Effects of γ-aminobutyric acid (GABA) agonists and GABA uptake inhibitors on pharmacosensitive and pharmacoresistant epileptiform activity in vitro
Institut für Physiologie der Charité, Abt. Neurophysiologie, Humboldt-Universität zu Berlin, Tucholskystr. 2, D-10117 Berlin, Germany
- 1Lowering of the extracellular Mg2+-concentration induces various patterns of epileptiform activity in combined rat entorhinal cortex-hippocampal brain slices. After a prolonged period of exposure to Mg2+-free medium seizure-like events in the entorhinal cortex change to a state of late recurrent discharges which cannot be blocked by clinically available antiepileptic drugs. This late epileptiform activity thus represents a useful model to test the effects of new anticonvulsant substances.
- 2A mechanism possibly underlying the development of sustained seizure-like activity is the loss of synaptically released γ-aminobutyric acid (GABA). Drugs which increase the amount of GABA available in presynaptic endings might thus be useful in the treatment of these therapeutically complicated forms of epilepsy.
- 3Therefore, we studied the effects of various substances increasing GABA-mediated inhibition on early and late forms of epileptiform activity. GABA and the GABAA receptor agonist muscimol blocked both the pharmacosensitive discharges in the hippocampus and entorhinal cortex as well as the late recurrent discharges in the medial entorhinal cortex. The GABAB receptor agonist baclofen blocked the recurrent short discharges very potently, but did not consistently block seizure-like events and late recurrent discharges in the entorhinal cortex.
- 4GABA uptake blockers showed a differential potency to block the various discharge patterns. Whereas nipecotic acid and β-alanine suppressed all forms of epileptiform activity albeit at high concentrations (1–5 mM), tiagabine was much more potent in blocking the hippocampal recurrent short discharges and the seizure-like events in the medial entorhinal cortex, but could not block the late recurrent discharges.
- 5Our data support the idea that prolonged neuronal overactivity might result in a loss of synaptically available GABA. Selective block of uptake into glia cells or substitution of the transmitter may therefore be an efficient strategy for the treatment of severe prolonged epileptic discharges whereas block of neuronal GABA uptake fails to counteract synchronized discharges in this situation.