Elsevier

The Lancet Neurology

Volume 1, Issue 4, August 2002, Pages 232-241
The Lancet Neurology

Review
The role of nitric oxide in multiple sclerosis

https://doi.org/10.1016/S1474-4422(02)00102-3Get rights and content

Summary

Nitric oxide (NO) is a free radical found at higher than normal concentrations within inflammatory multiple sclerosis (MS) lesions. These high concentrations are due to the appearance of the inducible form of nitric oxide synthase (iNOS) in cells such as macrophages and astrocytes. Indeed, the concentrations of markers of NO production (eg, nitrate and nitrite) are raised in the CSF, blood, and urine of patients with MS. Circumstantial evidence suggests that NO has a role in several features of the disease, including disruption of the blood–brain barrier, oligodendrocyte injury and demyelination, axonal degeneration, and that it contributes to the loss of function by impairment of axonal conduction. However, despite these considerations, the net effect of NO production in MS is not necessarily deleterious because it also has several beneficial immunomodulatory effects. These dual effects may help to explain why iNOS inhibition has not provided reliable and encouraging results in animal models of MS, but alternative approaches based on the inhibition of superoxide production, partial sodium-channel blockade, or the replacement of lost immunomodulatory function, may prove beneficial.

Section snippets

Evidence that NO concentrations are raised in MS

There is abundant evidence that the production of NO is significantly raised within MS lesions, arising not only from the pathological study of lesions themselves, but also from studies of the CSF, blood, and urine of patients, and the electron paramagnetic resonance spectroscopy of animals with experimental autoimmune encephalomyelitis,6 a recognised model for MS.

Role of NO in inflammation and demyelination in MS

NO may be involved in the development of several pathological features of MS, the hallmark of which is the demyelinated plaque with reactive glial scar formation.35 The demyelination occurs in association with a chronic inflammatory process, dominated by the infiltration of T lymphocytes, recruitment of haematogenous macrophages, and the local activation of microglia.36 The inflammatory process is associated with a disturbance of the blood-brain barrier (BBB) that is most extensive in active

NO and loss of function in MS

It seems likely that NO has a role in the loss of neurological function in MS, perhaps even a major role, although the evidence is so far only circumstantial.

NO-based therapy for MS

From the information presented in this review, it might appear that an effective therapy for MS could result from the inhibition of NO production, especially the inhibition of iNOS. However, over the past 10 years around 40 investigations have examined the role of NO in experimental autoimmune encephalomyelitis, but no clear picture has emerged. For example, whereas some studies have found that aminoguanidine (a partially selective inhibitor for iNOS) inhibits disease expression in a

Conclusion

In summary, the role of NO in MS is likely to be much more complicated than originally thought, with a complex interplay between largely deleterious direct effects on neurological tissues and broadly beneficial regulatory effects on the immune system. We are not aware of any current clinical trials in MS based (deliberately at least) on the modulation of NO, perhaps because of concern about disturbing the beneficial effects. However, it would be wrong to conclude that because the adverse and

Search strategy

Data for this review were selected following searches of Medline and pre-Medline databases. Additional references were selected from relevant articles and the authors' own files. Only papers published in English were reviewed. The original number of references was reduced substantially to 150 on request from the editor.

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