Region- and pattern-specific effects of glutamate uptake blockers on epileptiform activity in rat brain slices.
Many epileptic syndromes develop into pharmaco-resistant forms, calling for the development of new anticonvulsant strategies. The transmitter glutamate serves a double role as excitatory transmitter and as precursor for GABA, thus interfering with glutamate uptake may therefore exert complex effects on excitation-inhibition-balance in epileptic networks. In the present study we tested the effect of two different glutamate uptake blockers on acutely induced epileptiform activity in hippocampal-entorhinal cortex slices from adult rats: dihydrokainate (DHK) which blocks predominantly glial glutamate uptake, and threo-beta-benzyloxyaspartic acid (TBOA) which blocks both glial and neuronal glutamate uptake. Three different models were used to induce epileptiform discharges: (i) increasing NMDA receptor-mediated excitation by omitting Mg(2+)-ions; (ii) blocking potassium channels by 4-aminopyridine; (iii) reducing GABA(A) receptor-mediated inhibition by penicillin. Application of DHK or TBOA markedly reduced the frequency of epileptiform discharges in CA1 in the low magnesium and the 4-AP model while pathological activity was increased in the penicillin-model. In contrast, frequency of epileptiform discharges in EC was consistently increased by DHK and TBOA. Effects of DHK were more easily reversible than those of TBOA. Thus glutamate uptake blockers exert variable effects on epileptiform activity, depending on brain region and on the mechanism of ictogenesis.
Bertsche
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Department of Paediatric Neurology, Heidelberg University, Heidelberg, Germany.
Bruehl
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C
Pietz
J
J
Draguhn
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D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001224:Aspartic Acid / Q000494:pharmacology; D004594:Electrophysiology; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects
D000927:Anticonvulsants; D014179:Neurotransmitter Uptake Inhibitors; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; C020889:dihydrokainic acid; D015761:4-Aminopyridine; D007608:Kainic Acid