A combination of the aldose reductase inhibitor, statil, and the prostaglandin E1 analogue, OP1206.alpha CD, completely improves sciatic motor nerve conduction velocity in streptozocin-induced chronically diabetic rats.
In view of the possible implication of multifactorial mechanisms in the pathogenesis of diabetic neuropathy, the aldose reductase inhibitor (ARI), Statil, which ameliorates abnormal sorbitol or myo-inositol metabolism in diabetic nerves, and the prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), which improves diabetic vascular derangements, were administered simultaneously for 2 months to streptozocin (STZ)-induced diabetic rats with 5 months' duration of diabetes, and the effects on sciatic motor nerve conduction velocity (MNCV), Na(+)-K(+)-adenosine triphosphatase (ATPase) activity, and morphology of myelinated nerve fibers (MNF) were compared with the effects of a monotherapy with OP. The combination regimen ameliorated abnormal nerve sorbitol and myo-inositol levels and normalized decreased MNCV and enzyme activity. In contrast, neither sorbitol nor myo-inositol metabolism was ameliorated, and only insufficient improvement of MNCV and morphology of MNF was obtained with a monotherapy with OP. In addition, the combination therapy reversed both a decrease in the percent of large MNF and an increase in the percent of small MNF in diabetic rats, whereas a monotherapy with OP reversed only a decrease in the percent of large MNF. The results might suggest that a multiple-drug therapy with different mechanisms of action has greater effects on diabetic neuropathy than a single-drug therapy and is worthy of clinical consideration.
Yasuda
H
H
Third Department of Medicine, Shiga University of Medical Science, Japan.
Sonobe
M
M
Hisanaga
T
T
Kawabata
T
T
Maeda
K
K
Kikkawa
R
R
Shigeta
Y
Y
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000527:Alprostadil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007294:Inositol / Q000032:analysis; D008297:Male; D009431:Neural Conduction / Q000187:drug effects*; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology*; D011459:Prostaglandins E, Synthetic / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D013012:Sorbitol / Q000032:analysis
D007004:Hypoglycemic Agents; D010793:Phthalazines; D011459:Prostaglandins E, Synthetic; C042829:ponalrestat; D007294:Inositol; D013012:Sorbitol; C025090:ONO 1206; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; D000527:Alprostadil