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Cover ArticleResearch Articles, Neurobiology of Disease

NOS3 Inhibition Confers Post-Ischemic Protection to Young and Aging White Matter Integrity by Conserving Mitochondrial Dynamics and Miro-2 Levels

Chinthasagar Bastian, Jane Zaleski, Katharine Stahon, Brandon Parr, Andrew McCray, Jerica Day, Sylvain Brunet and Selva Baltan
Journal of Neuroscience 11 July 2018, 38 (28) 6247-6266; https://doi.org/10.1523/JNEUROSCI.3017-17.2018
Chinthasagar Bastian
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Jane Zaleski
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Katharine Stahon
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Brandon Parr
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Andrew McCray
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Jerica Day
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Sylvain Brunet
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Selva Baltan
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
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Abstract

White matter (WM) damage following a stroke underlies a majority of the neurological disability that is subsequently observed. Although ischemic injury mechanisms are age-dependent, conserving axonal mitochondria provides consistent post-ischemic protection to young and aging WM. Nitric oxide synthase (NOS) activation is a major cause of oxidative and mitochondrial injury in gray matter during ischemia; therefore, we used a pure WM tract, isolated male mouse optic nerve, to investigate whether NOS inhibition provides post-ischemic functional recovery by preserving mitochondria. We show that pan-NOS inhibition applied before oxygen-glucose deprivation (OGD) promotes functional recovery of young and aging axons and preserves WM cellular architecture. This protection correlates with reduced nitric oxide (NO) generation, restored glutathione production, preserved axonal mitochondria and oligodendrocytes, and preserved ATP levels. Pan-NOS inhibition provided post-ischemic protection to only young axons, whereas selective inhibition of NOS3 conferred post-ischemic protection to both young and aging axons. Concurrently, genetic deletion of NOS3 conferred long-lasting protection to young axons against ischemia. OGD upregulated NOS3 levels in astrocytes, and we show for the first time that inhibition of NOS3 generation in glial cells prevents axonal mitochondrial fission and restores mitochondrial motility to confer protection to axons by preserving Miro-2 levels. Interestingly, NOS1 inhibition exerted post-ischemic protection selectively to aging axons, which feature age-dependent mechanisms of oxidative injury in WM. Our study provides the first evidence that inhibition of glial NOS activity confers long-lasting benefits to WM function and structure and suggests caution in defining the role of NO in cerebral ischemia at vascular and cellular levels.

SIGNIFICANCE STATEMENT White matter (WM) injury during stroke is manifested as the subsequent neurological disability in surviving patients. Aging primarily impacts CNS WM and mechanisms of ischemic WM injury change with age. Nitric oxide is involved in various mitochondrial functions and we propose that inhibition of glia-specific nitric oxide synthase (NOS) isoforms promotes axon function recovery by preserving mitochondrial structure, function, integrity, and motility. Using electrophysiology and three-dimensional electron microscopy, we show that NOS3 inhibition provides a common target to improve young and aging axon function, whereas NOS1 inhibition selectively protects aging axons when applied after injury. This study provides the first evidence that inhibition of glial cell NOS activity confers long-lasting benefits to WM structure and function.

  • ischemia
  • Miro-2
  • mitochondria
  • nitric oxide synthase
  • oxidative stress
  • white matter
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The Journal of Neuroscience: 38 (28)
Journal of Neuroscience
Vol. 38, Issue 28
11 Jul 2018
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NOS3 Inhibition Confers Post-Ischemic Protection to Young and Aging White Matter Integrity by Conserving Mitochondrial Dynamics and Miro-2 Levels
Chinthasagar Bastian, Jane Zaleski, Katharine Stahon, Brandon Parr, Andrew McCray, Jerica Day, Sylvain Brunet, Selva Baltan
Journal of Neuroscience 11 July 2018, 38 (28) 6247-6266; DOI: 10.1523/JNEUROSCI.3017-17.2018

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NOS3 Inhibition Confers Post-Ischemic Protection to Young and Aging White Matter Integrity by Conserving Mitochondrial Dynamics and Miro-2 Levels
Chinthasagar Bastian, Jane Zaleski, Katharine Stahon, Brandon Parr, Andrew McCray, Jerica Day, Sylvain Brunet, Selva Baltan
Journal of Neuroscience 11 July 2018, 38 (28) 6247-6266; DOI: 10.1523/JNEUROSCI.3017-17.2018
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Keywords

  • ischemia
  • Miro-2
  • mitochondria
  • nitric oxide synthase
  • oxidative stress
  • white matter

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