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Nitric Oxide in Optic Neuritis and Multiple Sclerosis

Chuman, Hideki MD, PhD

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Journal of Neuro-Ophthalmology: June 2006 - Volume 26 - Issue 2 - p 85-86
doi: 10.1097/01.wno.0000221652.56574.99
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There has been an explosive growth of research on the role of nitric oxide (NO) in physiological and pathologic processes in the brain. Physiologically, NO functions as a neurotransmitter and a vasodilator for fine local control of cerebral blood flow. In pathologic states, NO is induced in response to various inflammatory conditions.

In this issue of the Journal of Neuro-Ophthalmology, Tsoi et al (1) report evidence for inducible nitric oxide synthase (iNOS) and peroxynitrite-mediated damage in optic neuritis (ON). The article is worth noticing because the optic nerves were obtained from a single patient with clinically isolated ON who died of causes unrelated to ON. Significantly, the patient was in clinical remission and undergoing interferon therapy. The authors compared the immunohistochemical findings in the patient with ON to control normal optic nerves obtained from an eye bank. In the patient with ON, the authors showed localized loss of myelin proteins, myelin breakdown, and the presence of iNOS and nitrotyrosine associated with inflammatory infiltrates on the edges of the nerve and reactive astrocytes. This evidence implicates the role of iNOS in the inflammation and demyelination of ON. Similarly, increased iNOS activity has been demonstrated in astrocytes in demyelinating lesions of postmortem tissues in multiple sclerosis (MS) (2). In addition, a 70% elevation in cerebrospinal nitrite has been reported in living patients with MS (3).

These reports raise interesting questions in regard to NO and MS. What is the role of NO in MS? We do not know the answer yet. It is likely to be much more complicated than originally thought with a complex interplay between broadly beneficial regulatory effects on the immune system and largely deleterious direct effects on neurologic tissues (4). NO can disturb the permeability of the blood-brain barrier (BBB) and facilitate antibody leakage into lesions (5), and it can inhibit T cell activation in the blood and lymphatic tissue, thereby inhibiting T cell-mediated inflammation (6). NO may also inhibit the expression of adhesion molecules at the BBB, thereby impairing the recruitment of inflammatory cells into the lesion (7), and it may also augment the apoptosis of T lymphocytes in the central nervous system contributing to the termination of the inflammatory reaction (8). At the same time, NO produced by iNOS-positive inflammatory cells may cause demyelination by destroying oligodendrocytes and/or damaging myelin (9), and it may also block conduction in demyelinated axons (10). Neural function may also be impaired by the effects of NO on synaptic transmission. NO may also directly damage axons and neurons.

Might NO inhibition therapy be effective in treating MS or ON? Unfortunately, no clear picture has yet emerged. Some studies have found that aminoguanidine, a partially selective inhibitor of iNOS, inhibits disease expression in a dose-dependent manner (11). However, other studies have found that NO inhibition can worsen the inflammation in experimental autoimmune encephalomyelitis (EAE) (12). Some studies have found that inhibition of type IV phosphodiesterase, which increases NO, suppressed inflammation in EAE. (13). Administration of uric acid, a scavenger of peroxynitrite, has also been found to be an effective therapy for EAE (14).

These studies involving the NO pathways are preliminary but promising. By showing that NO levels are abnormally high in ON as well as in MS lesions, Tsoi et al (1) provide impetus for further study in this area.


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© 2006 Lippincott Williams & Wilkins, Inc.