Electrically active axons degenerate when exposed to nitric oxide

Abstract

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if 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 vivo 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, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.

Mechanisms of axon-glial injury of the optic nerve

“…Electrically active axons are especially vulnerable and show irreversible conduction block with axonal degeneration after prolonged exposure to nitric oxide. 16 This analysis resonates with contemporary studies of axonal pathology in multiple sclerosis. Immunohistochemical staining for amyloid precursor protein confirms that axonal injury occurs as part of the acute demyelinating lesion.…”

Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death during Chronic Neurodegeneration

“…IL-1␤ expression is also known to induce iNOS (Serou et al, 1999) and thus may underlie the microglial expression of iNOS seen here. The production of the oxidant NO has been demonstrated previously to be involved in neuronal death and damage (Takeuchi et al, 1998;Smith et al, 2001).…”

Mechanisms and Patterns of Axonal Loss in Multiple Sclerosis

“…Perforin, an effector substance contained within these granules, polymerizes to form a pore that is inserted into the axonal membrane, allowing water and salt to flow into the axon. Na+ influx initiates reversal of the Na+/Ca++ exchanger, leading to a vicious cycle of increased Ca++ intracellular accumulation (Smith et al, 2001). Granzyme, a second CTL effector substance, degrades axonal proteins, disrupting fast transport and potentially triggering apoptosis (Figure 4).…”

“…High levels of nitric oxide (NO) radicals have been identified in MS lesions (Smith and Lassmann., 2002). NO radicals cause injury to mitochondria and disrupt axonal cytoarchitecture (Smith et al 2001;Smith and Lassmann, 2002). NO radical-induced mitochondrial injury reduces generation of ATP and, if exceeding a certain threshold, triggers apoptotic mechanisms by cleavage and activation of caspases.…”

“…The result is a vicious cycle of Ca++ influx which eventually leads to the demise of the axon. The positive feedback loop of protease activation-cytoskeletal disruption-ion channel insertion continues as more Ca++ rushes into the cell (Smith et al, 2001). Ultimately, swelling and structural damage reach a point where the axonal cytoskeleton dissolves (Lassmann et al, 2003).…”