Long-term treatment with ranirestat (AS-3201), a potent aldose reductase inhibitor, suppresses diabetic neuropathy and cataract formation in rats.
We investigated the chronic functional and histopathological changes in the sciatic nerve and lens of streptozotocin (STZ)-diabetic rats and evaluated the preventive effects of ranirestat (AS-3201), a potent aldose reductase inhibitor, on these changes. Sorbitol levels in the sciatic nerve and lens, motor nerve conduction velocity (MNCV), and development of cataracts were measured in STZ-diabetic rats given a ranirestat-admixed diet (0.0005%) for 35 weeks. Ranirestat reduced sorbitol accumulation in the sciatic nerve and improved the decrease in MNCV of STZ-diabetic rats. Morphological and morphometric examination of changes in sural nerve revealed that treatment with ranirestat prevented both the deformity of myelinated fibers and the decrease in their axonal and myelin areas (atrophy). Ranirestat also averted the changes in the size frequency histogram of myelinated fibers. Finally, STZ-diabetic rats developed early lens opacities 8 weeks after STZ injection and had cataract by the end of the experimental period. However, in the ranirestat-treated diabetic rats, no lens opacity was observed in any rat throughout the entire experimental period. This study suggests that the polyol pathway plays an important role in the progress of diabetic neuropathy and cataract formation in STZ-diabetic rats. Ranirestat should be a promising agent for the treatment of complications associated with diabetes, especially neuropathy.
Matsumoto
Takafumi
T
Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan. takafumi-matsumoto@ds-pharma.co.jp
Ono
Yoshiyuki
Y
Kuromiya
Akemi
A
Toyosawa
Kaoru
K
Ueda
Yoshinaka
Y
Bril
Vera
V
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002386:Cataract / Q000517:prevention & control*; D003929:Diabetic Neuropathies / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D011719:Pyrazines; D013141:Spiro Compounds; D000449:Aldehyde Reductase; C115070:ranirestat