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Int J Mol Sci. 2017 Jan 25;18(2). pii: E245. doi: 10.3390/ijms18020245.

Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model.

Maggio DM1,2,3, Singh A4, Iorgulescu JB5,6, Bleicher DH7, Ghosh M8,9, Lopez MM10, Tuesta LM11,12, Flora G13, Dietrich WD14,15,16,17,18,19, Pearse DD20,21,22,23,24.

Author information

1
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. dominic.maggio@nih.gov.
2
Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. dominic.maggio@nih.gov.
3
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institute of Heath, Bethesda, MD 20824, USA. dominic.maggio@nih.gov.
4
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. amanpu@gmail.com.
5
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. jbi2001@med.cornell.edu.
6
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. jbi2001@med.cornell.edu.
7
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. drew.bleicher@jhsmiami.org.
8
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. mghosh@med.miami.edu.
9
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. mghosh@med.miami.edu.
10
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Michael.Lopez@mch.com.
11
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. luis_tuesta@hms.harvard.edu.
12
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. luis_tuesta@hms.harvard.edu.
13
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. gjsflora@gmail.com.
14
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ddietrich@miami.edu.
15
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ddietrich@miami.edu.
16
The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ddietrich@miami.edu.
17
The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ddietrich@miami.edu.
18
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ddietrich@miami.edu.
19
Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA. ddietrich@miami.edu.
20
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. DPearse@med.miami.edu.
21
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. DPearse@med.miami.edu.
22
The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. DPearse@med.miami.edu.
23
The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA. DPearse@med.miami.edu.
24
Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL 33136, USA. DPearse@med.miami.edu.

Abstract

Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS-/- knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS-/- mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS-/- mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation.

KEYWORDS:

angiogenesis; axon; function; inducible nitric oxide synthase; knockout; neuroprotection; oxidative stress

PMID:
28125047
PMCID:
PMC5343782
DOI:
10.3390/ijms18020245
[Indexed for MEDLINE]
Free PMC Article

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