Effects of novel hydantoin derivatives with aldose reductase inhibiting activity on galactose-induced cataract in rats.
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 galactose-induced cataract formation in rats were investigated. Rats fed a 30% galactose diet developed lenticular opacity in the peripheral region by the 6th day of galactose feeding and showed gradual progression of opacity from the equator to the center of lenses. Histological study on the 15th day showed apparent lens fiber swelling and vacuolation predominantly in the equatorial and anterior cortical regions. Biochemical changes such as accumulation of galactitol, depletion of myo-inositol and decrease in glutathione (GSH) content in lenses preceded the appearance of opacity. Remarkable increase in NADPH content and decrease in NADP+ content, in addition to elevation of the ratio of Na+/K+, in lenses were also observed on the 15th day. Both M16209 and M16287 (10, 30 and 100 mg/kg/day, p.o.) dose-dependently ameliorated these morphological and biochemical changes except that restoration of myo-inositol content was incomplete. These results indicate that M16209 and M16287 can prevent galactose-induced cataract formation through amelioration of metabolic disorders and thus have high potential for clinical use in the treatment of some 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* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002386:Cataract / Q000201:enzymology / Q000517:prevention & control*; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005690:Galactose; D006827:Hydantoins / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D001572:Benzofurans; D004791:Enzyme Inhibitors; D006827:Hydantoins; C068409:M 16209; C068408:M 16287; D000449:Aldehyde Reductase; D005690:Galactose