The effect of dichloroacetate in mouse models of epilepsy.

Abstract

A recent report has found that glucose oxidation and the activity of pyruvate dehydrogenase (PDH) are reduced in the chronic stage of the pilocarpine mouse epilepsy model. This is likely caused by increased phosphorylation by PDH kinase of the E1α subunit of PDH, downregulating its activity. Inhibition of this phosphorylation has not yet been explored as a possible approach to treat epilepsy. Chronic dichloroacetate (DCA, 50 and 100 mg/kg/day) treatment was tested in acute seizure and the chronic pilocarpine models. We also determined the effects on phosphorylation state, activity and protein levels of PDH in the chronic stage of the pilocarpine model. DCA treatment did not increase latencies to seizures in the acute flurothyl seizure test and was slightly proconvulsant in the 6 Hz test. The latencies to seizures in a second-hit flurothyl test were decreased in SE vs. No SE mice in the chronic stage, but were not restored by DCA. In mice that had experienced pilocarpine-induced SE and were in the chronic "epileptic" stage of the model, PDH activity was reduced by 65% compared to "healthy" No SE mice. This was partially alleviated with DCA treatment. Also, PDH protein levels were decreased by 37% and phosphorylation at Ser300 of PDH was increased by 52% in SE mice, but were not significantly changed with DCA. Moreover DCA treatment decreased the amounts of total PDH by 23% in No SE mice, which may explain the proconvulsant effects in the 6 Hz test. The reduction in PDH protein levels during the chronic epileptic stage suggests increased degradation of the protein, which may contribute to the deficient glucose oxidation found in epilepsy. Taken together, DCA did not have any anti-convulsant effects in the tested models. Future studies utilising other PDH kinase inhibitors are required to determine whether this treatment approach is viable.

• Authors: Dylan Durie, Tanya S McDonald, Karin Borges
• Journal: Epilepsy research (Epilepsy Res) Vol. 145 Pg. 77-81 (09 2018) ISSN: 1872-6844 [Electronic] Netherlands
• PMID: 29913407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Anticonvulsants
• Convulsants
• Pilocarpine
• Dichloroacetic Acid
• Flurothyl
• Ketone Oxidoreductases
• pyruvate dehydrogenase (NADP+)

Topics

• Analysis of Variance
• Animals
• Anticonvulsants (therapeutic use)
• Convulsants (toxicity)
• Dichloroacetic Acid (therapeutic use)
• Disease Models, Animal
• Electric Stimulation
• Epilepsy (chemically induced, drug therapy)
• Flurothyl (toxicity)
• Ketone Oxidoreductases (metabolism)
• Male
• Mice
• Mitochondria (metabolism, pathology)
• Pilocarpine (toxicity)