Effects of novel aldose reductase inhibitors, M16209 and M16287, on streptozotocin-induced diabetic neuropathy in rats.
We investigated the effects of novel aldose reductase inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), on neuropathy in streptozotocin-induced (STZ) diabetic rats. Both compounds (3-100 mg/kg per day, p.o.) dose dependently improved the decreased motor nerve conduction velocity in the sciatic nerve during a 14-day treatment period. These compounds also partially ameliorated the diabetes-induced histological changes in the sciatic nerve. A distinct increase in sorbitol content and a slight decrease in myo-inositol content was observed in the sciatic nerve of STZ diabetic rats, and the sorbitol accumulation was dose dependently suppressed by treatment with M16209 and M16287. Treatment started at an earlier period was more effective in the suppression of sorbitol accumulation. There was a significant correlation between motor nerve conduction velocity and nerve sorbitol content, whereas there was none between motor nerve conduction velocity and myo-inositol content. The present study indicates that M16209 and M16287 are potent aldose reductase inhibitors expected to be useful for the treatment of diabetic complications.
Kato
K
K
Department of Pharmacology, Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Tokyo, Japan.
Nakayama
K
K
Ohta
M
M
Murakami
N
N
Murakami
K
K
Mizota
M
M
Miwa
I
I
Okuda
J
J
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006827:Hydantoins / Q000494:pharmacology*; D007294:Inositol / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000502:physiology; D009431:Neural Conduction / Q000502:physiology; D011108:Polymers / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013311:Streptozocin
D001572:Benzofurans; D006827:Hydantoins; D011108:Polymers; C024617:polyol; C068409:M 16209; C068408:M 16287; D007294:Inositol; D013311:Streptozocin; D000449:Aldehyde Reductase