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.