ABSTRACT
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.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Cataract/prevention & control , Diabetic Neuropathies/prevention & control , Enzyme Inhibitors/administration & dosage , Pyrazines/administration & dosage , Spiro Compounds/administration & dosage , Animals , Enzyme Inhibitors/therapeutic use , Pyrazines/therapeutic use , Rats , Spiro Compounds/therapeutic useABSTRACT
Hyperlipidemic ocular lesions are described for Watanabe heritable hyperlipidemic (WHHL) rabbits. Male WHHL rabbits 8 months old exhibited serum hyperlipidemia and ophthalmoscopically yellowish-white lesions along the corneoscleral junction and in the iris. Histopathologically, foamy macrophages aggregated in the stroma of the cornea, iris, and ciliary body were observed. These findings have been interpreted as lipid keratopathy. In addition, multiple clusters of a large number of foamy macrophages occurred throughout the choroid and sclera in association with the blood vessels. The lesions in the choroid and sclera could not be detected ophthalmoscopy, yet were much more prominent than those in the cornea, iris, and ciliary body, suggesting greater involvement and earlier onset of lipidosis at these sites associated with hyperlipidemia in WHHL rabbits.
