Increases in extracellular
glutamate during
cerebral ischemia may play an important role in neuronal injury.
Lubeluzole is a novel
neuroprotective drug, which in previous in vitro and focal
ischemia studies has been shown to inhibit
nitric oxide synthesis, to block voltage-gated Na+-
ion channels, and to inhibit
glutamate release. In this study, we investigated the ability of
lubeluzole to inhibit
glutamate accumulation during episodes of transient global
cerebral ischemia. Twenty-five New Zealand white rabbits were randomized to one of four groups: a normothermic control group; a hypothermic group; a 1.25 mg/kg
lubeluzole group; or a 2.5 mg/kg
lubeluzole group. The animals were anesthetized, intubated, and ventilated before microdialysis probes were placed in the hippocampus.
Lubeluzole was given intravenously 90 min before the onset of
ischemia. Esophageal temperature was maintained at 38 degrees C in the control, and
lubeluzole treated groups, while the animals in the
hypothermia group were cooled to 30 degrees C. A 15-min period of global
cerebral ischemia was produced by inflating a neck
tourniquet.
Glutamate concentrations in the microdialysate were determined using high-performance liquid chromatography (HPLC). During
ischemia and early reperfusion,
glutamate concentrations increased significantly in the control group and returned to baseline after 15 min of reperfusion. In the lubleuzole 2.5 mg/kg and
hypothermia groups,
glutamate levels were significantly lower (P<0.05) than in the control group and there was no significant change from baseline levels during the entire experiment. This study suggests that
lubeluzole is effective in inhibiting extracellular
glutamate accumulation during global
cerebral ischemia, and has the potential to produce potent neuroprotection when instituted prior to an ischemic event.