tretinoin and Diabetic-Neuropathies

Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neuropathy. All-trans retinoic acid (RA) increases the expression of neural growth factor and its receptor participating in translation pathways. This study evaluates RA as a treatment of diabetic neuropathy: 120 mice were assigned randomly to 4 groups. Group A (n = 30) was taken as control; group B (n = 30) received 50 mg/kg intraperitoneal streptozotocin (STZ); group C (n = 30) received STZ, and after diabetic neuropathy developed, they were treated with subcutaneous RA 20 mg/kg daily during 60 days; and group D (n = 30) only received RA. Plasma glucose, thermosensitive tests, serum, and the nerve contents of NGF were measured in all animals. Evaluation by electron microscopy was performed in search of morphologic changes secondary to neuropathy and nerve regeneration. Diabetic mice had an increased threshold to pain. Treatment with RA in diabetic mice reverted changes in sensitivity as compared with diabetic mice that received placebo (P < 0.001). No differences in pain threshold among controls, RA, and diabetes mellitus (DM) + RA groups were found. Glucose levels were not affected by the treatment with RA. NGF diminished significantly in the sciatic nerve in diabetic mice as compared with controls and with the RA group. Animals with DM + RA had a significant increase of NGF in nerves as compared with the other groups. RA also regressed the ultrastructural changes induced by diabetes that showed increased neural regeneration. RA can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of the increased of NGF concentrations in nerve terminals.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drug Evaluation, Preclinical; Male; Mice; Nerve Growth Factor; Nerve Regeneration; Random Allocation; Sciatic Nerve; Tretinoin

Decreased production of nerve growth factor (NGF) may contribute to diabetic neuropathy; however, exogenous administration of NGF induces only a modest benefit. Retinoic acid (RA) promotes the endogenous expression of nerve growth factor and its receptor. We studied the effects of RA on diabetic neuropathy in mice with streptozotocin-induced diabetes.. One hundred and twenty National Institutes of Health (NIH) albino mice randomly separated into three groups (A, n = 30; B, n = 30; C, n = 60). Diabetes mellitus was induced with streptozotocin in groups A and B. Animals from group A received a subcutaneous injection of 25 microl of mineral oil daily for 90 days, while those from group B received a subcutaneous injection of 20 mg kg(-1) of all trans RA. Animals from group C were taken as controls. At the end of the experiment, blood glucose and NGF levels (both in serum and sciatic nerve) were measured. Two behavioural tests were conducted in a blind fashion to detect abnormalities of thermal and nociceptive thresholds.. Contents of NGF in healthy untreated mice were 1490 +/- 190 pg mg(-1) in nerve and 113 +/- 67 pg mg(-1) in serum; in diabetic untreated mice the values were 697 +/- 219 pg mL(-1) in nerve and 55 +/- 41 pg mL(-1) in serum; and in diabetic mice treated with RA the values were 2432 +/- 80 pg mL(-1) in nerve and 235 +/- 133 pg mg(-1) in serum (P < 0.002). Ultrastructural evidence of nerve regeneration and sensitivity tests improved in diabetic mice treated with RA as compared with nontreated diabetic mice.. Our findings indicate that administration of RA increases serum and nerve contents of NGF in diabetic mice and suggest a potential therapeutic role for retinoic acid in diabetic patients.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Male; Mice; Nerve Growth Factor; Nerve Regeneration; Sciatic Nerve; Tretinoin

We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression.. Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose.. AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase.. The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Caspase 3; Caspase Inhibitors; Caspases; Cell Line, Tumor; Choline O-Acetyltransferase; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drug Synergism; Enzyme Inhibitors; Esophagogastric Junction; Ganglia; Gene Expression; Glucose; Glycation End Products, Advanced; Immunohistochemistry; Insulin; Male; Nitrergic Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Penis; Rats; Rats, Wistar; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Serum Albumin; Tretinoin