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

Timothy Simeone, Stephanie A. Matthews, Kaeli K. Samson, Kristina A. Simeone

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)54-64
Number of pages11
JournalExperimental Neurology
Volume287
DOIs
StatePublished - Jan 1 2017

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Ketogenic Diet
PPAR gamma
Seizures
Peroxisome Proliferator-Activated Receptors
Brain
pioglitazone
Oxidants
Flurothyl
Anti-Inflammatory Agents
Nuclear Proteins
Knockout Mice
Epilepsy
Transcription Factors

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

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Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. / Simeone, Timothy; Matthews, Stephanie A.; Samson, Kaeli K.; Simeone, Kristina A.

In: Experimental Neurology, Vol. 287, 01.01.2017, p. 54-64.

Research output: Contribution to journalArticle

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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.",
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