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The Journal of Neuroscience, October 31, 2007, 27(44):12007-12011; doi:10.1523/JNEUROSCI.3163-07.2007

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Brief Communications
Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats

Xiao-Yuan Lian, Firdous A. Khan, and Janet L. Stringer

Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Dr. Janet L. Stringer, Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: janets{at}bcm.edu

A variety of observations suggest that decreasing glycolysis and increasing levels of reduced glutathione, generated by metabolism of glucose through the pentose phosphate pathway, would have an anticonvulsant effect. Because fructose-1,6-bisphosphate (F1,6BP) shifts the metabolism of glucose from glycolysis to the pentose phosphate pathway, it was hypothesized to have anticonvulsant activity. The anticonvulsant activity of F1,6BP was determined in rat models of acute seizures induced by pilocarpine, kainic acid, or pentylenetetrazole. The efficacy of F1,6BP was compared with that of 2-deoxyglucose (2-DG; an inhibitor of glucose uptake and glycolysis), valproic acid (VPA), and the ketogenic diet. One hour before each convulsant, Sprague Dawley rats received either saline (as seizure controls), F1,6BP (0.25, 0.5 or 1 g/kg), 2-DG (0.25 or 0.5 g/kg), or VPA (0.3 g/kg). Additional animals received the ketogenic diet (starting at 20 or 60 d old). Time to seizure onset, seizure duration, and seizure score were measured in each group. F1,6BP had dose-dependent anticonvulsant activity in all three models, whereas VPA had partial efficacy. 2-DG was only effective in the pilocarpine model. The ketogenic diet had no effect in these models. F1,6BP was also partially effective when given at the first behavioral seizure after pilocarpine. Administration of sodium lactate, which bypasses the block in the glycolytic pathway, abolished the anticonvulsant activity of 2-DG in the pilocarpine model, but only decreased the efficacy of F1,6BP. These data demonstrate that F1,6BP has significant anticonvulsant efficacy.

Key words: fructose-1,6-bisphosphate; seizures; pentose phosphate pathway; 2-deoxyglucose; ketogenic diet; valproic acid

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Received May 4, 2007; revised Aug. 15, 2007; accepted Sept. 11, 2007.

Correspondence should be addressed to Dr. Janet L. Stringer, Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: janets{at}bcm.edu

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