Nodal Na +-channel displacement is associated with nerve-conduction slowing in the chronically diabetic BB/W rat: Prevention by aldose reductase inhibition

Abstract

Chronic nerve conduction slowing in experimental diabetic neuropathy has been associated with decreased nodal Na + permeability and an ultrastructurally identifiable loss of axo-glial junctions, which comprise the paranodal voltage channel barrier separating nodal Na + channels from paranodal K + channels. In human and experimental diabetic neuropathy these structural changes of the paranodal apparatus correlate closely with the nerve conduction defect. The present immunocytochemical study of the α-subunit of the Na + channel examined whether the breach of the voltage channel barrier may account for a shift in the distribution of Na + channels explaining decreased nodal Na + permeability. Biobreeding Wistar (BB/W) rats diabetic for 4–8 months showed a progressive redistribution of nodal Na + channels across the paranodal barrier into the paranodal and internodal domains which was associated with chronic nerve conduction slowing. The present data suggest that structural damage to the paranodal barrier system in diabetic nerve facilitates the lateral displacement of Na + channels from the nodal axolemma thereby diminishing their nodal density and the nodal Na + permeability associated with the chronic nerve conduction defect in experimental diabetes. These abnormalities were prevented by the treatment with an aldose reductase inhibitor, belonging to a class of drugs that, in neuropathic patients, improves nerve-conduction velocity and repairs axo-glial dysjunction of the paranodal apparatus.