Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice.
OBJECTIVE
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.
Kaminski
Rafal M
RM
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4457, U.S.A.
Livingood
Matthew R
MR
Rogawski
Michael A
MA
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002998:Clonazepam / Q000494:pharmacology / Q000627:therapeutic use; D003315:Cornea / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004828:Epilepsies, Partial / Q000209:etiology* / Q000517:prevention & control; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D018079:Receptors, GABA / Q000187:drug effects*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D013256:Steroids / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D018757:GABA Modulators; D018079:Receptors, GABA; D013256:Steroids; D002998:Clonazepam; C105051:ganaxolone; D011280:Pregnanolone