Ketogenic diet-induced peroxisome proliferator-activated receptor-γ activation decreases neuroinflammation in the mouse hippocampus after kainic acid-induced seizures

Exp Neurol. 2011 Dec;232(2):195-202. doi: 10.1016/j.expneurol.2011.09.001. Epub 2011 Sep 14.


Similar to fasting, the ketogenic diet (KD) has anti-inflammatory effects and protects against excitotoxicity-mediated neuronal cell death. Recent studies have shown that peroxisome proliferator-activated receptor (PPAR)γ has anti-inflammatory effects in seizure animal models. However, the exact mechanisms underlying the anti-inflammatory effects of the KD have not been determined for seizures. Here we investigated the effect of the KD and acetoacetate (AA) on neuroinflammation in a seizure animal model and glutamate-treated HT22 cells, respectively. Mice were fed the KD for 4 weeks and sacrificed 2 or 6h after KA injection. The KD reduced hippocampal tumor necrosis factor alpha (TNF-α) levels and nuclear factor (NF)-κB translocation into the nucleus 2h after KA treatment. KD-induced PPARγ activation was decreased by KA in neurons as assessed by western blotting and immunofluorescence. Finally, the KD inhibited cyclooxygenase (COX)-2 and microsomal prostaglandin E(2) synthase-1 (mPGES-1) expression in the hippocampus 6h after KA treatment. AA treatment also protected against glutamate-induced cell death in HT22 cells by reducing TNF-α and PPARγ-mediated COX-2 expression. Thus, the KD may inhibit neuroinflammation by suppressing a COX-2-dependent pathway via activation of PPARγ by the KD or AA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetoacetates / metabolism
  • Acetoacetates / pharmacology
  • Animals
  • Body Weight / physiology
  • CD11b Antigen / metabolism
  • Cell Line
  • Cell Survival / immunology
  • Cyclooxygenase 2 / metabolism
  • Diet, Ketogenic*
  • Encephalitis / diet therapy*
  • Encephalitis / etiology
  • Encephalitis / immunology
  • Epilepsy / chemically induced*
  • Epilepsy / complications
  • Epilepsy / diet therapy*
  • Excitatory Amino Acid Agonists / toxicity
  • Glutamic Acid / toxicity
  • Hippocampus / cytology
  • Hippocampus / immunology*
  • Hippocampus / metabolism
  • Kainic Acid / toxicity
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neurons / cytology
  • Neurons / metabolism
  • PPAR gamma / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Acetoacetates
  • CD11b Antigen
  • Excitatory Amino Acid Agonists
  • PPAR gamma
  • Tumor Necrosis Factor-alpha
  • Glutamic Acid
  • acetoacetic acid
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Kainic Acid