Electrophysiological effects of the anticonvulsant remacemide hydrochloride and its metabolite ARL 12495AA on rat CA1 hippocampal neurons in vitro

Abstract

The electrophysiological actions of the putative anticonvulsants remacemide hydrochloride and its des-glycine metabolite ARL 12495AA were examined using whole-cell recordings from CA1 hippocampal neurons in adult rat brain in vitro. Remacemide hydrochloride (4–400 μM) and ARL 12495AA (4–400 μM) limited sustained high frequency repetitive firing (SRF) induced by application of long duration depolarizing current pulses (20–400 pA, 500 msec). This SRF limitation was concentration-dependent, and equipotent IC 50 values of 66 and 60 μM were calculated for remacemide hydrochloride and ARL 12495AA, respectively. Examination of the spike configuration revealed that, over the same concentration range, each compound caused a concentration-related reduction of: (a) the action potential amplitude; and (b) the rate-of-rise. Remacemide hydrochloride or ARL 12495AA increased spike duration and decreased or eliminated the spike after-hyperpolarization. Possible mechanisms for these electrophysiological actions including modulation of sodium and/or potassium channel activity are considered. It is suggested that such multiple mechanisms, including inhibition of SRF may be relevant to the anticonvulsant properties of remacemide hydrochloride and its metabolite, ARL 12495AA. The activity of both compounds as modulators of neuronal excitability indicates that metabolic conversion of remacemide hydrochloride to ARL 12495AA could enhance the therapeutic efficacy of the former.