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 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.
Anderson
Neil J
NJ
Neuropharmacology Department, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. nand@lundbeck.com
Slough
Scott
S
Watson
William P
WP
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D010672:Phenytoin / Q000627:therapeutic use; D010862:Pilocarpine; D010889:Piracetam / Q000031:analogs & derivatives / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012684:Sensory Thresholds / Q000187:drug effects; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism
D000927:Anticonvulsants; D001562:Benzimidazoles; D051640:Small-Conductance Calcium-Activated Potassium Channels; D010862:Pilocarpine; D000077287:Levetiracetam; D010672:Phenytoin; C102635:1-ethyl-2-benzimidazolinone; D010433:Pentylenetetrazole; D010889:Piracetam