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Argon Inhalation for 24 h After Closed-Head Injury Does not Improve Recovery, Neuroinflammation, or Neurologic Outcome in Mice

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Abstract

Background/Objective

In recent years, the noble gas argon (Ar) has been extensively studied for its organ protection properties. While mounting in vitro and in vivo evidence indicates that argon provides neuroprotection in ischemic brain injury, its neuroprotective potential in traumatic brain injury (TBI) has not been evaluated in vivo. We tested the hypothesis that prolonged inhalation of 70% or 79% argon for 24 h after closed-head injury (CHI) improves neurologic outcome and overall recovery at 36 days post-injury. We also compared effects of the 30% or 21% residual oxygen on argon’s potential neuroprotective capacity.

Methods

Adult male C57/black mice (n = 240) were subjected to closed-head traumatic brain injury, followed by inhalation of 70% argon or nitrogen (30% oxygen), or 79% argon or nitrogen (21% oxygen) for 24 h. Neurologic outcome (rotarod, neuroscore, and Morris water maze) was evaluated for up to 36 days post-injury. Histologic parameters of neurologic degeneration (Fluoro-Jade staining) and inflammation (F4/80 microglia immunostaining) were assessed in subgroups at 24 h and on post-injury day 7.

Results

Our CHI protocol consistently resulted in significant brain injury. After argon inhalation for 24 h at either concentration, mice did not show significant improvement with regard to neuroscores, rotarod performance, Morris water maze performance, or overall recovery (body weight), compared to nitrogen controls, up to 36 days. At 7 days post-injury, histologic markers of neurodegeneration and inflammation, particularly in the hippocampus, consistently demonstrated significant injury. Notably, recovery was reduced in mice treated with the higher oxygen concentration (30%) after CHI compared to 21%.

Conclusions

Prolonged argon treatment did not improve neurologic outcome, overall recovery (weight), nor markers of neurodegeneration or neuroinflammation after significant CHI compared to nitrogen. While neuroprotective in predominately ischemic injury, argon did not provide protection after TBI in this model, highlighting the crucial importance of assessing argon’s strengths and weaknesses in preclinical models to fully understand its organ protective potential in different pathologies and gas mixtures.

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Acknowledgements

Special thanks go to Kathy Gage for her support and scientific editing of our work.

Funding

DREAM Award, Duke Anesthesiology to UH; Donald B. Sanders Fund for Residents and Fellows, Duke University to JC.

Author information

Authors and Affiliations

  1. Department of Neurology, Duke University Medical Center, Durham, NC, USA

    Jennifer Creed, Viviana Cantillana-Riquelme, Haichen Wang & Daniel T. Laskowitz

  2. Department of Anesthesiology, Center for Perioperative Organ Protection (CPOP), Duke University Medical Center, Box 3094, Durham, NC, 27710, USA

    Bai Hui Yan, Shuang Ma, Dongmei Chu, Dennis A. Turner, Daniel T. Laskowitz & Ulrike Hoffmann

  3. Departments of Neurosurgery, Neurobiology, and Biomedical Engineering, Duke University Medical Center, Durham, NC, USA

    Dennis A. Turner

  4. Department of Anesthesiology, The Second Affiliated Hospital of Xi’an JiaoTong University, Xi’an, ShaanXi Province, China

    Bai Hui Yan

  5. Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liao Ning, China

    Shuang Ma

  6. Department of Pediatrics, The Fifth Central Hospital of Tianjin, Tianjin, China

    Dongmei Chu

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  1. Jennifer Creed
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Contributions

The experiments were conceived and designed by JC, UH, DTL. The experiments were performed by JC, UH, VCR, BHY, SM, DC, HW. The data were analyzed by JC, UH, DTL. The paper was written by JC, DAT, UH.

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Correspondence to Ulrike Hoffmann.

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Ethical approvals (IACUC Duke University) were obtained before the study.

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Animal studies followed and adhered to the ARRIVE Guidelines.

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Creed, J., Cantillana-Riquelme, V., Yan, B.H. et al. Argon Inhalation for 24 h After Closed-Head Injury Does not Improve Recovery, Neuroinflammation, or Neurologic Outcome in Mice. Neurocrit Care 34, 833–843 (2021). https://doi.org/10.1007/s12028-020-01104-0

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