Abstracts

Rationale: Fructose-1,6-diphosphate (FDP) shifts the metabolism of glucose from glycolysis to the pentose phosphate pathway, has anticonvulsant activity in several acute animal models. In the present study, we investigated the effects of FDP in antiepileptogenesis as well as fully kindled seizures of amygdaloid-kindling, which is an animal model of the most common form of human temporal lobe epilepsy. In hippocampal neurons, cation-chloride cotransporters (CCCs) control the reversal potential of GABAA receptor-mediated current and voltage responses and, consequently, modulate the function of GABAergic inhibition. The hippocampal expression of the neuron-specific K+-Cl co-transporter 2 (KCC2) and Na+-K+-Cl co-transporter 1 (NKCC1), which are the main members of CCC, was also measured.Methods: In experiment 1, rats were divided into three groups matched for after discharge threshold (ADT). FDP was administered once daily at the doses of 0.5 g/kg and 1.0 g/kg; while in the control group, an equivalent volume of saline was administered. Animals were stimulated daily at ADT intensity until control group were fully kindled. In experiment 2, after becoming fully kindled, rats were divided into three groups. Rats respectively received pre-kindling ADT intensity as the kindling current daily for 5 days. After behavioral experiment, the ipsilateral hippocampus were dissected and total RNA was extracted. The KCC2 and NKCC1 as well as GAPDH expressions were tested. Statistical evaluation of the group differences in kindling acquisition was performed with two-way analysis of variance (ANOVA). Other tests were performed with an analysis of one-way ANOVA when the data were normally distributed and the variances were homogeneous; otherwise, the nonparametric Mann Whitney U-tests were used as indicated in the figure legends.Results: FDP at the dose of 1.0 g/kg slowed the progression of seizure stages and shortened the corresponding ADD. FDP increased the number of stimulations to reach stage 2-5 and prolonged the cumulative ADD to reach stage 3-5. FDP also shortened staying days and cumulative ADD in stage 4-5. It showed no significant effect on fully kindled animals. The relative level of KCC2 increased and NKCC1 decreased when daily administration of 1.0 g/kg FDP in normal rats. Kindling downregulated the KCC2 expression, this was inhibited by FDP. FDP also decreased the expression of NKCC1 during the kindling session.Conclusions: Our results revealed that FDP may have dose related activity against partial and epileptogenesis from partial to generalized tonic-clonic seizures, but has no effect in fully kindled seizures. Our findings also suggested that an imbalance in the intracellular chloride level and GABA-mediated excitation may play a role in kindling acquisition and that FDP may function by preventing such an imbalance.