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Brain, Vol. 109, No. 4, 649-660, 1986
© 1986 Guarantors of Brain

research-article

PERHEXILINE-INDUCED LIPIDOSIS IN THE DARK AGOUTI (DA) RAT

AN ANIMAL MODEL OF GENETICALLY DETERMINED NEUROTOXICITY

CLAUS MEIER1,, AXEL WAHLLAENDER2, CHRISTIAN W. HESS1 and RUDOLF PREISIG2

1Departments of Neurology, University of Berne Switzerland 2Departments of Clinical Pharmacology, University of Berne Switzerland

Correspondence to: Correspondence to: Dr Claus Meier, Department of Neurology, Inselspital, CH-3010 Bern, Switzerland.

SUMMARY

Perhexiline maleate, an antianginal compound, may cause severe adverse effects such as weight loss, hepatic dysfunction and peripheral neuropathy in a small proportion of patients Since present evidence suggests that poor debrisoquine hydroxylators are at risk, we designed an experimental study comparing its neurotoxic effects in dark Agouti (DA) rats, with poor hydroxylation of debrisoquine with that in Sprague Dawley (SD) rats, which are vigorous hydroxylators. Light and electron microscopic investigations revealed neurotoxic changes in DA rats after cumulative doses which did not cause any changes in SD rats. Although there was no evidence of hepatic disturbance, morphological examination disclosed a heavy lipid deposition in neurons of dorsal root and sympatheticganglia in DA rats. This was correlated with increased plasma and tissue concentrations of the drug. The lipid accumulation was similar to that observed in man with perhexilene-induced neuropathy. Our results suggest that perhexilene neurotoxicity in the DA rat is related to a genetically determined impairment of hydroxylation. The DA rat may serve as an animal model for investigating the potential neurotoxicity of drugs which are metabolized by hydroxylation of the debrisoquine type

Received July 23, 1985. Revised September 27, 1985. Accepted November 19, 1985.


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