Effects of antiepileptic drugs on induced epileptiform activity in a rat model of dysplasia

Matthew D. Smyth, Nicholas Barbaro, Scott C. Baraban

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Seizure activity associated with cortical dysplasia (CD) is often resistant to standard pharmacologic treatments. Although several animal models exhibit CD, virtually nothing is known about antiepileptic drug (AED) responses in these animals. Here we have used rats exposed to methylazoxymethanol acetate (MAM) in utero, an animal model featuring nodular heterotopia, to investigate the effects of AEDs in the dysplastic brain. 4-aminopyridine (100 μM), a K+ channel blocker, was used to induce interictal epileptiform bursting in acute hippocampal slices from MAM-exposed and age-matched vehicle-injected control animals. Extracellular field recordings were used to monitor seizure activity in vitro. Five commonly used AEDs were tested: phenobarbital, 25-400 μM; carbamazepine, 25-200 μM; valproate (VPA), 0.19-4 mM; ethosuximide (ESM), 0.5-8 mM; and lamotrigine (LTG), 49-390 μM. 4-AP-induced bursting occurred with shorter latencies in slices from MAM-exposed rats in comparison with slices from controls, confirming the intrinsic hyperexcitability of dysplastic tissue. Each AED tested demonstrated significant burst suppression in control slices, but interictal epileptiform bursting in MAM-exposed slices was resistant to these treatments. Even at the highest concentrations, VPA, ESM and LTG had no effect on burst amplitude in slices from MAM-exposed rats. Pharmaco-resistance was further tested by measuring seizure latencies in awake, freely-moving rats after kainate administration (15 mg/kg, i.p.) with and without pre-treatment with VPA (400 mg/kg i.p.). Pre-treatment with VPA prolonged seizure latency in control rats, but had no effect in MAM-exposed animals. These results suggest MAM-exposed rats exhibit a dramatically reduced sensitivity to commonly prescribed AEDs.

Original languageEnglish (US)
Pages (from-to)251-264
Number of pages14
JournalEpilepsy Research
Volume50
Issue number3
DOIs
StatePublished - Jul 2002
Externally publishedYes

Fingerprint

Methylazoxymethanol Acetate
Anticonvulsants
Valproic Acid
Seizures
Ethosuximide
Malformations of Cortical Development
Animal Models
4-Aminopyridine
Kainic Acid
Carbamazepine
Phenobarbital

Keywords

  • 4-Aminopyridine
  • Anticonvulsant
  • Cortical dysplasia
  • Hippocampal slice
  • Methylazoxymethanol

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Neurology

Cite this

Effects of antiepileptic drugs on induced epileptiform activity in a rat model of dysplasia. / Smyth, Matthew D.; Barbaro, Nicholas; Baraban, Scott C.

In: Epilepsy Research, Vol. 50, No. 3, 07.2002, p. 251-264.

Research output: Contribution to journalArticle

Smyth, Matthew D. ; Barbaro, Nicholas ; Baraban, Scott C. / Effects of antiepileptic drugs on induced epileptiform activity in a rat model of dysplasia. In: Epilepsy Research. 2002 ; Vol. 50, No. 3. pp. 251-264.
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