Polyol pathway activity in nervous tissues of diabetic and galactose-fed rats: effect of dietary galactose withdrawal or tolrestat intervention therapy.
Enhanced polyol pathway activity resulting in an accumulation of sorbitol and a depletion of myoinositol in nervous tissues has been proposed to be important in development of diabetic neuropathies. This investigation demonstrated that in two models of diabetic complications, streptozocin (STZ)-induced diabetic rats and galactose-fed rats, 5 weeks of disease led to an accumulation of sorbitol or galactitol, respectively, in three cranial nerves (the optic (II), trigeminal (V), and vagus (X) nerves), as well as the sciatic nerve, cerebral cortex, and retina. In both models, the cranial nerves and cerebral cortex contained lower levels of accumulated polyol than the sciatic nerve. In addition, myoinositol depletion was observed in the sciatic nerve only. In a second galactose-fed rat study, returning 5-week galactose-fed rats to a normal diet for 6 weeks led to complete elimination of galactitol from the optic nerve, sciatic nerve, and retina and normalization of the sciatic nerve myoinositol concentration. Similarly, continuing the galactose diet for 6 more weeks (ie, a total of 11 weeks) as well as administration of the aldose reductase inhibitor (ARI) tolrestat (20 and 40 mg/kg/day), caused the sciatic nerve to contain a normal myoinositol concentration and a galactitol concentration that was 95% below the level observed in galactose-fed controls. In the optic nerve and retina, tolrestat was less effective, resulting in 69-78% lower galactitol levels. In conclusion, these findings indicate that sorbitol and galactitol accumulate in cranial nerves, brain, and retina without a concomitant decrease in myoinositol. Either withdrawal of the galactose diet or intervention with tolrestat normalized polyol levels in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)
Sredy
J
J
Experimental Therapeutics Department, Wyeth-Ayerst Research, Princeton, New Jersey.
Sawicki
D R
DR
Notvest
R R
RR
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002241:Carbohydrates / Q000032:analysis*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004032:Diet; D005690:Galactose / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D006601:Hexoses / Q000032:analysis; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D010525:Peripheral Nerves / Q000737:chemistry*; D011108:Polymers / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains; D012160:Retina / Q000737:chemistry; D013402:Sugar Alcohols / Q000032:analysis / Q000378:metabolism
D002241:Carbohydrates; D006601:Hexoses; D009281:Naphthalenes; D011108:Polymers; D013402:Sugar Alcohols; C024617:polyol; C040550:tolrestat; D000449:Aldehyde Reductase; D005690:Galactose