Profile of Neuronal Apoptosis After Exposure to Voltage Gated Sodium Channel Blockers: Comparison Between Phenytoin, Lacosamide, Zonisamide, and Rufinamide
Abstract number :
3.276
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2022
Submission ID :
2204513
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:25 AM
Authors :
Eric Witherspoon, BS – Georgetown University; Luke Shea, BS – Georgetown University; Patrick Forcelli, Ph.D – Associate Professor, Pharmacology & Physiology, Georgetown University
This abstract is a recipient of the Grass Young Investigator Award
This abstract has been invited to present during the Basic Science Poster Highlights poster session
This abstract has been invited to present during the Broadening Representation Inclusion and Diversity by Growing Equity (BRIDGE) poster session
Rationale: Acute exposure to many common antiseizure drugs (ASDs) induces widespread neuronal apoptosis during confined periods of early postnatal brain development in rodents. Prototypical antiseizure drugs, including phenobarbital, phenytoin, lamotrigine, and benzodiazepines all produce this effect. While phenytoin, phenobarbital and levetiracetam have traditionally been first-line therapies for the treatment of refractory neonatal seizures, concerns about both efficacy and neuronal toxicity underscore the need for alternate therapies. Several newer generation voltage-gated sodium channel blockers (e.g., lacosamide, rufinamide, zonisamide) are increasing in use in pregnancy and early life, but their safety profile with respect to induction of neuronal apoptosis remains unknown.
Methods: Male and female Sprague-Dawley rat pups were treated with vehicle, phenobarbital (75 mg/kg, positive control), phenytoin (50 mg/kg, positive control), rufinamide (12, 25, 50 mg/kg), zonisamide (12, 25, 50 mg/kg), or lacosamide (12, 25, 50 mg/kg) on postnatal day (P)7. 24 h after treatment, animals were euthanized, perfused, and brains were postfixed over night. Cryosections were made and tissue was processed with Pathogreen (a Fluorojade-like dye) to identify degenerating cells. We analyzed cell death in the hippocampus, striatum, cortex, nucleus accumbens, septum and lateral thalamus. Cells were quantified using QuPath software while blind to treatment status.
Results: Consistent with prior studies, we found that both phenobarbital and phenytoin significantly increased the number of degenerating cells in the hippocampus, nucleus accumbens, and lateral thalamus (P < 0.05). By contrast, rufinamide, zonisamide, and lacosamide were all without effect in all brain regions examined.
Anti-seizure Medications