کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2536944 1559169 2006 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
In vivo characterisation of the small-conductance KCa (SK) channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a potential anticonvulsant
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
In vivo characterisation of the small-conductance KCa (SK) channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a potential anticonvulsant
چکیده انگلیسی

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. 1-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 (TID10s 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 SKCa 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 546, Issues 1–3, 28 September 2006, Pages 48–53
نویسندگان
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