Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice

Epilepsia
Rafal M KaminskiM A Rogawski

Abstract

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. 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. 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 steroi...Continue Reading

Citations

Feb 5, 2013·Bioorganic & Medicinal Chemistry·Natalia SzkaradekHenryk Marona
Sep 3, 2013·Bioorganic & Medicinal Chemistry·Krzysztof KamińskiSabina Rzepka
Oct 8, 2013·Bioorganic & Medicinal Chemistry Letters·Maciej DawidowskiJadwiga Turło
Jul 23, 2013·Brain Research·Eric R DeutschDavid W Wright
Jun 20, 2013·European Journal of Medicinal Chemistry·Krzysztof KamińskiElżbieta Pękala
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Oct 6, 2005·Epilepsia·Amy R Brooks-Kayal
Jun 11, 2005·Epilepsia·Rafal M KaminskiMichael A Rogawski
Dec 12, 2007·Epilepsia·Adam L HartmanMaciej Gasior
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