UNLIKE LATE STAGE CHOLESTEROL INHIBITORS, LOVASTATIN EXACERBATE ATYPICAL ABSENCE SEIZURES WITH ONLY MINIMAL EFFECTS ON BRAIN STEROLS
Abstract number :
2.056
Submission category :
Year :
2003
Submission ID :
3924
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Irina Serbanescu, Mary A. Ryan, Stephen C. Cunnane, Miguel A. Cortez, O. Carter Snead III The Brain and Behavior Program, Hospital for Sick Children, Toronto, ON, Canada; Nutritional Sciences, University of Toronto, Toronto, ON, Canada; Neurology, Hospita
AY-9944 induces chronic recurrent seizures in rats that are analogous to atypical absence epilepsy in humans. The mechanism by which AY-9944 produces 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 induce AY-like seizures in rats.
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.
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 less than 10% and did not significantly change brain 7-dehydrocholesterol.
[Supported by: CIHR
Dairy Farmers of Canada]