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

Pushkar Saralkar; Alexander Mdzinarishvili; Tasneem A. Arsiwala; Yoon Kwang Lee; Patrick G. Sullivan; Mark V. Pinti; John M. Hollander; Eric E. Kelley; Xuefang Ren; Heng Hu; James Simpkins; Candice Brown; Lori E. Hazlehurst; Jason D. Huber; Werner J. Geldenhuys

doi:10.1007/s11095-021-03046-4

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

Pushkar Saralkar, Alexander Mdzinarishvili, Tasneem A. Arsiwala, Yoon Kwang Lee, Patrick G. Sullivan, Mark V. Pinti, John M. Hollander, Eric E. Kelley, Xuefang Ren, Heng Hu, James Simpkins, Candice Brown, Lori E. Hazlehurst, Jason D. Huber, Werner J. Geldenhuys

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English
Pages (from-to)	803-817
Number of pages	15
Journal	Pharmaceutical Research
Volume	38
Issue number	5
DOIs	https://doi.org/10.1007/s11095-021-03046-4
State	Published - May 2021

Bibliographical note

Funding 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.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

Bioenergetics
CDGSH
OXPHOS
PAMPA
iron-sulfur
t-MCAO

ASJC Scopus subject areas

Biotechnology
Molecular Medicine
Pharmacology
Pharmaceutical Science
Organic Chemistry
Pharmacology (medical)

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10.1007/s11095-021-03046-4

Cite this

Saralkar, P., Mdzinarishvili, A., Arsiwala, T. A., Lee, Y. K., Sullivan, P. G., Pinti, M. V., Hollander, J. M., Kelley, E. E., Ren, X., Hu, H., Simpkins, J., Brown, C., Hazlehurst, L. E., Huber, J. D., & Geldenhuys, W. J. (2021). The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke. Pharmaceutical Research, 38(5), 803-817. https://doi.org/10.1007/s11095-021-03046-4

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

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.",

keywords = "Bioenergetics, CDGSH, OXPHOS, PAMPA, iron-sulfur, t-MCAO",

author = "Pushkar Saralkar and Alexander Mdzinarishvili and Arsiwala, {Tasneem A.} and Lee, {Yoon Kwang} and Sullivan, {Patrick G.} and Pinti, {Mark V.} and Hollander, {John M.} and Kelley, {Eric E.} and Xuefang Ren and Heng Hu and James Simpkins and Candice Brown and Hazlehurst, {Lori E.} and Huber, {Jason D.} and Geldenhuys, {Werner J.}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2021",

month = may,

doi = "10.1007/s11095-021-03046-4",

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Saralkar, P, Mdzinarishvili, A, Arsiwala, TA, Lee, YK, Sullivan, PG, Pinti, MV, Hollander, JM, Kelley, EE, Ren, X, Hu, H, Simpkins, J, Brown, C, Hazlehurst, LE, Huber, JD & Geldenhuys, WJ 2021, 'The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke', Pharmaceutical Research, vol. 38, no. 5, pp. 803-817. https://doi.org/10.1007/s11095-021-03046-4

TY - JOUR

T1 - The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke

AU - Saralkar, Pushkar

AU - Mdzinarishvili, Alexander

AU - Arsiwala, Tasneem A.

AU - Lee, Yoon Kwang

AU - Sullivan, Patrick G.

AU - Pinti, Mark V.

AU - Hollander, John M.

AU - Kelley, Eric E.

AU - Ren, Xuefang

AU - Hu, Heng

AU - Simpkins, James

AU - Brown, Candice

AU - Hazlehurst, Lori E.

AU - Huber, Jason D.

AU - Geldenhuys, Werner J.

N1 - Funding 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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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KW - CDGSH

KW - OXPHOS

KW - PAMPA

KW - iron-sulfur

KW - t-MCAO

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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