Pronounced antiepileptic activity of the subtype-selective GABAA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model.

Abstract

AIM:

Antiepileptic drugs that modulate GABA have the potential to aggravate or improve the symptoms of absence epilepsy. PF-06372865 is a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines. The aim of this study was to assess the antiepileptic effect of PF-06372865 in a preclinical model of absence seizures.

METHODS:

Genetic absence epilepsy rats from Strasbourg (GAERS) was implanted with four cortical electrodes over the frontoparietal cortex, and the number and cumulated duration of spike-and-wave discharges (SWDs) were recorded for 10-90 minutes following administration of vehicle, PF-06372865, and positive controls diazepam and valproate.

RESULTS:

PF-06372865 (0.3, 1, 2, 10 mg kg-1 ) dose-dependently reduced the expression of SWDs, including full suppression at the highest doses by 30 minutes after administration.

CONCLUSIONS:

PF-06372865 demonstrated robust efficacy in suppressing SWDs in the GAERS model of absence epilepsy. To our knowledge, this is the first demonstration of antiepileptic activity of an α2/3/5-subtype-selective GABAA PAM in a model of absence epilepsy. Further study of the antiepileptic properties of PF-06372865 is warranted in patients with absence seizures.

• Authors: Venceslas Duveau, Derek L Buhl, Alexis Evrard, Céline Ruggiero, Betty Mandé-Niedergang, Corinne Roucard, Rachel Gurrell
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 25 Issue 2 Pg. 255-260 (02 2019) ISSN: 1755-5949 [Electronic] England
• PMID: 30101518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 John Wiley & Sons Ltd.

Chemical References

• Anticonvulsants
• GABA Modulators
• Imidazoles
• PF-06372865
• Pyridazines
• Receptors, GABA-A
• Valproic Acid
• Diazepam

Topics

• Animals
• Anticonvulsants (therapeutic use)
• Diazepam (therapeutic use)
• Dose-Response Relationship, Drug
• Electrocorticography
• Electrodes, Implanted
• Electroencephalography
• GABA Modulators (therapeutic use)
• Imidazoles (therapeutic use)
• Male
• Pyridazines (therapeutic use)
• Rats
• Receptors, GABA-A (drug effects)
• Seizures (drug therapy)
• Valproic Acid (therapeutic use)