Age-dependent anticonvulsant actions of perampanel and brivaracetam in the methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3
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SHORT COMMUNICATION
Age‑dependent anticonvulsant actions of perampanel and brivaracetam in the methyl‑6,7‑dimethoxy‑4‑ethyl‑beta‑carboline‑3‑carboxylate (DMCM) model of seizures in developing rats Marko Culjat1,2 · Megan N. Huizenga2 · Patrick A. Forcelli2,3,4 Received: 7 September 2020 / Revised: 9 October 2020 / Accepted: 31 October 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background The antiseizure drugs commonly used as first- and second-line treatments for neonatal seizures display poor efficacy. Thus, drug mechanisms of action that differ from these typical agents might provide better seizure control. Perampanel, an AMPA-receptor antagonist, and brivaracetam, a SV2A ligand, might fill that role. Methods We utilized methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) to evoke seizures in rats to assess the efficacy of perampanel and brivaracetam treatment in clinically relevant doses. Results In postnatal day (P)10 rats, neither perampanel nor brivaracetam suppressed seizure activity. By contrast, in P21 rats, both drugs decreased the severity of seizures. This effect was evident at the 20 and 40 mg/kg doses of brivaracetam and at the 0.9 and 2.7 mg/kg doses of perampanel. Conclusions These data indicate that while the efficacy of these drugs may be limited for neonatal seizures, their efficacy increases over early postnatal development. Keywords Neonatal seizure · SV2A ligand · AMPA receptor antagonist · Beta carboline Abbreviations AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid ASM Antiseizure medication BRV Brivaracetam DMCM Methyl-6,7-dimethoxy-4-ethyl-beta-carboline3-carboxylate LEV Levetiracetam PER Perampanel
* Patrick A. Forcelli [email protected] 1
Department of Neonatal‑Perinatal Medicine, MedStar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
2
Pharmacology and Physiology, Georgetown University, New Research Building W209B, Washington, DC 20057, USA
3
Neuroscience, Georgetown University, Washington, DC, USA
4
Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA
P Postnatal day SV2A Synaptic vesicle protein 2A
Introduction The incidence of neonatal seizures is 1–3 per 1000, with a markedly higher incidence in premature infants [1]. With approximately 3.9 million deliveries per year in the USA [2], an estimated 10,000 newborns each year are affected by the choice of antiseizure medications (ASMs) in the USA alone. Unfortunately, the first- and second-line therapies for neonatal seizures (phenobarbital and phenytoin, respectively) display poor (less than 50%) efficacy [3, 4]. Thus, therapies that work through different mechanisms of action are of interest. In the past several years, multiple ASMs with unique mechanisms of action have been approved for clinical use in pediatric populations, including cannabidiol, approved for treatment of Dravet and Lennox-Gastaut syndromes [5, 6], and eslicarbazepine, approved as an adjunctive treatment fo
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