DOSE-DEPENDENT CORRELATION OF ATYPICAL ABSENCE SEIZURES AND STEROL CHANGES INDUCED BY AY-9944
Abstract number :
1.066
Submission category :
Year :
2002
Submission ID :
3473
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
O. Carter Snead III, Irina Serbanescu, Miguel A. Cortez, Mary A. Ryan, Stephen C. Cunnane. Division of Neurology, The Brain Behaviour Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Nutritional Sciences, University of Toro
RATIONALE: Developmental treatment with AY-9944 (AY), leads to atypical absence seizures in waking adult rat and mice (Cortez MA et al., Neurology 2001; 56: 341- 349). AY induced seizures appear to be related to AY-induced changes in brain sterols but persisted long after the sterols had return to normal after the last injection (Cortez MA et al., Epilepsia 2002: 43 (1): 3- 8). Whether there is a dose-dependent correlation of atypical seizures and sterol changes induced by AY-9944, remains to be determined.
METHODS: Six groups of Neonatal Long Evans Hooded rats (n=8) received four subcutaneous AY-9944 (AY) injections at 2.5, 5.0, 7.5, 10, 15 and 22.5 mg/kg respectively, or the equivalent volume of saline to controls (n=8). AY or saline treatment was performed every six days with from P2 to P20. Brain harvest was performed 24 hours after each AY or saline injections. Sterol measurements were made with capillary gas chromatograms. Chronic electrodes were implanted from P40 to P50. ECoG recordings at P55, in AY treated and controls.
RESULTS: There was a gradual increment in AY- SWD (Mean seconds/Hour [plusminus] SEM) from 300 [plusminus] 100 at 2.5 mg/kg to 680 [plusminus] 150 at 22.5 mg/Kg. Brain cholesterol decreased from 12 mg/g at 2.5mg Kg to 3.75 mg/g at the dose of 22.5 mg/Kg. 7-dehydrocholesterol increased from 1.75 mg/g at the lowest AY dose to 6 mg/g at the highest AY dose, compared to controls. (p[lt] 0.05)(Student t Test).
CONCLUSIONS: Length, severity of AY-induced seizures and sterol changes increase with the AY dose.
AY - induced atypical absence seizures appear to be closely related to the sterol effects of the drug.
[Supported by: Bloorview Childrens Hospital Foundation, The Hospital for Sick Children Pediatric Consultants, Dairy Farmers of Canada and The Canadian Institutes of Health Research.]