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

Rafal M. Kaminski, Matthew R. Livingood, Michael A Rogawski

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

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 (5α,3α-P) and several structural analogues with varying degrees of activity as positive allosteric modulators of γ-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) > 5α,3α-P (14.2 mg/kg) ≥ 5β,3α-P (14.4 mg/kg) > 5<,3>-P (> 100 mg/kg). CZP also was protective (ED50 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.

Original languageEnglish (US)
Pages (from-to)864-867
Number of pages4
JournalEpilepsia
Volume45
Issue number7
DOIs
StatePublished - Jul 2004
Externally publishedYes

Fingerprint

Pregnanolone
GABA-A Receptors
Electric Stimulation
Seizures
Steroids
Pentylenetetrazole
Aminobutyrates
Clonazepam
Anticonvulsants
Biological Availability
Progesterone
Epilepsy
Pharmaceutical Preparations

Keywords

  • 6-Hz model
  • Allopregnanolone
  • Clonazepam
  • GABA -receptor modulation
  • Ganaxolone
  • Mouse
  • Neuroactive steroid
  • Seizure

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Allopregnanolone analogs that positively modulate GABAA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice. / Kaminski, Rafal M.; Livingood, Matthew R.; Rogawski, Michael A.

In: Epilepsia, Vol. 45, No. 7, 07.2004, p. 864-867.

Research output: Contribution to journalArticle

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abstract = "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 (5α,3α-P) and several structural analogues with varying degrees of activity as positive allosteric modulators of γ-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) > 5α,3α-P (14.2 mg/kg) ≥ 5β,3α-P (14.4 mg/kg) > 5<,3>-P (> 100 mg/kg). CZP also was protective (ED50 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.",
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