Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice

Abstract

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.