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Novel anticonvulsants against organophosphate-induced epileptiform activity in the guinea-pig hippocampal slice



Novel anticonvulsants against organophosphate-induced epileptiform activity in the guinea-pig hippocampal slice



Society for Neuroscience Abstracts 27(1): 1257



Central cholinergic overstimulation as a consequence of organophosphate (OP) anticholinesterase poisoning can result in seizures and convulsions which are traditionally treated with a benzodiazepine (e.g. diazepam). However, this may not be the optimal therapy. We have developed a hippocampal slice model of OP-induced epileptiform activity to determine the potential of a variety of anticonvulsant compounds to reverse OP-induced epileptiform bursting. Transverse hippocampal slices were prepared from male Dunkin Hartley guinea-pigs (250 to 500 g) and perfused (at 31degreeC) in a medium containing (mM): NaCl 118, KCl 3, CaCl 1.5, MgCl2 1, NaH2PO4 1.2, NaHCO3 25, D-glucose 10 (gassed with 95% O2/ 5% CO2). Recording electrodes were positioned in CA1 stratum pyramidale to monitor activity extracellularly. Baseline activity was monitored for at least 30 min and spontaneously active slices rejected prior to organophosphate (soman) administration. In the majority of slices studied, application of 100 nM soman led to the appearance of epileptiform bursting which, in the absence of anticonvulsant intervention, persisted for at least 240 min. Baclofen (1 muM), biperiden (0.1-10 muM), clozapine (3-30 muM), cyclopentyladenosine (1-100 nM), midazolam (3-30 muM) and phenytoin (10100 muM) all inhibited soman-induced bursting, while gabapentin (100-300 muM) and the NK1 antagonist, L-733,060 (3-30 muM), were ineffective. These data support the idea that the guinea-pig hippocampal slice model may be a valuable tool in the search for new therapies in OP poisoning.

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