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Glibenclamide and Therapeutic Hypothermia Have Comparable Effect on Attenuating Global Cerebral Edema Following Experimental Cardiac Arrest

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Abstract

Background

Cerebral edema is one of the major causes of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). A subunit of the sulfonylurea receptor 1–transient receptor potential M4 (Sur1–TRPM4) channel has been implicated in the pathogenesis of ischemia-evoked cerebral edema. In this study, we examined whether glibenclamide (GBC), a Sur1–TRPM4 channel inhibitor, attenuates cerebral edema following CA/CPR and further examined the efficacy of GBC combined with therapeutic hypothermia.

Methods

Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 7-min CA/CPR were randomized into five groups: sham operation, control with normothermia, GBC with normothermia, control with hypothermia, and GBC with hypothermia. The primary outcome was to evaluate regional brain water content; the secondary outcome was to measure blood glucose level, Sur1–TRPM4 expression, and pro-inflammatory factor expression.

Results

Compared with normothermia, GBC treatment or hypothermia significantly attenuated brain water content in mice subjected to CA/CPR. GBC combined with hypothermia had no additional effects on attenuating cerebral edema. Pro-inflammatory factor messenger RNA expression (TNF-α and IL-6), NFκβ activation, and SUR1–TRPM4 levels were upregulated after CA/CPR. Compared with normothermia, hypothermia, but not GBC, partly suppressed these factors’ expression.

Conclusions

GBC attenuated cerebral edema following CA/CPR by blocking Sur1–TRPM4 channels upregulated by CA insult. The effect of GBC was comparable with that of therapeutic hypothermia alone. These results suggest that GBC is an alternative approach for treating CA-evoked cerebral edema.

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Number 17K11564.

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Authors and Affiliations

  1. Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

    Shin Nakayama & Makoto Tanaka

  2. Department of Anesthesiology, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, University of Tsukuba, Ibaraki, Japan

    Noriko Taguchi

  3. Technical Service Office for Medical Sciences, University of Tsukuba, Ibaraki, Japan

    Yumi Isaka & Takako Nakamura

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  1. Shin Nakayama
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Correspondence to Shin Nakayama.

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Nakayama, S., Taguchi, N., Isaka, Y. et al. Glibenclamide and Therapeutic Hypothermia Have Comparable Effect on Attenuating Global Cerebral Edema Following Experimental Cardiac Arrest. Neurocrit Care 29, 119–127 (2018). https://doi.org/10.1007/s12028-017-0479-3

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