Studies on the mechanisms of the epileptiform activity induced by U186661. I Gross alteration of the lipids of synaptosomes and myelin.
U18666A, 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 present study was undertaken to examine the possibility that this drug-induced epilepsy was related to changes in other brain lipids. Chronic treatment of rat with U18666A, beginning at one 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 weeks of age, brain lipids of all subcellular fractions examined returned to normal levels by 8 weeks, and no epileptiform activity was detected. However, following 8 weeks 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; however, 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. We suggest that some epileptiform conditions could be directly related to alterations in the lipid composition of critical neuronal structures.
D000736:Androstenes; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D003897:Desmosterol / Q000378:metabolism; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D050356:Lipid Metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D000736:Androstenes; D005732:Gangliosides; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D003897:Desmosterol; D002784:Cholesterol