title: Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy.
abstract: 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, PPARγ, regulates genes involved in anti-inflammatory and anti-oxidant pathways. Moreover, endogenous ligands of PPARγ include fatty acids suggesting a potential role in the effects of the KD. Here, we tested the hypothesis that PPARγ contributes to the anti-seizure efficacy of the KD. We found that the KD increased nuclear protein content of the PPARγ2 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 PPARγ1. The KD reduced the frequency of seizures in Kv1.1KO mice by ~70% (P<0.01). GW9662, a PPARγ antagonist, prevented KD-mediated changes in PPARγ2 expression and prevented the anti-seizure efficacy of the KD in Kv1.1KO mice. Further supporting the association of PPARγ2 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 PPARγ2KO mice and neuron-specific PPARγKO mice. Finally, administering the PPARγ agonist pioglitazone increased PPARγ2 expression by 2-fold (P<0.01) and reduced seizures in Kv1.1KO mice by ~80% (P<0.01). Our findings implicate brain PPARγ2 among the mechanisms by which the KD reduces seizures and strongly support the development of PPARγ2 as a therapeutic target for severe, refractory epilepsy.
authors.affiliation: Creighton University, School of Medicine, Department of Pharmacology, Omaha, NE 68174, USA. Electronic address: timothysimeone@creighton.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Simeone
authors.affiliation: Creighton University, School of Medicine, Department of Pharmacology, Omaha, NE 68174, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Matthews
authors.affiliation: Creighton University, School of Medicine, Department of Pharmacology, Omaha, NE 68174, USA.
authors.forename: Kaeli K
authors.initials: KK
authors.lastname: Samson
authors.affiliation: Creighton University, School of Medicine, Department of Pharmacology, Omaha, NE 68174, USA.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Simeone
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D000367:Age Factors; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003292:Convulsants / Q000633:toxicity; D055423:Diet, Ketogenic / Q000379:methods*; D004195:Disease Models, Animal; D004326:Drinking / Q000187:drug effects / Q000502:physiology; D004827:Epilepsy / Q000139:chemically induced / Q000178:diet therapy* / Q000188:drug therapy / Q000473:pathology*; D005481:Flurothyl / Q000633:toxicity; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051662:Kv1.1 Potassium Channel / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000927:Anticonvulsants; D001786:Blood Glucose; D003292:Convulsants; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D051662:Kv1.1 Potassium Channel; D005481:Flurothyl; D020155:3-Hydroxybutyric Acid; D000077205:Pioglitazone
keywords: Epilepsy; Kcna1; Ketogenic diet; Kv1.1; Nutrition; PPARgamma2; Peroxisome proliferator activated receptor; Seizure