Anticonvulsant and proconvulsant actions of 2-deoxy-d-glucose

Authors

  • Maciej Gasior,

    1. Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A.
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  • Jessica Yankura,

    1. Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A.
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  • Adam L. Hartman,

    1. Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A.
    2. The John M. Freeman Pediatric Epilepsy Center, Johns Hopkins Hospital, Baltimore, Maryland, U.S.A.
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  • Amy French,

    1. Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A.
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  • Michael A. Rogawski

    1. Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A.
    2. Department of Neurology and Center for Neuroscience, University of California, Davis, Sacramento, California, U.S.A.
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  • Preliminary findings of this study were presented during the 60th annual meeting of the American Epilepsy Society, San Diego, December 1–5, 2006. M.G.’s current address is Clinical Research, Cephalon, Inc., 41 Moores Road, Frazer, PA 19355, U.S.A.; e-mail: mgasior@cephalon.com.

Address correspondence to Michael A. Rogawski, M.D., Ph.D., Department of Neurology, University of California, Davis, 4860 Y Street, Suite 3700, Sacramento, California 95817, U.S.A. E-mail: rogawski@ucdavis.edu

Summary

Purpose:  2-Deoxy-d-glucose (2-DG), a glucose analog that accumulates in cells and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes, has anticonvulsant actions. Recognizing that severe glucose deprivation can induce seizures, we sought to determine whether acute treatment with 2-DG can promote seizure susceptibility by assessing its effects on seizure threshold. For comparison, we studied 3-methyl-glucose (3-MG), which like 2-DG accumulates in cells and reduces glucose uptake, but does not inhibit glycolysis.

Methods:  Mice were treated with 2-DG or 3-MG and the seizure threshold determined in the 6-Hz test, the mouse electroshock seizure threshold (MEST) test, and the intravenous pentylenetetrazol (i.v. PTZ) or kainic acid (i.v. KA) seizure threshold tests. 2-DG was also tested in fully amygdala-kindled rats.

Results:  2-DG (125–500 mg/kg, i.p., 30 min before testing) significantly elevated the seizure threshold in the 6-Hz seizure test. 2-DG (250–500 mg/kg) decreased the threshold in the MEST and i.v. PTZ and i.v. KA tests. 3-MG had no effect on seizure threshold in the 6-Hz test but, like 2-DG, decreased seizure threshold in the i.v. PTZ test. 2-DG (250 and 500 mg/kg, i.p., 30 min before testing) had no effect on amygdala-kindled seizures.

Conclusions:  Although 2-DG protects against seizures in the 6-Hz seizure test, it promotes seizures in some other models. The proconvulsant action may relate to reduced glucose uptake, whereas the anticonvulsant action may require inhibition of glycolysis and shunting of glucose metabolism through the pentose phosphate pathway.

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