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The anticonvulsant BW534U87 depresses epileptiform activity in rat hippocampal slices by an adenosine‐dependent mechanism and through inhibition of voltage‐gated Na + channels
Author(s) -
Dupere Joe R B,
Dale Tim J,
Starkey Sarah J,
Xie Xinmin
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702881
Subject(s) - ehna , adenosine , inhibitory postsynaptic potential , adenosine deaminase , chemistry , adenosine deaminase inhibitor , excitatory postsynaptic potential , adenosine receptor antagonist , chinese hamster ovary cell , adenosine receptor , postsynaptic potential , biophysics , medicine , endocrinology , biology , biochemistry , receptor , agonist
The cellular and molecular actions of BW534U87 were studied using intracellular and extracellular recordings from the CA1 region of rat hippocampal slices and whole‐cell voltage‐clamp recordings of recombinant human brain type IIA Na + channels expressed in Chinese hamster ovary (CHO) cells. Normal excitatory and inhibitory postsynaptic potentials evoked in hippocampal slices were unaffected by BW534U87 or the adenosine deaminase inhibitor EHNA. However, epileptiform activity was depressed by BW534U87 (50 μ M ) and this inhibition was reversed by the adenosine receptor antagonist 8‐phenyl theophylline (8‐PT, 30 μ M ). EHNA (10 μ M ) mimicked the effects of BW534U87. Furthermore, BW534U87 enhanced the inhibitory effects of exogenous adenosine on evoked synaptic potentials. BW534U87 (50 μ M ) also voltage‐ and use‐dependently inhibited action potentials elicited by current injection, independent of the adenosine system, since it was not affected by 8‐PT. 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 μ M at a V h of −60 mV. Use‐dependent inhibition was evident at high‐frequencies (20×20 ms pulse train at 10 Hz). In conclusion, BW534U87 blocks hippocampal epileptiform activity by a dual mechanism. The first action is similar to that produced by EHNA and is dependent on endogenous adenosine probably by inhibition of adenosine deaminase. Secondly, BW534U87 directly inhibits voltage‐gated Na + channels in a voltage‐ and frequency‐dependent manner. Both actions of BW534U87 are activity‐dependent and may synergistically contribute to its overall anticonvulsant effects in animal models of epilepsy.British Journal of Pharmacology (1999) 128 , 1011–1020; doi: 10.1038/sj.bjp.0702881