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.
Highlights
Every year, approximately 16,000 Americans suffer a spinal cord injury (SCI) [1], leaving them with a permanently diminished ambulatory ability and decreased quality of life, aspects which remain a major focus for restorative approaches [2,3]
The slowing of these processes in inducible nitric oxide synthase (iNOS)−/− mice led to a delay in the manifestation of neuropathic pain, but they showed slower long-term resolution of pain compared to WT controls
INOS inhibitors have shown some efficacy in slowing disease in experimental autoimmune encephalitis (EAE), a model for Multiple Sclerosis (MS), induction of EAE in iNOS−/− mice led to a higher incidence and severity of disease, when compared to WT mice, that was characterized by an inability of iNOS−/− mice to undergo disease remission [35,36,37,38]
Summary
Approximately 16,000 Americans suffer a spinal cord injury (SCI) [1], leaving them with a permanently diminished ambulatory ability and decreased quality of life, aspects which remain a major focus for restorative approaches [2,3]. Propagation of reactive oxygen and nitrogen species, such as the superoxide anion (O2−), hydroxyl radical (OH), nitric oxide (NO), and peroxynitrite (ONOO−), can drive secondary injury processes. These reactive species and downstream effectors can directly damage intracellular proteins and membrane phospholipids through oxidation, as well as activate redox-responsive transcription factors that promote inflammation [5,6,7,8,9]. When NO is produced in an environment of oxidative stress, such as following SCI, NO combines with the superoxide radical to form the highly reactive oxidizing agent, peroxynitrite This molecule is highly apoptogenic due to its potent destruction of nucleic acids, as well as its ability to inactivate membrane lipoproteins and essential intracellular proteins [5,18,20].
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