Acetone Potentiation and Influence on the Reversibility of 2,5‐Hexanedione‐Induced Neurotoxicity Studied with Behavioural and Morphometric Methods in Rats

Abstract

The neurobehavioural and morphologic changes and the reversibility in 2,5‐hexanedione‐induced polyneuropathy in rats were studied. The potentiation and influence of acetone on the reversibility of the induced neurotoxicity was also evaluated. Male rats were treated for 6 weeks with 0.5% w/v 2,5‐hexanedione alone or in combination with 0.50% w/v acetone in the drinking water. During the treatment period, neurobehavioural tests (ambulation and rearing in open field, balance on the accelerating rotarod and fore‐and hindlimb muscle strength measurements) were performed weekly. After 6 weeks half of the rats was sacrificed and histopathological lesions in the sciatic nerve and tibial nerve were evaluated by morphometry. Neurotoxicity was induced by 2,5‐hexanedione, and acetone caused a potentiation of this effect in open field ambulation and rearing and in the rotarod test. In the pathological evaluation, giant axonal swelling was observed after 2,5‐hexanedione and 2,5‐hexanedione 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 rats treated with both 2,5‐hexanedione and acetone. The other half of the animals was used to study the reversibility of the neurotoxic effects 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 within the 10 weeks in the 2,5‐hexanedione‐treated rats and not in the combined 2,5‐hexanedione and acetone‐treated rats. The reduction in muscle strength was not reversible. Reversibility of the giant axonal swelling was seen within the recovery period. However, the normalization of the fibre size distribution of the large fibre was only seen in the tibial nerve and not in the sciatic nerve. It is concluded that acetone potentiates the 2,5‐hexanedione‐induced neurotoxicity as measured as enhancement 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 acetone 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.