1-Ethyl-2-benzimidazolinone (EBIO) suppresses epileptiform activity in in vitro hippocampus

Neuropharmacology. 2005 Sep;49(3):376-88. doi: 10.1016/j.neuropharm.2005.03.021.

Abstract

Ca2+-activated K+ currents with medium (mI(AHP)) and slow (sI(AHP)) kinetics, that mediate the post-spike medium and slow after-hyperpolarization (AHP), respectively, play critical roles in regulating neuronal excitability and the spread of epileptiform activity and could provide new therapeutic targets for the management of epileptic patients. We tested if the enhancement of the mI(AHP) by 1-ethyl-2-benzimidazolinone (EBIO) could suppress epileptiform activity in two in vitro models of epileptogenesis induced in CA3 hippocampal pyramidal neurons by superfusion with 4-AP- and kainate-Mg2+-free solutions. Both interictal- and ictal-like epileptiform activities were reversibly suppressed by EBIO concentrations between 200 microM and 1 mM. EBIO predominantly acted by a strong reduction of excitability via an increase (approximately 450%) of the mI(AHP), without changing the sI(AHP). Glutamatergic excitatory synaptic transmission was also diminished (approximately 50%) by 1 mM EBIO. In contrast, EBIO concentrations <400 microM had no effect on synaptic excitation, consistent with a lesser sensitivity to the drug than the mI(AHP). Apamine (100 nM), a toxin that specifically inhibits the mI(AHP), rapidly and reversibly antagonized the blocking effects of EBIO on epileptiform activity. Our results suggest that manipulations that enhance the mI(AHP) may prove adequate in the treatment of epilepsies; they also suggest that an abnormal down regulation of the mI(AHP) may be a key factor in the genesis of hyperexcitable states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Algorithms
  • Animals
  • Anticonvulsants / pharmacology*
  • Apamin / pharmacology
  • Benzimidazoles / pharmacology*
  • Calcium Channel Agonists / pharmacology*
  • Electric Stimulation
  • Electrophysiology
  • Epilepsy / drug therapy*
  • Epilepsy / physiopathology
  • Excitatory Amino Acid Agonists / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • N-Methylaspartate / pharmacology
  • Patch-Clamp Techniques
  • Potassium Channel Blockers / pharmacology
  • Potassium Channels, Calcium-Activated / drug effects
  • Pyramidal Cells / drug effects
  • Rats
  • Small-Conductance Calcium-Activated Potassium Channels
  • Synaptic Transmission / drug effects

Substances

  • Anticonvulsants
  • Benzimidazoles
  • Calcium Channel Agonists
  • Excitatory Amino Acid Agonists
  • Potassium Channel Blockers
  • Potassium Channels, Calcium-Activated
  • Small-Conductance Calcium-Activated Potassium Channels
  • Apamin
  • N-Methylaspartate
  • 1-ethyl-2-benzimidazolinone