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Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus.
Neuropharmacology. 2013 Apr; 67:136-43.N

Abstract

Benzodiazepines (BZDs) are first-line therapy for treatment of status epilepticus (SE). However, BZD treatment is negatively affected by seizure duration due to decreases in BZD-sensitive GABA(A) receptors during prolonged SE. Stiripentol (STP) is an anticonvulsant that is used as add-on treatment for Dravet Syndrome. Recent studies have shown that STP is a positive allosteric modulator of the GABA(A) receptor. The subunit selectivity of STP at this receptor suggests that it would be anticonvulsant in both brief as well as prolonged SE. We tested this possibility by comparing the ability of STP and diazepam (DZP), a commonly used BZD, to terminate behavioral convulsions in a rodent model of pharmacoresistant SE. We found that STP was anticonvulsant in this model and remained effective during prolonged SE, unlike DZP which exhibited a 14 fold increase in its ED(50). Whole cell recording from hippocampal slices from these animals revealed that STP potentiated GABAergic IPSCs, as well as tonic GABAergic current by acting at a site on the GABA(A) receptor separate from the BDZ binding site. Potentiation of GABAergic currents by STP remained intact during prolonged SE, while potentiation by DZP was lost. Both IPSC potentiation and anticonvulsant activity of STP were greater in younger animals than in adults. These findings suggest that at doses that yield therapeutically relevant concentrations, STP is anticonvulsant by potentiating GABAergic inhibition and that the subunit selectivity profile of STP enables it to remain effective despite GABA(A) receptor subunit changes during prolonged SE.

Authors+Show Affiliations

Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, School of Medicine, Columbia, SC 29208, USA. Denise.Grosenbaugh@uscmed.sc.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23168114

Citation

Grosenbaugh, Denise K., and David D. Mott. "Stiripentol Is Anticonvulsant By Potentiating GABAergic Transmission in a Model of Benzodiazepine-refractory Status Epilepticus." Neuropharmacology, vol. 67, 2013, pp. 136-43.
Grosenbaugh DK, Mott DD. Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. Neuropharmacology. 2013;67:136-43.
Grosenbaugh, D. K., & Mott, D. D. (2013). Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. Neuropharmacology, 67, 136-43. https://doi.org/10.1016/j.neuropharm.2012.11.002
Grosenbaugh DK, Mott DD. Stiripentol Is Anticonvulsant By Potentiating GABAergic Transmission in a Model of Benzodiazepine-refractory Status Epilepticus. Neuropharmacology. 2013;67:136-43. PubMed PMID: 23168114.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. AU - Grosenbaugh,Denise K, AU - Mott,David D, Y1 - 2012/11/17/ PY - 2012/08/29/received PY - 2012/11/06/revised PY - 2012/11/07/accepted PY - 2012/11/22/entrez PY - 2012/11/22/pubmed PY - 2013/11/5/medline SP - 136 EP - 43 JF - Neuropharmacology JO - Neuropharmacology VL - 67 N2 - Benzodiazepines (BZDs) are first-line therapy for treatment of status epilepticus (SE). However, BZD treatment is negatively affected by seizure duration due to decreases in BZD-sensitive GABA(A) receptors during prolonged SE. Stiripentol (STP) is an anticonvulsant that is used as add-on treatment for Dravet Syndrome. Recent studies have shown that STP is a positive allosteric modulator of the GABA(A) receptor. The subunit selectivity of STP at this receptor suggests that it would be anticonvulsant in both brief as well as prolonged SE. We tested this possibility by comparing the ability of STP and diazepam (DZP), a commonly used BZD, to terminate behavioral convulsions in a rodent model of pharmacoresistant SE. We found that STP was anticonvulsant in this model and remained effective during prolonged SE, unlike DZP which exhibited a 14 fold increase in its ED(50). Whole cell recording from hippocampal slices from these animals revealed that STP potentiated GABAergic IPSCs, as well as tonic GABAergic current by acting at a site on the GABA(A) receptor separate from the BDZ binding site. Potentiation of GABAergic currents by STP remained intact during prolonged SE, while potentiation by DZP was lost. Both IPSC potentiation and anticonvulsant activity of STP were greater in younger animals than in adults. These findings suggest that at doses that yield therapeutically relevant concentrations, STP is anticonvulsant by potentiating GABAergic inhibition and that the subunit selectivity profile of STP enables it to remain effective despite GABA(A) receptor subunit changes during prolonged SE. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/23168114/Stiripentol_is_anticonvulsant_by_potentiating_GABAergic_transmission_in_a_model_of_benzodiazepine_refractory_status_epilepticus_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(12)00536-9 DB - PRIME DP - Unbound Medicine ER -