In vivo characterisation of the small-conductance KCa (SK) channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a potential anticonvulsant.

Abstract

Owing to their activation by increased intracellular Ca(2+) levels following burst firing, and the resultant hyperpolarisation and dampening of neuronal excitability, the small-conductance Ca(2+)-activated K(+) (SK(Ca)) channels have been proposed as a potential target for novel antiepileptic drugs. Indeed, the channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) has been shown to reduce epileptiform activity in vitro. Accordingly, this study has investigated the therapeutic potential of 1-EBIO using a range of in vivo seizure models, and assessed the adverse effect liability with the rotarod and locomotor activity paradigms. To aid benchmarking of 1-EBIO's therapeutic and adverse effect potential, it was tested alongside two currently marketed antiepileptic drugs, phenytoin and levetiracetam. 1-EBIO was found to be effective at reducing seizure incidence in mice following maximal electroshock (ED(50) 36.0 mg/kg) as well as increasing the threshold to electrically- and pentylenetetrazole-induced seizures (TID(10)s 7.3 and 21.5 mg/kg, respectively). However, results from the mouse rotarod test revealed a strong adverse effect potential within the therapeutic dose range (ID(50) 35.6 mg/kg), implying a significantly inferior therapeutic index with respect to the comparator compounds. These results, therefore, support the in vitro data detailing 1-EBIO's reduction of epileptiform activity. However, the use of in vivo models has revealed a significant adverse effect potential within the therapeutic dose range. Nevertheless, given the multiplicity of SK(Ca) channel subunits and that 1-EBIO has been shown to enhance additional, non-SK(Ca) carried currents, these findings do not preclude the possibility that more selective enhancers of SK(Ca) function could prove to be effective as antiepileptic medications.

• Authors: Neil J Anderson, Scott Slough, William P Watson
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 546 Issue 1-3 Pg. 48-53 (Sep 28 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16925994 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anticonvulsants
• Benzimidazoles
• Small-Conductance Calcium-Activated Potassium Channels
• Pilocarpine
• Levetiracetam
• Phenytoin
• 1-ethyl-2-benzimidazolinone
• Pentylenetetrazole
• Piracetam

Topics

• Animals
• Anticonvulsants (adverse effects, therapeutic use)
• Benzimidazoles (adverse effects, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Electroshock
• Levetiracetam
• Male
• Mice
• Motor Activity (drug effects)
• Pentylenetetrazole
• Phenytoin (therapeutic use)
• Pilocarpine
• Piracetam (analogs & derivatives, therapeutic use)
• Seizures (chemically induced, metabolism, prevention & control)
• Sensory Thresholds (drug effects)
• Small-Conductance Calcium-Activated Potassium Channels (agonists, metabolism)