Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible

Abstract

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.

Mechanisms and Patterns of Axonal Loss in Multiple Sclerosis

“…Also, reactive nitrogen species disrupt the permeability of the axonal membrane, causing an influx of extracellular ions and axonal swelling. At low concentrations, NO species have been shown to block impulse conduction in axons even in the absence of structural damage (Redford et al, 1997). This demonstrates how clinical deficit may manifest in MS patients before dramatic degenerative changes are detectable in axons (Lassmann et al, 2003).…”

Nitric oxide – mediated signalization and nitrosative stress in neuropathology / Azot oksid – posredovana signalizacija i nitrozativni stres u neuropatologiji

“…NO reactive species (nitrate, nitrite, peroxynitrite), produced as a consequence of activated glia cells, promote nitrosative stress disorders -myelin and nerve tissue destruction. It is supposed that NO provokes block in the action potential transmission, since NO donors occur as a reversible blocking agents in normal and demyelinating conditions, not only in the central, but also in the peripheral nerve system (10). This could be the result of direct NO effects on glutamatergic transmission, since it has been reported to induce N-methyl-D-aspartate (NMDA) up regulation due to nitrosylation processes (11).…”

Investigation of a neuronal nitric oxide synthase gene (NOS1) polymorphism in a multiple sclerosis population

“…Linkage studies also indicate the presence of an MS locus on chromosome 12q24.2 [5]. This genomic region is known to harbour the neuronal nitric oxide synthase gene (nNOS) [6].…”