Nerve fiber regeneration following axotomy in the diabetic biobreeding Worcester rat: The effect of ARI treatment

Abstract

Diabetic neuropathy is characterized by progressive nerve fiber degeneration resulting in nerve fiber loss. In order to examine what role impaired nerve fiber regeneration may play in the progressive net nerve fiber loss, spontaneously diabetic biobreeding Worcester (BB/W) rats were subjected to sciatic nerve axotomy at 6 weeks of diabetes. Myelinated nerve fiber regeneration was examined morphologically and morphometrically at various time points following axotomy. The data were compared with those of axotomized control rats and diabetic rats treated with an aldose reductase inhibitor (ARI) from 1 week after onset of diabetes. Diabetic rats showed a significant attenuation of nerve fiber regeneration during the first 6 weeks following axotomy, which was normalized at 4 months postaxotomy. ARI treatment resulted in an initial burst of supranormal regeneration, which was normalized at 4 months postaxotomy. Impaired nerve fiber regeneration in diabetic rats was associated with a marked delay in preceding Wallerian degeneration and decreased phagocytic activity by macrophages, changes not demonstrated in ARI-treated diabetic rats. We propose that the impaired nerve fiber regeneration in the diabetic BB/W rat may, in part, be the result of impaired recruitment and/or function of macrophages necessary for the initiation of normal nerve fiber regeneration. The corrective effects of ARI treatment on the regenerative ability of diabetic peripheral nerve suggest that an activated polyol pathway may impact on both intrinsic and extrinsic mechanisms governing nerve fiber regeneration.