

This work was conducted in the Department of Anesthesiology of Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China.

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Zhang, Hp., Sun, Yy., Chen, Xm. et al. The Neuroprotective Effects of Isoflurane Preconditioning in a Murine Transient Global Cerebral Ischemia–Reperfusion Model: The Role of the Notch Signaling Pathway. Neuromol Med 16, 191–204 (2014). https://doi.org/10.1007/s12017-013-8273-7

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  • DOI: https://doi.org/10.1007/s12017-013-8273-7

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