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Synergistic protection against acute flurothyl‐induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone
Author(s) -
Simeone Timothy A.,
Matthews Stephanie A.,
Simeone Kristina A.
Publication year - 2017
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13809
Subject(s) - pioglitazone , ketogenic diet , epilepsy , pharmacology , endocrinology , peroxisome proliferator activated receptor , medicine , anticonvulsant , agonist , diabetes mellitus , type 2 diabetes , chemistry , receptor , psychiatry
Summary Objective We have previously found that the transcription factor peroxisome proliferator‐activated receptor γ ( PPAR γ) contributes to the mechanism of action of the ketogenic diet ( KD ), an established treatment for pediatric refractory epilepsy. We have found that the KD increases brain PPAR γ and that inhibition or genetic loss of PPAR γ prevents the antiseizure effects of the KD on (1) acutely induced seizures in nonepileptic mice and (2) spontaneous recurrent seizures in epileptic mice. Here, we tested the hypothesis that adjuvant treatment of KD ‐treated mice with a PPAR γ agonist, pioglitazone, would result in an additive effect. Methods Acute seizures were induced in three groups of C57Bl/6 mice by inhalation exposure to flurothyl gas. In Group 1, mice were weaned onto either a standard diet or KD comprised of a fat:carbohydrate/protein ratio of either 6:1, 3:1, or 1:1 for 2 weeks. In Group 2, vehicle or pioglitazone (0.1, 1, 10, 80 mg/kg) was administered 4 h prior to flurothyl exposure. In Group 3, vehicle or increasing doses of pioglitazone were administered to KD ‐treated mice 4 h prior to flurothyl exposure. Latency times to clonic seizures and generalized tonic–clonic ( GTC ) seizures were recorded, and isobolographic analysis was used to determine combinatorial interactions. Results Neither KD treatment nor pioglitazone alone or in combination affected clonic seizures. However, the latency to GTC seizures was dose‐dependently and significantly increased by both KD (~57%, p < 0.05) and pioglitazone (~28%, p < 0.05). Coadministration of an ineffective 1:1 KD and pioglitazone resulted in ~47–55% (p < 0.05) increase in latency to GTC . Isobolographic analysis indicated a synergistic interaction of the KD and pioglitazone. Significance These results suggest coadministration may enable reduction of the KD ratio without loss of seizure protection. Such adjuvant treatment could improve quality of life and limit adverse effects of a classic KD or high‐dose pioglitazone.