Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes

The purpose of this study was to examine the effect of the anti-convulsant agent, riluzole, on high-affinity glutamate uptake as measured in rat spina l cord synaptosomes. The rate of glutamate uptake was significantly increas ed in the presence of 0.1 mu M and 1.0 mu M riluzole, but not at the higher concentrations examined. Kinetics analysis demonstrated that riluzole (0.1 mu M) decreased the apparent K-m by 21% and increased the V-max by 31%. Gl utamate uptake also was significantly increased in spinal cord synaptosomes obtained from rats treated with 8 mg/kg (i.p.) of riluzole and sacrificed 4 h later. The increase in glutamate uptake in vitro was not affected by pr etreatment either with H7, an inhibitor of PKA and PKC, or with the PKC act ivating phorbol ester, 12-O-tetradecanoylphorbol 13-acetate. Previous studi es have shown that some of the actions of riluzole are mediated by G protei ns sensitive to pertussis toxin. Surprisingly, treatment of synaptosomes wi th pertussis toxin alone increased the rate of glutamate uptake, while havi ng no effect on uptake in the presence of riluzole. However, pretreatment w ith cholera toxin was found to completely block the effects of riluzole on glutamate uptake. These results reveal an additional mechanism by which ril uzole can affect glutamatergic neurotransmission, and provides further supp ort that riluzole may prove beneficial in the treatment of traumatic centra l nervous system injuries involving the excitotoxic actions of glutamate. ( C) 2000 Elsevier Science B.V. All rights reserved.