Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models†
Corresponding Author
Carl E. Stafstrom MD, PhD
Department of Neurology, University of Wisconsin, Madison, WI
Department of Pediatrics, University of Wisconsin, Madison, WI
Department of Neurology, H6-574, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792Search for more papers by this authorJeffrey C. Ockuly BS
Department of Neurology, University of Wisconsin, Madison, WI
Search for more papers by this authorLauren Murphree PhD
Antiepileptic Screening Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMatthew T. Valley MS
Department of Neurology, University of Wisconsin, Madison, WI
Search for more papers by this authorAvtar Roopra PhD
Department of Neurology, University of Wisconsin, Madison, WI
Search for more papers by this authorThomas P. Sutula MD, PhD
Department of Neurology, University of Wisconsin, Madison, WI
Department of Anatomy, University of Wisconsin, Madison, WI
Search for more papers by this authorCorresponding Author
Carl E. Stafstrom MD, PhD
Department of Neurology, University of Wisconsin, Madison, WI
Department of Pediatrics, University of Wisconsin, Madison, WI
Department of Neurology, H6-574, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792Search for more papers by this authorJeffrey C. Ockuly BS
Department of Neurology, University of Wisconsin, Madison, WI
Search for more papers by this authorLauren Murphree PhD
Antiepileptic Screening Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMatthew T. Valley MS
Department of Neurology, University of Wisconsin, Madison, WI
Search for more papers by this authorAvtar Roopra PhD
Department of Neurology, University of Wisconsin, Madison, WI
Search for more papers by this authorThomas P. Sutula MD, PhD
Department of Neurology, University of Wisconsin, Madison, WI
Department of Anatomy, University of Wisconsin, Madison, WI
Search for more papers by this authorPotential conflict of interest: C.E.S., A.R., and T.P.S. are inventors on a patent application on this work through the Wisconsin Alumni Research Foundation. T.P.S. has an equity interest in Neurogenomex for preclinical development of 2-deoxy-D-glucose.
Abstract
Objective
Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy.
Methods
Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K+]o, 4-aminopyridine, or bicuculline, and in vivo against seizures evoked by 6Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path.
Results
2DG (10mM) reduced interictal epileptiform bursts induced by 7.5mM [K+]o, 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6Hz stimulation in mice (effective dose [ED]50 = 79.7mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures.
Interpretation
The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions, and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis. Ann Neurol 2009;65:435–448.
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