TY - JOUR
T1 - Synergistic protection against acute flurothyl-induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone
AU - Simeone, Timothy A.
AU - Matthews, Stephanie A.
AU - Simeone, Kristina A.
N1 - Funding Information:
This work was supported by the Citizens United for Research in Epilepsy Foundation (T.A.S.), National Institutes of Health (NIH) NS072179 (K.A.S.), and NIH NS085389 (T.A.S.). 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 NIH. Please note that K.A.S. has published under the names K Dorenbos, KA Fenoglio, KA Fenoglio-Simeone, and KA Simeone.
Publisher Copyright:
Wiley Periodicals, Inc. © 2017 International League Against Epilepsy
PY - 2017/8
Y1 - 2017/8
N2 - Objective: We have previously found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ and that inhibition or genetic loss of PPARγ 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 PPARγ 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.
AB - Objective: We have previously found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ and that inhibition or genetic loss of PPARγ 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 PPARγ 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.
UR - http://www.scopus.com/inward/record.url?scp=85019679559&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019679559&partnerID=8YFLogxK
U2 - 10.1111/epi.13809
DO - 10.1111/epi.13809
M3 - Article
C2 - 28555877
AN - SCOPUS:85019679559
VL - 58
SP - 1440
EP - 1450
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 8
ER -