Pronounced Antiepileptic Activity of the Subtype-selective GABA -positive Allosteric Modulator PF-06372865 in the GAERS Absence Epilepsy Model

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2018 Aug 14

PMID 30101518

Citations 14

Authors

Venceslas Duveau

Derek L Buhl

Alexis Evrard

Celine Ruggiero

Betty Mande-Niedergang

Corinne Roucard

Rachel Gurrell

Affiliations

Soon will be listed here.

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 GABA 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 ) 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 GABA PAM in a model of absence epilepsy. Further study of the antiepileptic properties of PF-06372865 is warranted in patients with absence seizures.

Citing Articles

Huperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model of genetic generalized epilepsy with absence seizures.

Casillas-Espinosa P, Garcia-Olivares J, Li R, Li C, Yu C, Formella A Epilepsia Open. 2024; 9(5):1826-1836.

PMID: 39096485 PMC: 11450589. DOI: 10.1002/epi4.13016.

An Update on Stiripentol Mechanisms of Action: A Narrative Review.

Bacq A, Depaulis A, Castagne V, Le Guern M, Wirrell E, Verleye M Adv Ther. 2024; 41(4):1351-1371.

PMID: 38443647 PMC: 10960919. DOI: 10.1007/s12325-024-02813-0.

Challenges and directions in epilepsy diagnostics and therapeutics: Proceedings of the 17th Epilepsy Therapies and Diagnostics Development conference.

Terman S, Kirkpatrick L, Kerr W, Akiyama L, Baajour W, Atilgan D Epilepsia. 2023; 65(4):846-860.

PMID: 38135921 PMC: 11018495. DOI: 10.1111/epi.17875.

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development.

Perucca E, White H, Bialer M CNS Drugs. 2023; 37(9):781-795.

PMID: 37603261 PMC: 10501930. DOI: 10.1007/s40263-023-01025-4.

Anesthesia and analgesia for experimental craniotomy in mice and rats: a systematic scoping review comparing the years 2009 and 2019.

King H, Reiber M, Philippi V, Stirling H, Aulehner K, Bankstahl M Front Neurosci. 2023; 17:1143109.

PMID: 37207181 PMC: 10188949. DOI: 10.3389/fnins.2023.1143109.

References

Genton P . When antiepileptic drugs aggravate epilepsy. Brain Dev. 2000; 22(2):75-80. DOI: 10.1016/s0387-7604(99)00113-8. View

Riss J, Cloyd J, Gates J, Collins S . Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008; 118(2):69-86. DOI: 10.1111/j.1600-0404.2008.01004.x. View

Manning J, Richards D, Bowery N . Pharmacology of absence epilepsy. Trends Pharmacol Sci. 2003; 24(10):542-9. DOI: 10.1016/j.tips.2003.08.006. View

Liu L, Zheng T, Morris M, Wallengren C, Clarke A, Reid C . The mechanism of carbamazepine aggravation of absence seizures. J Pharmacol Exp Ther. 2006; 319(2):790-8. DOI: 10.1124/jpet.106.104968. View

Macdonald R, Kang J, Gallagher M . Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol. 2010; 588(Pt 11):1861-9. PMC: 2901974. DOI: 10.1113/jphysiol.2010.186999. View

Duveau V, Buhl D, Evrard A, Ruggiero C, Mande-Niedergang B, Roucard C . Pronounced antiepileptic activity of the subtype-selective GABA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model. CNS Neurosci Ther. 2018; 25(2):255-260. PMC: 6488884. DOI: 10.1111/cns.13046. View

Dedeurwaerdere S, van Raay L, Morris M, Reed R, Hogan R, OBrien T . Fluctuating and constant valproate administration gives equivalent seizure control in rats with genetic and acquired epilepsy. Seizure. 2010; 20(1):72-9. DOI: 10.1016/j.seizure.2010.10.011. View

Fradley R, Guscott M, Bull S, Hallett D, Goodacre S, Wafford K . Differential contribution of GABA(A) receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands. J Psychopharmacol. 2006; 21(4):384-91. DOI: 10.1177/0269881106067255. View

Vrielynck P . Current and emerging treatments for absence seizures in young patients. Neuropsychiatr Dis Treat. 2013; 9:963-75. PMC: 3716601. DOI: 10.2147/NDT.S30991. View

10.

Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kalviainen R . Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013; 54(3):551-63. DOI: 10.1111/epi.12074. View

11.

Depaulis A, David O, Charpier S . The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies. J Neurosci Methods. 2015; 260:159-74. DOI: 10.1016/j.jneumeth.2015.05.022. View

12.

Panayiotopoulos C, Agathonikou A, Sharoqi I, PARKER A . Vigabatrin aggravates absences and absence status. Neurology. 1997; 49(5):1467. DOI: 10.1212/wnl.49.5.1467. View

13.

VERGNES M, Marescaux C, Micheletti G, Depaulis A, Rumbach L, Warter J . Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mal-like epilepsy. Neurosci Lett. 1984; 44(1):91-4. DOI: 10.1016/0304-3940(84)90226-x. View

14.

McKernan R, Whiting P . Which GABAA-receptor subtypes really occur in the brain?. Trends Neurosci. 1996; 19(4):139-43. DOI: 10.1016/s0166-2236(96)80023-3. View

15.

Gurbanova A, Aker R, Berkman K, Onat F, van Rijn C, van Luijtelaar G . Effect of systemic and intracortical administration of phenytoin in two genetic models of absence epilepsy. Br J Pharmacol. 2006; 148(8):1076-82. PMC: 1752009. DOI: 10.1038/sj.bjp.0706791. View

16.

Nickolls S, Gurrell R, van Amerongen G, Kammonen J, Cao L, Brown A . Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA receptor positive allosteric modulator PF-06372865. Br J Pharmacol. 2017; 175(4):708-725. PMC: 5786456. DOI: 10.1111/bph.14119. View

17.

Wallengren C, Li S, Morris M, Jupp B, OBrien T . Aggravation of absence seizures by carbamazepine in a genetic rat model does not induce neuronal c-Fos activation. Clin Neuropharmacol. 2005; 28(2):60-5. DOI: 10.1097/01.wnf.0000159955.87511.bc. View

18.

Coenen A, Blezer E, van Luijtelaar E . Effects of the GABA-uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behaviour of rats. Epilepsy Res. 1995; 21(2):89-94. DOI: 10.1016/0920-1211(95)00015-3. View

19.

Cope D, Di Giovanni G, Fyson S, Orban G, Errington A, Lorincz M . Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009; 15(12):1392-8. PMC: 2824149. DOI: 10.1038/nm.2058. View

20.

van Luijtelaar E, Drinkenburg W, van Rijn C, Coenen A . Rat models of genetic absence epilepsy: what do EEG spike-wave discharges tell us about drug effects?. Methods Find Exp Clin Pharmacol. 2003; 24 Suppl D:65-70. View