Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphate


Address correspondence to Janet L. Stringer, M.D., Ph.D., Cañada College, 4200 Farm Hill Boulevard, Redwood City, CA 94061-1099, U.S.A. E-mail: stringerj@smccd.edu


Fructose-1,6-diphosphate (FDP), an intracellular metabolite of glucose, has anticonvulsant activity in several models of acute seizures in laboratory animals. The anticonvulsant effect of FDP is most likely due to a direct effect since intraperitoneal and oral administration results in significant increases in brain levels. A number of mechanisms have been proposed for this action of FDP. One possibility is that peripheral administration of FDP results in changes in brain metabolism that are anticonvulsant. Glucose can be metabolized through the glycolytic or pentose phosphate pathway. There is evidence that the pentose phosphate pathway is more active in the brain than in other tissues, and that, in the presence of elevated levels of FDP, the majority of glucose is metabolized by the pentose phosphate pathway. The pentose phosphate pathway generates NADPH, which is used to reduce glutathione. The reduced form of endogenous glutathione has been shown to have anticonvulsant activity. Taken together, the data suggest a hypothesis that exogenously administered FDP gets into the brain and astrocytes where it increases the flux of glucose through the pentose phosphate pathway, generating additional NADPH for the reduction of glutathione.