The objective of this project is to explore new strategies for the rational development of antiepileptic drugs based upon their interaction with neuronal ion channel systems. Cellular electrophysiological recording techniques are used to study drug modulation of neurotransmitter-gated and voltage-activated ion channels in brain slices, cultured neurons and heterologous cells transfected with cloned ion channel subunit genes. Correlative studies are carried out in animal models. In the present reporting period, we completed a project examining the potential of cooling as an epilepy treatment approach. Cooling has been previously shown to terminate experimentally induced epileptiform activity in models of epilepsy without causing injury to the cooled brain, suggesting that cooling could represent an approach to seizure control in intractable focal epilepsies. We sought to determine the most effective way to apply cooling to abort spontaneous epileptiform discharges in in vitro brain slice models. We induced spontaneous epileptiform activity in rat brain slices by exposure to 4-aminopyridine (4-AP), 4-AP plus bicuculline, and magnesium-free artificial CSF (aCSF) at 28?34 ?C. Extracellular field recordings were made at hippocampal or neocortical sites. Slice temperature was reduced by perfusion with cold aCSF. Rapid cooling at rates of 2?5 ?C/s was compared to cooling at slower rates of 0.1?1 ?C/s. Cooling at both rates reversibly aborted epileptiform discharges in all three models and at all recording sites. With rapid cooling, small temperature drops were highly effective in terminating discharges, an effect that was sustained for as long as the reduced temperature level was maintained. In contrast, slow cooling required much larger temperature drops to inhibit discharges. With slow cooling, absolute temperature drops to 21?22 ?C caused a 90% reduction in event frequency, but cooling to 14?15 ?C was required to terminate discharges. We conclude that rapid cooling as effectively aborts discharges in in vitro epilepsy models as does slow cooling, but the magnitude of the temperature change required is less. Practical devices to inhibit seizure activity may only need to induce small temperature drops, if the cooling can be applied sufficiently rapidly.
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