Abstracts

Rationale: Peroxisome proliferator activated receptor gamma (PPARg) is a transcription factor that regulates genes involved in neuroprotection and regulating inflammation. As such, PPARg is under consideration as therapy for ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis and traumatic brain injury. Previous in vivo experiments using acute seizure models suggest PPARg agonists have anticonvulsant efficacy. Here, we tested the hypothesis that acute application of a PPARg agonist, pioglitazone, would reduce seizure-like events (SLEs) in an in vitro model of epilepsy. Methods: Recordings of spontaneous and evoked extracellular field potentials were acquired using a 64 multi-electrode array. Acutely isolated hippocampal slices from wild-type mice were positioned with electrodes in the fields of CA1, CA3 and dentate gyrus. Either vehicle or pioglitazone with or without GW9662, a selective PPARg irreversible antagonist, was bath applied for 90 minutes. During drug wash-in paired pulse stimulations (50 ms ISI) of Schaffer-collaterals assessed effects on field potentials and synaptic plasticity. After drug wash-in, the aCSF was switched to a high potassium (8 mM) aCSF that contained the appropriate drug. The high potassium aCSF induced SLEs in all slices. Analyses quantified latency to first SLE, SLE duration, intra-SLE spike frequencies and inter-SLE intervals. Results: Pioglitazone significantly decreased field potential slopes and increased paired pulse ratios. In addition, application of pioglitazone increased the latency to the first high potassium SLE by ~62% (p<0.05) and slowed spiking during the SLEs, as the intra-SLE frequency decreased by ~50% (p<0.05). These effects were attenuated by GW9662. Conclusions: These data suggest that PPARg activation is a potential anticonvulsant target. The increased PPR indicates that these effects may involve decreased excitatory neurotransmission via a reduction in presynaptic neurotransmitter release.