Early intervention with levetiracetam prevents the development of cortical hyperexcitability and spontaneous epileptiform activity in two models of neurotrauma in rats.

Dec 21, 2020

Contributor: Lie Yang,Sonia Afroz,Helen A Valsamis,Hillary B Michelson,Jeffrey H Goodman,Douglas S F Ling

Early intervention with levetiracetam prevents the development of cortical hyperexcitability and spontaneous epileptiform activity in two models of neurotrauma in rats.

This study examined the antiepileptogenic potential of the antiseizure drug (ASD) levetiracetam (LEV) using the in vitro traumatized-slice and in vivo controlled cortical impact (CCI) models of traumatic brain injury (TBI) in rats when administered early after the injury. For the in vitro model, acute coronal slices (400-450 μm) of rat neocortex (P21-32) were injured via a surgical cut that separated the superficial layers from the deeper regions. Persistent stimulus-evoked epileptiform activity developed within 1-2 h after trauma. In randomly selected slices, LEV (500 μM) was bath-applied for 1 h starting immediately or delayed by 30-80 min after injury. Treated and untreated slices were examined for epileptiform activity via intracellular and extracellular recordings. For the in vivo model, rats (P24-32) were subjected to a non-penetrating, focal, CCI injury targeting the neocortex (5.0 mm diameter; 2.0 mm depth). Immediately after injury, rats were given either a single dose of LEV (60-150 mg/kg, i.p.) or the saline vehicle. At 2-3 weeks after the injury, ex vivo cortical slices were examined for epileptiform activity. The results from the traumatized-slice experiments showed that in vitro treatment with LEV within 60 min of injury significantly reduced (> 50%) the proportion of slices that exhibited stimulus-evoked epileptiform activity. LEV treatment also increased the stimulus intensity required to trigger epileptiform bursts in injured slices by 2-4 fold. Consistent with these findings, LEV treatment of CCI-injured rats (n = 15) significantly reduced the proportion of animals that exhibited spontaneous and stimulus-evoked epileptiform bursts in ex vivo cortical slices compared to saline-treated controls (n = 15 rats), and also significantly increased the stimulus intensity required to evoke epileptiform bursts. These results suggest that early administration of LEV has the potential to prevent or reduce posttraumatic epileptogenesis and that there may be a narrow therapeutic window for successful prophylactic intervention.
Copyright © 2020. Published by Elsevier Inc.

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About The Expert

Lie Yang

Departments of Physiology and Pharmacology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Program in Neural and Behavioral Science and the Robert F. Furchgott Center for Behavioral and Neural Science, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA.

Sonia Afroz

Departments of Physiology and Pharmacology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Program in Neural and Behavioral Science, UNY and Chief of Neurology KCHC, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 1213, Brooklyn, NY 1120, USA.

Helen A Valsamis

Departments of Physiology and Pharmacology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Departments of Physiology and Neurology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Program in Neural and Behavioral Science and the Robert F. Furchgott Center for Behavioral and Neural Science, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Neurology Service, Kings County Hospital Center, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 1213, Brooklyn, NY 11203, USA. Electronic address: helen.valsamis@nychhc.org.

Hillary B Michelson

Departments of Physiology and Pharmacology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Program in Neural and Behavioral Science, UNY and Chief of Neurology KCHC, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 1213, Brooklyn, NY 1120, USA; Program in Neural and Behavioral Science and the Robert F. Furchgott Center for Behavioral and Neural Science, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA. Electronic address: hillary.michelson@downstate.edu.

Jeffrey H Goodman

Departments of Physiology and Pharmacology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Departments of Physiology and Neurology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Program in Neural and Behavioral Science, UNY and Chief of Neurology KCHC, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 1213, Brooklyn, NY 1120, USA; Program in Neural and Behavioral Science and the Robert F. Furchgott Center for Behavioral and Neural Science, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Department of Developmental Neurobiology, The New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. Electronic address: jeffrey.goodman@downstate.edu.

Douglas S F Ling

Departments of Physiology and Pharmacology, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA; Program in Neural and Behavioral Science, UNY and Chief of Neurology KCHC, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 1213, Brooklyn, NY 1120, USA; Program in Neural and Behavioral Science and the Robert F. Furchgott Center for Behavioral and Neural Science, SUNY Downstate Health Sciences University, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA. Electronic address: douglas.ling@downstate.edu.

References

PubMed