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Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice.
MedLine Citation:
PMID:  15230714     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Low-frequency (6 Hz), long-duration (3 s) electrical stimulation in mice produces seizures characterized by immobility, focal clonus, and automatic behaviors reminiscent of human limbic epilepsy. Renewed interest has been expressed in this seizure model with the recognition that it is sensitive to a broad spectrum of anticonvulsants (AEDs) and may have distinct pharmacologic responsiveness from other in vivo tests of AED efficacy. Here we sought to determine whether the progesterone-derived neuroactive steroid allopregnanolone (5alpha,3alpha-P) and several structural analogues with varying degrees of activity as positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors are protective in the 6-Hz seizure model. METHODS: Mice were pretreated with neuroactive steroids (15 min before) or clonazepam (CZP; 30 min before) to 6-Hz corneal stimulation (32 mA). Animals that failed to exhibit immobility were considered protected. RESULTS: The neuroactive steroids prevented 6-Hz seizures with rank order of potencies (ED50 values): ganaxolone (6.3 mg/kg) > 5alpha,3alpha-P (14.2 mg/kg) > or = 5beta,3alpha-P (14.4 mg/kg) > 5alpha,3beta-P (>100 mg/kg). CZP also was protective (ED(50) value, 0.075 mg/kg). The potencies of the neuroactive steroids and CZP are similar to their previously reported activities in the pentylenetetrazol (PTZ) seizure model. CONCLUSIONS: Neuroactive steroids have comparable potencies in the 6-Hz and PTZ models. Their structural specificity in both models corresponds with their activities as positive allosteric modulators of GABAA receptors, although ganaxolone is more potent than expected, probably because it has greater bioavailability. The 6-Hz model may be a valuable tool in drug development for the identification of GABAergic AEDs.
Rafal M Kaminski; Matthew R Livingood; Michael A Rogawski
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Epilepsia     Volume:  45     ISSN:  0013-9580     ISO Abbreviation:  Epilepsia     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-07-02     Completed Date:  2004-08-11     Revised Date:  2007-02-05    
Medline Journal Info:
Nlm Unique ID:  2983306R     Medline TA:  Epilepsia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  864-7     Citation Subset:  IM    
Copyright Information:
Copyright 2004 International League Against Epilepsy
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4457, U.S.A.
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MeSH Terms
Anticonvulsants / pharmacology,  therapeutic use
Clonazepam / pharmacology,  therapeutic use
Cornea / physiology
Disease Models, Animal
Dose-Response Relationship, Drug
Electric Stimulation*
Epilepsies, Partial / etiology*,  prevention & control
GABA Modulators / pharmacology,  therapeutic use
Pregnanolone / analogs & derivatives*,  pharmacology*,  therapeutic use
Receptors, GABA / drug effects*
Seizures / etiology,  prevention & control*
Steroids / pharmacology,  therapeutic use
Reg. No./Substance:
0/Anticonvulsants; 0/GABA Modulators; 0/Receptors, GABA; 0/Steroids; 128-20-1/Pregnanolone; 1622-61-3/Clonazepam; 38398-32-2/ganaxolone

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