Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

The ketogenic diet (KD) is an effective therapy primarily used in pediatric patients whom are refractory to current anti-seizure medications. The mechanism of the KD is not completely understood, but is thought to involve anti-inflammatory and anti-oxidant processes. The nutritionally-regulated transcription factor peroxisome proliferator activated receptor gamma, PPAR gamma, regulates genes involved in anti-inflammatory and anti-oxidant pathways. Moreover, endogenous ligands of PPAR gamma include fatty acids suggesting a potential role in the effects of the KD. Here, we tested the hypothesis that PPAR gamma contributes to the anti-seizure efficacy of the KD. We found that the KD increased nuclear protein content of the PPAR gamma 2 splice variant by 2-4 fold (P < 0.05) in brain homogenates from wild-type (WT) and epileptic Kv1.1 knockout (KO) mice, while not affecting PPAR gamma 1. The KD reduced the frequency of seizures in Kv1.1KO mice by similar to 70% (P < 0.01). GW9662, a PPAR gamma antagonist, prevented KD-mediated changes in PPAR-gamma 2 expression and prevented the anti-seizure efficacy of the KD in Kv1.1KO mice. Further supporting the association of PPAR gamma 2 in mediating KD actions, the KD significantly prolonged the latency to flurothyl-induced seizure in WT mice by similar to 20-35% (P < 0.01), but was ineffective in PPAR gamma 2KO mice and neuron-specific PPAR gamma KO mice. Finally, administering the PPAR gamma agonist pioglitazone increased PPAR-gamma 2 expression by 2-fold (P < 0.01) and reduced seizures in Kv1.1KO mice by similar to 80% (P < 0.01). Our findings implicate brain PPAR gamma 2 among the mechanisms by which the KD reduces seizures and strongly support the development of PPAR gamma 2 as a therapeutic target for severe, refractory epilepsy. (C) 2016 Elsevier Inc. All rights reserved.