Studies on the Mechanism of the Epileptiform Activity Induced by U18666A. I. Gross Alteration of the Lipids of Synaptosomes and Myelin

Abstract

U18666A [3-.beta.-(2-diethylaminoethoxy)androst-5-en-17-one HCl], an inhibitor of desmosterol reductase (a terminal enzyme in cholesterol synthesis), has been found to produce chronic epileptiform activity in laboratory animals. Since desmosterol might substitute for cholesterol in neuronal membranes without detriment, the possibility that this drug-induced epilepsy was related to changes in other brain lipids was examined. Chronic treatment of the rat with U18666A, beginning at 1 day of age, resulted in pronounced decreases in the concentration of phospholipids and increases in gangliosides of brain microsomal, synaptosomal and crude myelin fractions. Since total sterol levels were not changed, the ratio of sterols to phospholipids also increased. If drug treatment was stopped at 4 wk of age, brain lipids of all subcellular fractions examined returned to normal levels by 8 wk, and no epileptiform activity was detected. Following 8 wk of continuous treatment, epileptiform activity was present, and the changes in brain lipids were focused in the myelin fraction. Phospholipid levels and the sterol:phospholipid ratio of microsomes and synaptosomes, in contrast to myelin, were near normal; gangliosides were still clearly elevated in all fractions. A reported ability to induce epileptiform activity in rats by treatment with antiserum to brain gangliosides could indicate a special significance of the altered myelin and synaptic gangliosides to the U18666A-induced epilepsy. Some epileptiform conditions could be directly related to alterations in the lipid composition of critical neuronal structures.