Nitric oxide-mediated neuronal injury in multiple sclerosis

doi:10.1016/0306-9877(92)90175-C

Medical Hypotheses

Volume 39, Issue 2, October 1992, Pages 143-146

https://doi.org/10.1016/0306-9877(92)90175-C Get rights and content

Abstract

Although several explanations have been proposed for destruction of myelin and oligodendrocytes in multiple sclerosis, there is no proven mechanism of injury. We postulate that the autoimmune response seen in multiple sclerosis results in a cytokine-mediated increase in nitric oxide production by macrophages/microglia, smooth muscle cells and/or endothelium of the central nervous system. 3 mechanisms of cellular damage due to nitric oxide are proposed: 1. direct nitric oxide cytotoxicity; 2. injury due to peroxynitrite formation from superoxide anion and nitric oxide; and 3. nitric oxide-mediated elevations of cellular cGMP that enhance tumor necrosis factor-alpha toxicity. In support of these hypotheses, the anti-inflammatory effectors, dexamethasone and transforming growth factor-β, ameliorate symptoms seen in clinical multiple sclerosis and experimental allergic encephalitis, respectively. These 2 immunomodulators also inhibit induction of cytokine-mediated nitric oxide production by macrophages. An experimental design and therapeutic interventions which will evaluate the role of nitric oxide in the pathophysiology of experimental allergic encephalitis are presented.

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The aim of the study was to investigate the hypothesis that agmatine (AGM) provides protection against oxidative stress in experimental autoimmune encephalomyelitis (EAE).
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The EAE clinical expression manifested to greater extent in WT than KO mice, was significantly decreased during AGM treatment. We demonstrated significant elevations of superoxide dismutase activity in WT and KO EAE animals, in WEM and cerebellum tissues, which were decreased during AGM treatment in both groups. Superoxide anion content was increased in WEM of both study groups, with a decrease during AGM treatment. The observed changes were more pronounced in WT than in KO animals. Also, the increased expressions of transferrin receptor and glial fibrillary acidic protein observed in WT and KO EAE mice were significantly decreased during AGM treatment.
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Citation Excerpt :
The role of nitric oxide (NO) is microenvironment- and concentration-dependent (Beckman and Koppenol, 1996). Excessive NO production from iNOS has been implicated in the cytotoxicity of oligodendrocytes and in the pathology of MS and EAE (Brosnan et al., 1994; Merrill et al., 1993; Sherman et al., 1992). In the present study, our results show enhanced expression of iNOS in Wt mice at the peak of EAE whereas GMF-KO mice produced significantly lower levels of iNOS in both brain and spinal cord.
Pro-inflammatory cytokines/chemokines are implemented in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model with clinical and pathological similarities to multiple sclerosis. We have previously shown that over-expression of glia maturation factor (GMF) in glial cells cause excessive production and secretion of pro-inflammatory cytokines/chemokines sufficient to destroy the myelin-forming oligodendroglial cell in vitro. In this present investigation, we evaluate the expression of pro-inflammatory mediators in the central nervous system (CNS) of GMF+/+ (wild type) mice and GMF−/− (GMF-knockout) mice at the peak of EAE induced by immunization with MOG 35–55 peptide. GMF+/+ (Wt) mice developed severe EAE with a maximal mean clinical score of 3.6 ± 0.5 by day 16 post-immunization, whereas GMF-KO mice showed significantly delayed EAE with an average onset on day 26 pi with reduced mean clinical score of 1.3 ± 0.3. Three of fifteen Wt mice as compared to none of GMF-KO mice died of EAE. Encephalitogenic cells from Wt mice transferred to recipient GMF-KO mice caused very mild and with low incidence of EAE. We determined the differences in the expression of cytokines, IFN-γ, TNF-α, IL-1 β, IL-6, IL-4, IL-10, and chemokines, MIP-1, MIP-2, IP-10, MCP-1, GM-CSF mRNA by quantitative real-time RT–PCR in brain and spinal cord. Our results demonstrate significantly low levels of pro-inflammatory cytokines/chemokines in the CNS of GMF-KO mice and increased expression in Wt mice with EAE. Our data suggest that GMF play a critical role in CNS inflammation.
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Nitric oxide (NO) is a janus faced chemical messenger, which, in the recent years, has been the focus of neurobiologists for its involvement in neurodegenerative disorders in particular, Parkinson’s disease (PD). Nitric oxide synthase, the key enzyme involved in NO production exists in three known isoforms. The neuronal and inducible isoforms have been implicated in the pathogenesis of PD. These enzymes are subject to complex expressional and functional regulation involving mRNA diversity, phosphorylation and protein interaction. In the recent years, mRNA diversity and polymorphisms have been identified in the NOS isoforms. Some of these genetic variations have been associated with PD, indicating an etiological role for the NOS genes. This review mainly focuses on the NOS genes—their differential regulation and genetic heterogeneity, highlighting their significance in the pathobiology of PD.
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Nitric oxide-mediated neuronal injury in multiple sclerosis

Abstract

Immunol Today

Lancet

Curr Opin Immunol

J Neuroimmunol

Curr Opin Immunol

Arch Biochem Biophys

Biochem Biophys Res Commun

J Neuroimmunol

J Biol Chem

Blood

Cellular immune response in multiple sclerosis plaques

Am J Pathol

Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system

Neurology

In vitro and in vivo activation of human mononuclear phagocytes by interferon-γ. Studies with normal and AIDS monocytes

J Immunol

Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro

Ann Neurol

Association between tumor necrosis factor-α and disease progression in patients with multiple sclerosis

N Engl J Med

Tumor-alpha synthesis by cerebrospinal-fluid-derived T cell clones from patients with multiple sclerosis

Clin Exp Immunol

Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations?

Acta Neurol Scand

Cytokine accumulations in CSF of multiple sclerosis patients

Neurology