Anticonvulsant effects of PPAR-gamma activation in an in vitro model of seizure

Abstract

Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-modulated transcription factor belonging to the nuclear receptor superfamily. PPARγ regulates genes involved in adipocyte differentiation, insulin homeostasis, neuroprotection and anti-inflammation. As such, PPARγ 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 and preliminary studies in our laboratory using chronic seizure models suggest PPARγ agonists have anticonvulsant efficacy. These results, however, need to be replicated at a more concentrated level to understand tissue-specific effects. Thus, we performed extracellular electrophysiological experiments with a PPARγ agonist (pioglitazone) and an antagonist (GW 9662) to test their efficacy in an in vitro model of seizure using high potassium. We observed that pioglitazone delayed the latency to seizure-like events (SLE) onset and decreased the intraSLE frequency by increasing the duration of each SLE in WT slices. It also decreased the severity of SLEs, as indicated by a significant decrease in the linelength of the WT slices. GW 9662 reversed all of pioglitazone effects except the delayed SLE onset. Furthermore, pioglitazone failed to reduce high potassium-induced hyperexcitability in slices from PPARγ neuronal knock out (NKO) mice. These results support the hypothesis that activation of PPARγ via pioglitazone attenuates various parameters of high potassium-induced hyperexcitability. The effectiveness in this in-vitro acute hippocampal slice high potassium model of SLE affords a reduced system to study the anticonvulsant mechanism of pioglitazone via PPARγ activation.