Lacosamide Decreases Neonatal Seizures Without Increasing Apoptosis in Mice
Abstract number :
1.275
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2022
Submission ID :
2204122
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:23 AM
Authors :
Joseph Glykys, MD, PhD – The University of Iowa; Rachel Langton, BS – Research Assistant, Pediatrics, The University of Iowa; Shaunik Sharma, PhD – Post-doctoral researcher, Pediatrics, The University of Iowa; Grant Tiarks, BS – Research Assistant, Pediatrics, The University of Iowa; Alexander Bassuk, MD, PhD – Professor of Pediatrics and Neurology, Pediatrics, The University of Iowa
Rationale: Many seizing neonates fail to respond to first-line anticonvulsant medications. Phenobarbital, a GABAA receptor allosteric modulator, has low efficacy in treating neonatal seizures and causes neuronal apoptosis. Yet, it is one of the most used anticonvulsants in this age group. In neonatal mice, phenobarbital’s poor effectiveness is due to high intraneuronal chloride concentration causing depolarizing actions of GABA. Therefore, another approach to treating neonatal seizures could be using anticonvulsants that do not rely on GABAergic modulation. We evaluated if lacosamide, a non-GABAergic anticonvulsive drug, decreases seizure-like activity in neonatal mice and if it alters apoptosis in vitro and in vivo._x000D_
Methods: In vitro, we measured the effect of different lacosamide concentrations on seizure-like activity induced by the pro-convulsant drug 4- aminopyridine in neonatal (postnatal day, P8-11) and adult (1-1.6-month-old) neocortical brain slices (layer IV/V; C57BL/6J mice). In vivo, we recorded the effect of different lacosamide concentrations on neonatal behavioral seizures (P11-12) induced by kainic acid. We studied the number of neocortical apoptosis in vitro and in vivo using the TUNEL method.
Results: Lacosamide reduced epileptiform activity in neocortical brain slices of neonates and adults in a concentration-dependent manner and to a similar degree. The ratio of seizure-like events to total events also decreased with lacosamide in neonates and adults. In vivo, 40 mg/kg and 50 mg/kg concentrations of lacosamide reduced the duration and number of behavioral seizures while also increasing the latency to convulsive seizures. Lacosamide did not increase total or neuronal apoptosis in the neocortex in vitro or in vivo.
Conclusions: Lacosamide reduces neocortical seizure-like activity in neonatal mice in vitro and in vivo, with no increase in apoptosis. Our results support the use of lacosamide to treat neonatal seizures, with the advantage of not increasing apoptosis.
Funding: JG was funded by NIH/NINDS R01NS115800 and the Iowa Neuroscience Institute. AGB was supported by NIH R01NS098590 and the UNIDM/ Tross Family Fund.
Anti-seizure Medications