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Combined Treatment with Hydrophilic and Lipophilic Statins Improves Neurological Outcomes Following Experimental Cardiac Arrest in Mice

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Abstract

Background

Global ischemia due to cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) causes significant neuronal damage in vulnerable areas in the brain. Currently, a majority of patients eventually die after successful CPR due to neurological injury. Statins have pleiotropic effects including anti-inflammatory and/or antioxidant responses. These pleiotropic effects can have a beneficial role in the post-CPR phase. We tested whether two different types of statins, hydrophilic pravastatin and lipophilic simvastatin, attenuated neurological injury following CA/CPR. The efficacy of pravastatin and simvastatin combination treatment was also assessed.

Methods

Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 8-min CA/CPR were randomized into four groups: control, 2 mg/kg pravastatin, 20 mg/kg simvastatin, or a combination of 3 mg/kg pravastatin and 10 mg/kg simvastatin. Neurobehavioral assessment and histological analyses were performed to assess overall general health condition and neuronal injury, respectively.

Results

Combination treatment with pravastatin and simvastatin significantly reduced neuronal injury in the striatum and hippocampus, reduced cerebral edema, and improved general health at 4 days after CA/CPR. Combination statin treatment upregulated endothelial nitric oxide synthase mRNA in the brain. Pravastatin alone, but not simvastatin alone, improved general health after CA/CPR. Pravastatin was less potent than simvastatin at reducing neuronal injury in the brain.

Conclusion

Combination treatment with two different types of statins at the correct dose may be a promising approach to neuroprotection following CA/CPR.

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Funding

This study was supported by JSPS KAKENHI Grant Number 26462743.

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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, 3-2-7 Miya-Mach, Mito, Ibaraki, Japan

    Noriko Taguchi

  3. Technical Service Office for Medical Sciences, University of Tsukuba, 1-1-1 tennodai, Tsukuba, Ibaraki, Japan

    Yumi Isaka & Takako Nakamura

Authors
  1. Shin Nakayama
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  2. Noriko Taguchi
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  3. Yumi Isaka
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  4. Takako Nakamura
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  5. Makoto Tanaka
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Contributions

SN designed the study and prepared the protocol. SN, TN, YI, and NT performed experiments. MT contributed to critical revision of the manuscript. SN drafted and revised the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Shin Nakayama.

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The authors have no conflict of interests.

Ethical approval

The University of Tsukuba Subcommittee on Research Animal Care approved this study (protocol no. 15-125, 16-112).

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Nakayama, S., Taguchi, N., Isaka, Y. et al. Combined Treatment with Hydrophilic and Lipophilic Statins Improves Neurological Outcomes Following Experimental Cardiac Arrest in Mice. Neurocrit Care 33, 64–72 (2020). https://doi.org/10.1007/s12028-019-00862-w

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  • DOI: https://doi.org/10.1007/s12028-019-00862-w

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