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.
|Number of pages||15|
|State||Published - May 2021|
Bibliographical noteFunding Information:
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.
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Organic Chemistry
- Pharmacology (medical)