Early neurochemical changes in the autonomic neuropathy of the gut in experimental diabetes.

Some neurochemical changes in the gut of rats after five weeks of alloxan-induced diabetes were investigated. It was found that at this stage of diabetes the changes were restricted mainly to the small intestine with a special selectivity for the duodenum. No changes were found in the most part of the large intestine and rectum. The methionine-enkephalin content was markedly reduced throughout the small intestine, while vasoactive intestinal polypeptide was increased in duodenum, ileum and caecum. Substance P content was unaffected, while at later stages of the disease it was significantly reduced in the entire small intestine. Sympathetic noradrenaline and intrinsic serotonin contents were significantly increased in the duodenum and unchanged throughout the rest of the intestine. These data suggest that the small intestine and caecum might be the early target of diabetic autonomic neuropathy, that might involve progressively the rest of the large intestine at later stages as recent results have suggested. It is likely that the gastrointestinal dysfunctions, often present in diabetic patients, might also be due to the combined pre-synaptic alterations, and to the functional imbalance between Gs and Gi/Go transduction proteins recently reported. Insulin therapy, begun seven days after alloxan treatment, reduced drastically the hyperglycaemia, restored normal body growth and prevented all the gut neurochemical changes associated with alloxan-induced diabetes.

Peptide alterations in autonomic diabetic neuropathy prevented by acetyl-L-carnitine.

Autonomic neuropathy and gastrointestinal problems are among the most common complications of diabetes. In this report it is shown that a possible correlation between the two disorders might exist, since diabetes causes a profound alteration of the peptidergic innervation of the gut. It is reported that 14 weeks after diabetes induction with alloxan the levels of substance P and methionine-enkephalin are markedly reduced throughout the intestine, while vasoactive intestinal polypeptide content is dramatically increased. Therefore the enteric innervation of diabetic animals is completely disorganized, with some systems undergoing atrophy and others undergoing hypertrophy. Treatment of diabetic animals with acetyl-L-carnitine prevents the onset of the marked peptide changes described above. The results suggest a potential for acetyl-L-carnitine in the treatment of autonomic neuropathies.

Intraspinal degenerative atrophy caused by sciatic nerve lesions prevented by acetyl-L-carnitine.

Peripheral nerve lesions cause retrograde changes in the spinal cord, involving initially the descending serotoninergic pathways and later the substance P sensory input and methionine-enkephalin interneurons. Within 48 h after sciatic nerve resection there is a significant increase of 5-hydroxyindoleacetic acid in the lumbar spinal cord with no changes of serotonin metabolism in the cell body areas. The immunocytochemical analysis of the spinal cord shows that 20 days after nerve lesion there is a loss of substance P-positive boutons in the laminae I and II of the dorsal horn in the lumbar segment. Such a morphological change is correlated by radioimmunoassay for substance P and methionine-enkephalin, that reveals a significant loss of both peptides. Treatment with acetyl-L-carnitine prevents the early 5-hydroxyindoleacetic acid increase and the reduction of peptide content observed 20 days after lesioning the sciatic nerve. These data suggest that treatment with acetyl-L-carnitine exerts a neuroprotective activity preventing the retrograde changes triggered by peripheral nerve lesions.