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The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke

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Abstract

Purpose

Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics.

Method

In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke.

Results

NL-1 decreased hydrogen peroxide production with an IC50 of 5.95 μM in neuronal cells (N2A). The in vivo activity of NL-1 was evaluated in a murine 1 h transient middle cerebral artery occlusion (t-MCAO) model of ischemic stroke. We found that mice treated with NL-1 (10 mg/kg, i.p.) at time of reperfusion and allowed to recover for 24 h showed a 43% reduction in infarct volume and 68% reduction in edema compared to sham-injured mice. Additionally, we found that when NL-1 was administered 15 min post-t-MCAO, the ischemia volume was reduced by 41%, and stroke-associated edema by 63%.

Conclusion

As support of our hypothesis, as expected, NL-1 failed to reduce stroke infarct in a permanent photothrombotic occlusion model of stroke. This report demonstrates the potential therapeutic benefits of using mitoNEET ligands like NL-1 as novel mitoceuticals for treating reperfusion-injury with cerebral stroke.

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Acknowledgements

We are grateful for the technical support from Deborah Corbin in the tissue processing. The project described was supported by the National Institute Of General Medical Sciences, U54GM104942, 1R41NS110070-01 and the WVU Stroke CoBRE Grant 2P20GM109098. The project described was supported by the National Heart, Lung and Blood Institute Grant HL-128485. The project described was supported by the Community Foundation for the Ohio Valley Whipkey Trust. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Author notes

  1. Pushkar Saralkar and Alexander Mdzinarishvili contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Drive, Morgantown, West Virginia, 26506, USA

    Pushkar Saralkar, Tasneem A Arsiwala, Lori E. Hazlehurst, Jason D. Huber & Werner J. Geldenhuys

  2. Department of Neurology, College of Medicine, University of Oklahoma HSC, Oklahoma City, Oklahoma, USA

    Alexander Mdzinarishvili

  3. Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA

    Yoon-Kwang Lee

  4. Department of Neuroscience, Spinal and Brain Injury Research Center, School of Medicine, University of Kentucky, Lexington, Kentucky, USA

    Patrick G. Sullivan

  5. Department of Neuroscience, School of Medicine, West Virginia University, Morgantown, West Virginia, USA

    Mark V. Pinti, Xuefang Ren, Heng Hu, James Simpkins, Candice Brown, Jason D. Huber & Werner J. Geldenhuys

  6. Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University, Morgantown, West Virginia, USA

    Mark V. Pinti, John M. Hollander & Werner J. Geldenhuys

  7. Division of Exercise Physiology, School of Medicine, West Virginia University, Morgantown, West Virginia, USA

    John M. Hollander

  8. Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia, USA

    Eric E. Kelley

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  1. Pushkar Saralkar
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Saralkar, P., Mdzinarishvili, A., Arsiwala, T.A. et al. The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke. Pharm Res 38, 803–817 (2021). https://doi.org/10.1007/s11095-021-03046-4

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  • DOI: https://doi.org/10.1007/s11095-021-03046-4

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