Pathogenesis of diabetic neuropathy--do hyperglycemia and aldose reductase inhibitors affect neuroactive steroid formation in the rat sciatic nerves?
The activation of the polyol pathway through aldose reductase (AR) might be involved in diabetic neuropathy. A considerable structural similarity exists between AR and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) (both belonging to aldo-keto reductase superfamily); 3alpha-HSD forms 5alpha-reduced-3alpha-hydroxylated steroids, possibly possessing neurotrophic functions. Aim of these experiments was to test "in vitro" in rat sciatic nerves, whether glucose concentrations in the diabetic range might affect the capacity of 3alpha-HSD to transform dihydroprogesterone (DHP) into tetrahydroprogesterone (THP), a steroid proved to possess neurotrophic effects. The capability of AR inhibitors, drugs used to avoid diabetic complications, to decrease THP formation was also assessed. 3alpha-HSD activity was evaluated by the conversion of labelled DHP into THP (in a single case dihydrotestosterone was used as substrate, and the corresponding 3alpha-hydroxylated metabolite was evaluated). Freshly prepared rat sciatic nerve homogenates were used as source of the enzyme. Whole brain, liver and prostate served as "control" tissues. The results show that glucose added up to a concentration of 400 mg/dL (well above the euglycemic upper level) does not affect the 3alpha-HSD activity in the sciatic nerve and in the other tissues considered. Similarly, when the enzyme was challenged by two AR inhibitors, tolrestat and sorbinil, added in a concentration about 10 times higher than their IC50 for AR, no significant changes were observed. Analogous results were achieved when DHT was used in presence of glucose (400 mg/dL) and sorbinil. We conclude that hyperglycemia or the administration of the AR inhibitors do not affect 3alpha-HSD activity in peripheral nerves and therefore do not reduce the formation of steroid metabolites possibly endowed with neurotrophic action.
Colciago
A
A
Department of Endocrinology, University of Milano, Italy.
Negri-Cesi
P
P
Celotti
F
F
D004092:20-alpha-Dihydroprogesterone / Q000031:analogs & derivatives / Q000096:biosynthesis; D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003929:Diabetic Neuropathies / Q000209:etiology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D009281:Naphthalenes; D013196:Dihydrotestosterone; C040550:tolrestat; D004092:20-alpha-Dihydroprogesterone; D015096:3-Hydroxysteroid Dehydrogenases; D000449:Aldehyde Reductase; C026411:sorbinil