TY - JOUR
T1 - Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy
AU - Simeone, Timothy A.
AU - Matthews, Stephanie A.
AU - Samson, Kaeli K.
AU - Simeone, Kristina A.
N1 - Funding Information:
The authors thank G. Medina-Gomez (Universidad Rey Juan Carlos) for the kind gift of PPARγ2 heterozygous mice. We thank J.M. Olefsky (University of California-San Diego) and M.W. Schwartz (University of Washington) for the kind gifts of control PPARγ fl/fl mice and Synapsin I-Cre + PPARγ fl/fl knockout mice. This work was supported by a Nebraska State LB692 grant (TAS), Epilepsy Foundation of America grant (TAS), Citizens United for Research in Epilepsy Foundation grant (TAS), NIH NS072179 (KAS) and NIH NS085389 (TAS). The project described was also supported by the National Center for Research Resources grant G20RR024001 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Please note, the last author has published under the names K. Dorenbos, K.A. Fenoglio, K.A. Fenoglio-Simeone and K.A. Simeone.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.expneurol.2016.08.006
DO - 10.1016/j.expneurol.2016.08.006
M3 - Article
C2 - 27527983
AN - SCOPUS:84995394885
VL - 287
SP - 54
EP - 64
JO - Neurodegeneration
JF - Neurodegeneration
SN - 0014-4886
ER -