Effect of NGF and neurotrophin-3 treatment on experimental diabetic autonomic neuropathy

Peripheral neuropathy is a significant complication of diabetes resulting i n increased patient morbidity and mortality. Deficiencies of neurotrophic s ubstances (e.g. NGF; NT-3, and IGF-I) have been proposed as pathogenetic me chanisms in the development: of distal symmetrical sensory diabetic polyneu ropathy, and salutary effects of exogenous NGF administration have been rep orted in animal models. In comparison, relatively little is known concernin g the effect of NGF on experimental diabetic sympathetic autonomic neuropat hy. We have developed an experimental animal model of diabetic autonomic ne uropathy characterized by the regular occurrence of pathologically distinct ive dystrophic axons in prevertebral sympathetic ganglia and ileal mesenter ic nerves of rats with chronic streptozotocin (STZ)-induced diabetes. Treat ment of STZ-diabetic rats for 2-3 months with pharmacologic doses of NGF or NT-3, neurotrophic substances with known effects on the adult sympathetic nervous system, did not normalize established neuroaxonal dystrophy (NAD) i n diabetic rats in the prevertebral superior mesenteric ganglia (SMG) and i leal mesenteric nerves as had pancreatic islet transplantation and IGF-I in earlier experiments. NGF treatment of control animals actually increased t he frequency of NAD in the SMG. New data suggests that, in adult sympatheti c ganglia, NGF may contribute to the pathogenesis of NAD rather than its am elioration, perhaps as the result of inducing intraganglionic axonal sprout s in which dystrophic changes are superimposed. NT-3 administration did not alter the frequency of NAD in diabetic animals, although it resulted in a significant decrease in NAD in control SMG. Although deficiencies of neurot rophic substances may represent the underlying pathogenesis of a variety of experimental neuropathies, delivery of excessive levels of selected substa nces may produce untoward effects.