The anticonvulsant BW534U87 depresses epileptiform activity in rat hippocampal slices by an adenosine-dependent mechanism and through inhibition of voltage-gated Na+ channels

1 The cellular and molecular actions of BW534U87 were studied using intrace llular and extracellular recordings from the CA1 region of rat hippocampal slices and whole-cell voltage-clamp recordings of recombinant human brain t ype IIA Na+ channels expressed in Chinese hamster ovary (CHO) cells. 2 Normal excitatory and inhibitory postsynaptic potentials evoked in hippoc ampal slices were unaffected by BW534U87 or the adenosine deaminase inhibit or EHNA. However, epileptiform activity was depressed by BW534U87 (50 mu M) and this inhibition was reversed by the adenosine receptor antagonist 8-ph enyl theophylline (8-PT, 30 mu M). EHNA (10 mu M) mimicked the effects of B W534U87. Furthermore, BW534U87 enhanced the inhibitory effects of exogenous adenosine on evoked synaptic potentials. BW534U87 (50 mu M) also voltage- and use-dependently inhibited action potentials elicited by current injecti on, independent of the adenosine system, since it was not affected by 8-PT. 3 In CHO cells expressing the recombinant human brain Na+ channel, BW534U87 produced a concentration- and voltage-dependent inhibition of Na+ currents with a half-maximal inhibitory concentration of 10 mu M at a V-h of -60 mV . Use-dependent inhibition was evident at high-frequencies (20 x 20 ms puls e train at 10 Hz). 4 In conclusion, BW534U87 blocks hippocampal epileptiform activity by a dua l mechanism. The first action is similar to that produced by EHNA and is de pendent on endogenous adenosine probably by inhibition of adenosine deamina se. Secondly, BW534U87 directly inhibits voltage-gated Na+ channels in a vo ltage- and frequency-dependent manner. Both actions of BW534U87 are activit y-dependent and may synergistically contribute to its overall anticonvulsan t effects in animal models of epilepsy.