Submitted on March 8, 2004
Revised on August 16, 2004
Accepted on August 7, 2004
Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols
Irina Serbanescu, Mary A. Ryan, Ruchika Shukla, Miguel A. Cortez, O. Carter Snead . III, and Stephen C. Cunnane
Department of Neurology, Hospital for Sick Children, Toronto, Ontario M5G 1X8
Corresponding Author: miguel.cortez{at}sickkids.ca
Purpose. AY-9944 exacerbates chronic recurrent seizures in rats which are analogous to atypical absence epilepsy in humans. The mechanism by which AY-9944 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 AY-9944-induced seizures are due to significant reduction in brain cholesterol and/or raised brain 7-dehydrocholesterol by assessing whether three other cholesterol synthesis inhibitors mimic AY-like seizures in rats. Methods. Effects of AY-9944 on brain sterols and spike-and-wave discharge duration were compared with those of two other late stage cholesterol inhibitors (BM 15.766 and U 18,666A) and to the HMG CoA reductase (early stage cholesterol) inhibitor, lovastatin. Results. With BM 15.766 or U18,666A, prolongation of seizure duration and brain sterol changes was similar to that caused by AY-9944. AY-9944 effects on both brain sterols and seizure duration were dose-related. Lovastatin, with or without concurrent AY-9944, also mimicked AY-9944-like seizures but reduced brain cholesterol by <10% and did not significantly change brain 7-dehydrocholesterol. Conclusions. 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.
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