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Stiripentol in refractory status epilepticus.
Epilepsia. 2013 Sep; 54 Suppl 6:103-5.E

Abstract

Benzodiazepines (BZDs), which enhance γ-aminobutyric acid (GABAA) receptor-mediated inhibition, are the first-line therapy for treatment of status epilepticus (SE). However, pharmacoresistance to BZDs develops rapidly after SE initiation. This is due to an activity-dependent internalization of BZD-sensitive GABAA receptors during SE. Stiripentol (STP) is a positive allosteric modulator of GABAA receptors with a unique subunit selectivity profile. We report that in a rodent model of SE, STP terminates behavioral seizures and remains effective in established SE when seizures have become BZD resistant. The anticonvulsant effects of STP are age dependent, with greater potency in juvenile animals. Whole cell recordings from dentate granule cells in hippocampal slices reveal that STP potentiates GABAergic inhibitory postsynaptic currents (IPSCs) and tonic GABAergic currents by acting at a site on the GABAA receptor that is separate from the benzodiazepine binding site. This potentiation persists in established SE, whereas potentiation of GABAergic inhibition by BZDs is lost. STP potentiates IPSCs in juvenile animals with greater potency than in adult animals. We suggest that STP, either alone or as add-on therapy, may prove useful in treating established and BZD-resistant status epilepticus. Furthermore, STP may be particularly effective in terminating SE in children when SE is most prevalent.

Authors+Show Affiliations

Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29209, U.S.A.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

24001087

Citation

Grosenbaugh, Denise K., and David D. Mott. "Stiripentol in Refractory Status Epilepticus." Epilepsia, vol. 54 Suppl 6, 2013, pp. 103-5.
Grosenbaugh DK, Mott DD. Stiripentol in refractory status epilepticus. Epilepsia. 2013;54 Suppl 6:103-5.
Grosenbaugh, D. K., & Mott, D. D. (2013). Stiripentol in refractory status epilepticus. Epilepsia, 54 Suppl 6, 103-5. https://doi.org/10.1111/epi.12291
Grosenbaugh DK, Mott DD. Stiripentol in Refractory Status Epilepticus. Epilepsia. 2013;54 Suppl 6:103-5. PubMed PMID: 24001087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stiripentol in refractory status epilepticus. AU - Grosenbaugh,Denise K, AU - Mott,David D, PY - 2013/9/5/entrez PY - 2013/9/6/pubmed PY - 2013/12/16/medline KW - Anticonvulsant KW - Benzodiazepine KW - Dentate gyrus KW - GABAergic inhibition KW - IPSC KW - Seizure SP - 103 EP - 5 JF - Epilepsia JO - Epilepsia VL - 54 Suppl 6 N2 - Benzodiazepines (BZDs), which enhance γ-aminobutyric acid (GABAA) receptor-mediated inhibition, are the first-line therapy for treatment of status epilepticus (SE). However, pharmacoresistance to BZDs develops rapidly after SE initiation. This is due to an activity-dependent internalization of BZD-sensitive GABAA receptors during SE. Stiripentol (STP) is a positive allosteric modulator of GABAA receptors with a unique subunit selectivity profile. We report that in a rodent model of SE, STP terminates behavioral seizures and remains effective in established SE when seizures have become BZD resistant. The anticonvulsant effects of STP are age dependent, with greater potency in juvenile animals. Whole cell recordings from dentate granule cells in hippocampal slices reveal that STP potentiates GABAergic inhibitory postsynaptic currents (IPSCs) and tonic GABAergic currents by acting at a site on the GABAA receptor that is separate from the benzodiazepine binding site. This potentiation persists in established SE, whereas potentiation of GABAergic inhibition by BZDs is lost. STP potentiates IPSCs in juvenile animals with greater potency than in adult animals. We suggest that STP, either alone or as add-on therapy, may prove useful in treating established and BZD-resistant status epilepticus. Furthermore, STP may be particularly effective in terminating SE in children when SE is most prevalent. SN - 1528-1167 UR - https://www.unboundmedicine.com/medline/citation/24001087/Stiripentol_in_refractory_status_epilepticus_ L2 - https://doi.org/10.1111/epi.12291 DB - PRIME DP - Unbound Medicine ER -