Diseases such as multiple sclerosis and Guillain-Barré syndrome are characterized not only by widespread loss of myelin from nerve fibres, but also by widespread inflammation in the central and peripheral nervous systems, respectively. While the demyelination alone is sufficient to block conduction and thereby cause symptoms, there is increasing evidence that the inflammation may also contribute significantly to the conduction block, although the mechanisms are not understood. Nitric oxide is an important inflammatory mediator which is elevated within the central nervous system in multiple sclerosis and which can be experimentally applied to tissues using nitric oxide donors. We report that such compounds cause reversible conduction block in both normal and demyelinated axons of the central and peripheral nervous systems. Notably, conduction in demyelinated and early remyelinated axons is particularly sensitive to block by nitric oxide, so that at lower concentrations, including those expected at sites of inflammation, demyelinated axons are selectively affected. We therefore propose that inflammation may directly cause symptoms via nitric oxide release, and that the inhibition of such release may open a new therapeutic avenue for demyelinating disease.
Several observations suggest that tumour necrosis factor (TNF) plays a role in demyelination, although direct evidence for this is lacking. We have examined ultrastructurally rat sciatic nerves injected with TNF-alpha or TNF-beta: the effects of the two cytokines were found to be qualitatively similar. One day after injection nerves were oedematous and contained many inflammatory cells. Leucocytes were adherent to the walls of endoneurial vessels and sometimes were packed into the sub-endothelial layer apparently occluding the vascular lumen. Occasional myelinated axons were associated with macrophages and showed signs of myelin damage. By 3 days the inflammatory changes had diminished: some axons were degenerating or demyelinating. By 6-7 days, the vascular changes had resolved, and the endoneurium contained significant numbers of demyelinating and degenerating axons. Control nerves, which received injections of vehicle, showed no vascular changes and either no, or significantly fewer, degenerating or demyelinating axons. We conclude that the intraneural injection of TNF produces inflammatory vascular changes within the endoneurium, together with demyelination and axonal degeneration. We have also observed demyelination and degeneration in a preliminary study of the effects of TNF-alpha in mice. These findings may be relevant to the pathogenesis of demyelinating diseases such as Guillain-Barré syndrome.
Matrix metalloproteinases (MMPs) and the cytokine tumour necrosis factor (TNF)-alpha are implicated in the pathology of inflammatory demyelinating diseases of the CNS, and may also be involved in peripheral demyelinating diseases such as acute inflammatory demyelinating polyradiculoneuropathy. We have tested an inhibitor of MMP activity and TNF-alpha processing, BB-1101, in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome. Treatment with BB-1101 from the time of immunization prevented the development of EAN, and when given from the onset of symptoms, it significantly reduced disease severity. These results indicate that MMPs and/or TNF-alpha are involved in the pathogenesis of EAN, and that drugs of this type may have potential as novel therapeutic agents in the therapy of peripheral nervous system demyelinating diseases.
Human immunoglobulin is an effective treatment for Guillain-Barré syndrome, although the mechanism of action is not understood. We have investigated the effect of human immunoglobulin in an animal model of Guillain-Barré syndrome, namely experimental autoimmune neuritis (EAN), induced in Lewis rats by immunization with bovine spinal root myelin. Human immunoglobulin administered intraperitoneally at the time of onset of disease accelerated the rate of recovery from EAN. This improvement was associated with a reduction in the titre of anti-rat myelin antibodies and may be due to earlier remyelination of demyelinated nerve fibres. This model may facilitate further investigation of the mechanism of therapeutic action of immunoglobulin in inflammatory neuropathy.
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