title: Profile of anticonvulsant action of levetiracetam, tiagabine and phenobarbital against seizures evoked by DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in neonatal rats.
abstract: Levetiracetam (LEV) and tiagabine (TGB) are utilized for the treatment of seizures, including neonatal seizures. However, relatively little is known about the preclinical therapeutic profile of these drugs during brain development. The relative paucity of information regarding these drugs in neonatal animals may be due to their unusual profile of anticonvulsant action in experimental models. LEV and TGB are without effect against seizures in several common screening models (e.g., the maximal electroshock test, maximal pentylenetetrazole seizures), instead showing preferential efficacy against models of partial seizures. We have recently described a method for reliably evoking partial seizures in neonatal animals by systemic administration of the chemoconvulsant, DMCM (Kulick et al., 2014, Eur. J. Pharmacol., doi:10.1016/j.ejphar.2014.06.012). DMCM is a negative allosteric modulator of GABAA receptors, and offers a wide separation between doses required to evoke complex partial as compared to tonic-clonic seizures. Here we used DMCM to evaluate the effect of LEV and TGB against seizures in postnatal day (P) 10 rat pups. We compared the profile of LEV and TGB to that of phenobarbital (PB), the most widely utilized anticonvulsant in neonates. We found that LEV significantly protected against DMCM seizures when administered in doses of 10mg/kg and greater. TGB protected against DMCM-evoked seizures when administered in doses of 1mg/kg or greater. PB protected against DMCM-evoked seizures when administered in doses of 5mg/kg or greater. These data provide preclinical evidence for the efficacy of LEV and TGB in neonates and underscore the utility of DMCM for screening anticonvulsant action in neonatal animals.
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Catherine V
authors.initials: CV
authors.lastname: Kulick
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Gutherz
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Veronica C
authors.initials: VC
authors.lastname: Beck
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Medvedeva
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Soper
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA; Interdisciplinary Program in Neuroscience, Georgetown University, School of Medicine, Washington, DC 20007, USA. Electronic address: paf22@georgetown.edu.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Forcelli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D000077287:Levetiracetam; D008297:Male; D009557:Nipecotic Acids / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy*; D000078308:Tiagabine
chemical_list: D000927:Anticonvulsants; D002243:Carbolines; D009557:Nipecotic Acids; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D000077287:Levetiracetam; D010634:Phenobarbital; D000078308:Tiagabine; D010889:Piracetam
keywords: (2S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracatam, PubChem CID: 5284583); (3R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]piperidine-3-carboxylic acid (Tiagabine hydrochloride, PubChem CID: 91274); 5-ethyl-4,6-dioxo-5-phenyl-1H-pyrimidin-2-olate (Phenobarbital sodium, PubChem CID: 23674889); Antiepileptic drug; Beta carboline; Complex partial seizure; Ontogeny; methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM, PubChem CID: 45261899)