Autonomic Ganglia

Prominent physiological and less dramatic pathological changes are present in auto-nomic ganglia of DAN. There is a significant reduction in blood flow in autonomic ganglia such as superior cervical ganglion (32,33). This reduction by about 50% is present as early as 1 week and is persistent over 24 weeks (4). Glucose uptake was reduced to 30% of control values in superior cervical ganglion in rats with DAN. a-Lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose, but reversed the deficit in DAN, with a threshold between 10 and 25 mg/kg. ATP, creatine phosphate, and lactate were measured in sciatic nerve and superior cervical ganglion. a-Lipoic acid prevented the reduction in autonomic ganglion creatine phosphate (34).

In both diabetic humans and experimental animals, neuroaxonal dystrophy of auto-nomic nerve terminals has been found, particularly in the prevertebral superior mesen-teric and celiac ganglia, which innervate the diabetic small intestine. However, NGF content, NGF receptor expression, p75 low-affinity neurotrophin receptor (NTR), and trkA (high-affinity NGF receptor) expression showed an approximate doubling of NGF content in the diabetic superior mesenteric and celiac ganglia. No change in NGF

content was detected in the diabetic superior cervical ganglion (35). These observations suggest that increased NGF content in sympathetic ganglia innervating the diabetic alimentary tract coupled with intact receptor expression may produce aberrant axonal sprouting and neuroaxonal dystrophy.

Treatment of STZ-diabetic rats for 2-3 months with pharmacological doses of NGF or NT-3, neurotrophic substances with known effects on the adult sympathetic nervous system, did not prevent and instead increased the frequency of neuroaxonal dystrophy in the superior mesenteric ganglion of normal rats (36). The sorbitol dehydrogenase inhibitor SDI-158 resulted in a dramatically increased frequency of neuroaxonal dystrophy in ileal mesenteric nerves and superior mesenteric ganglion of SDI-treated vs untreated diabetics. The effect of SDI on diabetic ganglion was completely prevented by concomitant administration of the aldose reductase inhibitor sorbinil. Treatment of diabetic rats with sorbinil also prevented these dystrophic changes in diabetic rats not treated with SDI. These findings indicate that sorbitol pathway-linked metabolic imbalances play a critical role in the development of neuroaxonal dystrophy in this model of diabetic sympathetic autonomic neuropathy (37). The morphological changes are confined to neuroaxonal dystrophy. There is no loss of neurons in either superior mesen-teric or superior cervical ganglia after 10 months of severe untreated diabetes (38). A role or aberrant neurofilamentous phosphorylation and its possible involvement in the impaired delivery of neurofilament to the distal axon have been suggested as the relevant mechanism (39).

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