THE PREVENTIVE EFFECT OF ALDOSE REDUCTASE INHIBITION ON DIABETIC OPTIC NEUROPATHY IN THE BB W-RAT/

A polyol-pathway-related mechanism has been invoked in the pathogenesi s of murine and human diabetic peripheral neuropathy in which progress ive axonal atrophy and axo-glial dysjunction constitute the cardinal s tructural abnormalities. We have previously reported similar neuroanat omical changes in the optic nerve of 6-month diabetic BB/W-rats. In th e present study we demonstrate progression of axonal atrophy and axo-g lial dysjunction in the optic nerve in 12-month diabetic BB/W-rats. Th ese structural lesions showed highly significant correlations with the associated prolongation of the latencies of the visual evoked potenti als, suggesting that axo-glial dysjunction and axonal atrophy are majo r determinants for impaired optic nerve function. As in peripheral ner ve, the polyol-pathway is present in the optic nerve and is activated by hyperglycaemia and galactosaemia. In this study we further examined the treatment effect of the aldose reductase inhibitor ponalrestat, g iven from 3 weeks of diabetes and continued throughout the study proto col. This regimen resulted ih complete prevention of axo-glial dysjunc tion, and had a significant ameliorating effect on visual evoked poten tial latencies, but had no effect on optic nerve axonal atrophy. This latter finding differs from the effect of aldose reductase inhibition on diabetic peripheral nerve and suggests that axonal atrophy of centr al nerve tracts in diabetes may be the consequence of other metabolic abnormalities or alternatively the present regimen was insufficient to protect central axons from the effects of an increased activity of th e polyol pathway.