Electrically active axons degenerate when exposed to nitric oxide

Axonal degeneration is a major cause of permanent deficit in inflammatory n eurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that loca lly produced inflammatory factors mediate the phenomenon. One such factor i s nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend t hem to show that axons exhibit the early stages of wallerian degeneration i f they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vi vo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, m orphological examination of exposed roots at the end of the recording perio d revealed nodal and paranodal changes consistent with acute wallerian dege neration in roots stimulated at 50 or 100 Hz. This interpretation was confi rmed in a few experiments that were prolonged to permit more obvious indica tors of degeneration to develop. In these experiments the formation of myel in ovoids and frank axonolysis occurred in more than 95% of fibers. Roots s timulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal deg eneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorde rs.