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

Owing to their activation by increased intracellular Ca2+ levels following burst firing, and the resultant hyperpolarisation and dampening of neuronal excitability, the small-conductance Ca2+-activated K+ (SKCa) 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. I-EBIO was found to be effective at reducing seizure incidence in mice following maximal electroshock (ED50 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 (ID50 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 SYCa channel subunits and that 1-EBIO has been shown to enhance additional, non-SKCa carried currents, these findings do not preclude the possibility that more selective enhancers of SKCa function could prove to be effective as antiepileptic medications. (c) 2006 Elsevier B.V. All rights reserved.