Lubeluzole inhibits accumulation of extracellular glutamate in the hippocampus during transient global cerebral ischemia

Increases in extracellular glutamate during cerebral ischemia may play an i mportant role in neuronal injury. Lubeluzole is a novel neuroprotective dru g, which in previous in vitro and focal ischemia studies has been shown to inhibit nitric oxide synthesis, to block voltage-gated Na+-ion channels, an d to inhibit glutamate release. In this study, we investigated the ability of lubeluzole to inhibit glutamate accumulation during episodes of transien t global cerebral ischemia. Twenty-five New Zealand white rabbits were rand omized to one of four groups: a normothermic control group; a hypothermic g roup; a 1.25 mg/kg lubeluzole group; or a 2.5 mg/kg lubeluzole group. The a nimals were anesthetized, intubated, and ventilated before microdialysis pr obes were placed in the hippocampus. Lubeluzole was given intravenously 90 min before, the onset of ischemia. Esophageal temperature was maintained at 38 degreesC in the control, and lubeluzole treated groups, while the anima ls in the hypothermia group were cooled to 30 degreesC. A 15-min period of global cerebral ischemia was produced by inflating a neck tourniquet. Gluta mate concentrations in the microdialysate were determined using high-perfor mance liquid chromatography (HPLC). During ischemia and early reperfusion, glutamate concentrations increased significantly in the control group and r eturned to baseline after 15 min of reperfusion. In the lubleuzole 2.5 mg/k g and hypothermia groups, glutamate levels were significantly lower (P<0.05 ) than in the control group and then was no significant change from baselin e levels during the entire experiment. This study suggests that lubeluzole is effective in inhibiting extracellular glutamate accumulation during glob al cerebral ischemia, and has the potential to produce potent neuroprotecti on when instituted prior to an ischemic event. (C) 2001 Published by Elsevi er Science B.V.