ACETONE POTENTIATION AND INFLUENCE ON THE REVERSIBILITY OF 2,5-HEXANEDIONE-INDUCED NEUROTOXICITY STUDIED WITH BEHAVIORAL AND MORPHOMETRIC METHODS IN RATS

The neurobehavioural and morphologic changes and the reversibility in 2,5-hexanedione-induced polyneuropathy in rats were studied. The poten tiation and influence of acetone on the reversibility of the induced n eurotoxicity was also evaluated. Male rats were treated for 6 weeks wi th 0.5% w/v 2,5-hexanedione alone or in combination with 0.50% w/v ace tone in the drinking water. During the treatment period, neurobehaviou ral tests (ambulation and rearing in open field, balance on the accele rating rotarod and fore-and hindlimb muscle strength measurements) wer e performed weekly. After 6 weeks half of the rats was sacrificed and histopathological lesions in the sciatic nerve and tibial nerve were e valuated by morphometry. Neurotoxicity was induced by 2,5-hexanedione, and acetone caused a potentiation of this effect in open field ambula tion and rearing and in the rotarod test. In the pathological evaluati on, giant axonal swelling was observed after 2,5-hexanedione and 2,5-h exanedione plus acetone. In nerve fibre cross sections, a significant change of the distribution of fibre area size was observed in animals treated with 2,5-hexanedione. Aggravation of the lesions was seen in r ats treated with both 2,5-hexanedione and acetone. The other half of t he animals was used to study the reversibility of the neurotoxic effec ts within a dose-free period of 10 weeks. Reversibility of the effect on ambulation was complete within the recovery period, but the effects on rearing and balance in the rotarod test were only reversible withi n the 10 weeks in the 2,5-hexanedione-treated rats and not in the comb ined 2,5-hexanedione and acetone-treated rats. The reduction in muscle strength was not reversible. Reversibility of the giant axonal swelli ng was seen within the recovery period. However, the normalization of the fibre size distribution of the large fibre was only seen in the ti bial nerve and not in the sciatic nerve. It is concluded that acetone potentiates the 2,5-hexanedione-induced neurotoxicity as measured as e nhancement of the behavioural and morphological changes. The combined acetone and 2,5-hexanedione effects are similar to the effects of 2,5- hexanedione alone. The most probable mechanism of action of the aceton e potentiation is an effect on the toxicokinetics of 2,5-hexanedione. The combined neurotoxic effects of acetone and 2,5-hexanedione are not reversible within a recovery period of 10 weeks.