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

Abstract

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.

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

“…The latency to the first behavioral seizure after pilocarpine administration, referred to as the seizure onset time (SOT), was defined by the occurrence of forelimb clonus, rearing, and loss of balance, and was recorded to the nearest second for each animal by an individual blind to the postnatal treatment of the animal. Seizure onset time is a commonly used measure to describe seizure susceptibility to convulsant compounds in rats (Galic and Persinger, 2005;Lian et al, 2007). Electroencephalographic recordings at the time of overt convulsive behaviors have previously been shown to reveal clear, paroxysmal epileptiform discharges (Cavalheiro et al, 1987;Turski et al, 1989).…”

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

“…We concluded earlier that the anticonvulsant mechanism(s) of the ketogenic diet in mice may involve a reduction of glucose utilization as fuel. 20 The anticonvulsant actions of 2-deoxyglucose and fructose 1,6-bisphosphate found in animal models [36][37][38] also suggest that reduced glycolysis and/or increased PPP can be anticonvulsant. As trioctanoin appears to alter glucose utilization through glycolysis and the PPP, it is possible that these metabolic alterations are involved in increasing the seizure threshold in naïve mice in this model with trioctanoin but not triheptanoin.…”

Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats

“…Recently, it has been shown that exogenous administration of FDP can reduce the duration and severity of seizures in laboratory animals (4). In these experiments, the FDP was given into the peritoneal cavity.…”