Potential 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.
Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models†
Article first published online: 18 MAR 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 65, Issue 4, pages 435–447, April 2009
How to Cite
Stafstrom, C. E., Ockuly, J. C., Murphree, L., Valley, M. T., Roopra, A. and Sutula, T. P. (2009), Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models. Ann Neurol., 65: 435–447. doi: 10.1002/ana.21603
- Issue published online: 27 APR 2009
- Article first published online: 18 MAR 2009
- Accepted manuscript online: 18 MAR 2009 12:00AM EST
- Manuscript Accepted: 7 NOV 2008
- Manuscript Revised: 3 NOV 2008
- Manuscript Received: 29 SEP 2007
- NIH. Grant Number: NINDS RO1-25020
- Wisconsin Alumni Research Foundation
- The Charlie Foundation
- National Institute of Neurological Disorders and Stroke Antiepileptic Screening Program
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.
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.
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.
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.