Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols.
AY-9944 (AY) exacerbates chronic recurrent seizures in rats that are analogous to atypical absence epilepsy in humans. The mechanism by which AY affects the slow spike-and-wave discharges associated with these seizures is not known, but is thought to involve inhibition of cholesterol synthesis. We tested the hypothesis that seizures seen with AY are due to significant reduction in brain cholesterol and/or elevated brain 7-dehydrocholesterol by assessing whether three other cholesterol synthesis inhibitors mimic AY seizures in rats. Effects of AY on brain sterols and spike-and-wave discharge duration were compared with those of two other late-stage cholesterol inhibitors [BM 15.766 (BM) and U18666A (UA)] and to an HMG-CoA reductase (early-stage cholesterol) inhibitor, lovastatin. With BM or UA, prolongation of seizure duration and brain sterol changes was similar to that caused by AY. AY effects on both brain sterols and seizure duration were dose-related. Lovastatin, with or without concurrent AY, mimicked AY seizures but reduced brain cholesterol by <10% and did not significantly change brain 7-dehydrocholesterol. Either lovastatin has a different mechanism of action than these late-stage cholesterol inhibitors or the brain sterol changes are not directly responsible for seizures in this model.
Division of Neurology, Brain and Behavior Program, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Irina
I
Serbanescu
Mary Ann
MA
Ryan
Ruchika
R
Shukla
Miguel A
MA
Cortez
O Carter
OC
Snead
Stephen C
SC
Cunnane
D000818:Animals; D001835:Body Weight; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D003684:Dehydrocholesterols / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004832:Epilepsy, Absence / Q000188:drug therapy*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000378:metabolism / Q000494:pharmacology*; D008954:Models, Biological; D051381:Rats; D020318:Rats, Long-Evans; D013261:Sterols / Q000378:metabolism; D013997:Time Factors; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
D003684:Dehydrocholesterols; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; D002784:Cholesterol; D008148:Lovastatin; C016705:7-dehydrocholesterol