Naphthalene-induced
cataract in rat
lenses can be completely prevented by AL01576, an
aldose reductase inhibitor (ARI). In an attempt to understand the mechanism of this inhibition, several ARIs were examined to compare their efficacies in preventing
naphthalene cataract, using both in vitro and in vivo models. Two classes of ARIs were tested: One group including AL01576, AL04114 (a AL01576 analog) and
Sorbinil contained the spirohydantoin group, while
Tolrestat contained a
carboxylic acid group. Furthermore, to clarify if
aldose reductase played a role in
naphthalene-induced cataractogenesis in addition to its role in
sugar cataract formation, a new dual
cataract model was established for ARI evaluations. This was achieved by feeding rats simultaneously with high
galactose and
naphthalene or incubating rat
lenses in
culture media containing high
galactose and
naphthalene dihydrodiol. Under these conditions, both cortical
cataract and
perinuclear cataract developed in the same lens. It was found that at the same dosage of 10 mg/kg/day, both AL01576 and AL04114 completely prevented all morphological and biochemical changes in the
lenses of
naphthalene-fed rats.
Sorbinil was less efficacious, while
Tolrestat was inactive. AL01576 showed a dose-response effect in preventing
naphthalene cataract and
at 10 mg/kg/day, it was also effective as an intervention agent after cataractogenesis had begun. With the dual
cataract model,
Tolrestat prevented the high
galactose-induced cortical
cataract but showed no protection against the
naphthalene-induced
perinuclear cataract. AL01576, on the other hand, prevented both
cataract formations. Results for
dulcitol and
glutathione levels were in good agreement with the morphological findings. AL04114, and ARI as potent as AL01576 but without its property for
cytochrome P-450 inhibition, displayed similar efficacy in preventing
naphthalene cataract. Based on these results, it was concluded that the prevention of the
naphthalene cataract probably results from inhibition of the conversion of
naphthalene dihydrodiol to
1,2-dihydroxynaphthalene and that the effect of the ARIs cannot be explained by their inhibition of the
dihydrodiol dehydrogenase activity of
aldose reductase.