Imbalances in N-CAM, SAM and polysialic acid may underlie the paranodal ion channel barrier defect in diabetic neuropathy.

Breakdown of protective tissue barrier systems characterizes the chronic diabetic complications affecting the retina, and peripheral and central nerve tracts. The progressive damages to the blood-retina-, blood-nerve-, and paranodal ion channel barriers have pathophysiological consequences for the relentless progression of these complications. The continuing damage to the paranodal ion channel barrier in the spontaneously diabetic BB/W rat is associated with an increasingly irreversible nerve conduction defect, due to impaired nodal Na+ currents associated with displacement of nodal Na+ channels across the damaged paranodal barrier. The structural substrate for the mechanical barrier of the paranode is provided by electron-dense junctional complexes made up by a moiety of neural cell adhesive-(N-CAM), neural-glial adhesive (Ng-CAM), substrate adhesive molecules (SAMs) and polysialic acid (PSA). To further explore the mechanism underlying the protective barrier defect in diabetic neuropathy we examined the expression and immunolocalization of these molecules in peripheral nerve. In 6-month diabetic BB/W rats, direct and indirect ELISAs revealed significantly up-regulated N-CAM (P < 0.05), tenascin (Ng-CAM), (P < 0.001) and N-cadherin (A-CAM) (P < 0.03). On the other hand, SAMs showed little change, except for PSA which showed a significantly (P < 0.03) decreased concentration in the diabetic nerve. Immunocytochemical identification of these molecules revealed no visually detectable differences between diabetic and control rats. In conclusion, these data suggest that imbalances between highly interactive molecules responsible for the adhesiveness between terminal Schwann cell loops and the paranodal axolemma may underlie the critical paranodal barrier defect in diabetic neuropathy.