| First Author | Simeone TA | Year | 2017 |
| Journal | Exp Neurol | Volume | 287 |
| Issue | Pt 1 | Pages | 54-64 |
| PubMed ID | 27527983 | Mgi Jnum | J:262128 |
| Mgi Id | MGI:6152822 | Doi | 10.1016/j.expneurol.2016.08.006 |
| Citation | Simeone TA, et al. (2017) Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. Exp Neurol 287(Pt 1):54-64 |
| abstractText | 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, PPARgamma, regulates genes involved in anti-inflammatory and anti-oxidant pathways. Moreover, endogenous ligands of PPARgamma include fatty acids suggesting a potential role in the effects of the KD. Here, we tested the hypothesis that PPARgamma contributes to the anti-seizure efficacy of the KD. We found that the KD increased nuclear protein content of the PPARgamma2 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 PPARgamma1. The KD reduced the frequency of seizures in Kv1.1KO mice by ~70% (P<0.01). GW9662, a PPARgamma antagonist, prevented KD-mediated changes in PPARgamma2 expression and prevented the anti-seizure efficacy of the KD in Kv1.1KO mice. Further supporting the association of PPARgamma2 in mediating KD actions, the KD significantly prolonged the latency to flurothyl-induced seizure in WT mice by ~20-35% (P<0.01), but was ineffective in PPARgamma2KO mice and neuron-specific PPARgammaKO mice. Finally, administering the PPARgamma agonist pioglitazone increased PPARgamma2 expression by 2-fold (P<0.01) and reduced seizures in Kv1.1KO mice by ~80% (P<0.01). Our findings implicate brain PPARgamma2 among the mechanisms by which the KD reduces seizures and strongly support the development of PPARgamma2 as a therapeutic target for severe, refractory epilepsy. |
