2-DEOXYGLUCOSE EXERTS ANTICONVULSANT AND ANTIEPILEPTIC ACTIONS IN EXPERIMENTAL EPILEPSY MODELS
C. E. Stafstrom, S. M. Kriegler, M. T. Valley, J. C. Ockuly, A. S. Roopra, and T. P. Sutula
Rationale: When glucose is not fully available as a energy source (e.g., fasting, ketogenic diet and other carbohydrate-restricted diets), metabolites such as lactate, pyruvate, or β-hydroxybutyrate can supply the brain's energy needs. Decreased carbohydrate availability may reduce neuronal excitability and exert an anticonvulsant effect. The mechanism by which low glucose might reduce neuronal excitability is unclear. We tested the hypothesis that the glucose analog 2-deoxyglucose (2DG) protects against seizures in vivo (kindling) and in vitro (hippocampal slices in elevated [K+]o).
Methods:Anticonvulsant actions of 2DG were assessed by its effects on: (1) high K+ epileptiform burst frequency in hippocampal slices and (2) evoked afterdischarge threshold (ADT) in kindled rats. Antiepileptic actions of 2DG were assessed by its effects on the progression of ADT reduction and the development of kindled seizures.
Adult male rats received twice daily kindling stimulations to olfactory bulb or perforant path. Initial ADT served as a baseline to compare the effects of repeated kindling stimulations. After achieving the 3rd evoked AD, a subset of rats received 2DG (250 mg/kg i.p.), 30 min prior to each kindling stimulation.
Hippocampal slices from naïve P14–35 rats were exposed to elevated [K+]o to elicit epileptiform bursts. Glucose was substituted by alternative fuel sources (e.g., lactate). 2DG, which inhibits phosphoglucose isomerase, was added to the bathing medium to assess the effect of glycolysis inhibition on epileptiform bursting.
Results:Anticonvulsant effects. (1) In 7.5 mM [K+]o hippocampal slices developed synchronized epileptiform bursts at a frequency of about 30/min. In 10 mM glucose, addition of 1 mM 2DG decreased burst frequency to 25–80% of baseline; this decrease persisted after 2DG washout. In 10 mM glucose plus 20 mM lactate, addition of 1 mM 2DG decreased burst frequency to a similar degree. These results suggest that the anticonvulsant effect of 2DG is not attributable to reduction of energy supply through inhibition of glycolysis by 2DG. (2) Mean ADT for 2DG treated rats was significantly greater than ADT for saline treated rats (p < 0.001). Antiepileptic effects. The number of ADs to achieve class III, IV or V kindled seizures was significantly higher in 2DG treated rats than controls (p = 0.03). Mean ADT as a function of AD number, compared to baseline, exhibited the expected decrease with successive stimulations in saline treated rats, but an unexpected and significant increase in 2DG-treated rats (p < 0.001), demonstrating a persistent antiepileptic effect.
Conclusions: 2DG has potent anticonvulsant and antiepileptic effects. By acting as a "low calorie mimic" of glucose, 2DG supports neuronal energy needs but reduces synchronous firing that comprises seizure activity. Therefore, 2DG has potential as a novel epilepsy treatment. (Supported by NINDS RO1 25020 (TPS) and The Charlie Foundation (CES).)