Ketogenic diet regulates the antioxidant catalase via the transcription factor PPARγ2.

Highlights • The ketogenic diet increases hippocampal catalase mRNA and protein. • The ketogenic diet does not increase catalase mRNA or protein in the hippocampus of mice lacking PPARγ2. • Inhibiting catalase occluded the KD antiseizure effects. Abstract We have previously found that the transcription factor PPARγ2 contributes to the mechanism of action of the ketogenic diet (KD), an established treatment for pediatric refractory epilepsy. Among the wide-array of genes regulated by PPARγ, previous studies have suggested that antioxidants such as catalase may have prominent roles in KD neuroprotective and antiseizure effects. Here, we tested the hypothesis that the KD increases catalase through activation of PPARγ2, and that this action is part of the mechanism of antiseizure efficacy of the KD. We determined catalase mRNA and protein expression in hippocampal tissue from epileptic Kcna1 −/− mice, Ppar γ2+/+ mice and Ppar γ2−/− mice. We found that a KD increases hippocampal catalase expression in Kcna1 −/− and Ppar γ2+/+ mice, but not Ppar γ2−/− mice. Next, we determined whether catalase contributes to KD seizure protection. We found that the KD reduces pentylenetetrazole (PTZ)-induced seizures; however, pretreatment with a catalase inhibitor occluded KD effects on PTZ seizures. These results suggest that the KD regulates catalase expression through PPARγ2 activation, and that catalase may contribute to the KD antiseizure efficacy. [ABSTRACT FROM AUTHOR]