TY - JOUR
T1 - Lubeluzole inhibits accumulation of extracellular glutamate in the hippocampus during transient global cerebral ischemia
AU - Koinig, Herbert
AU - Vornik, Vadim
AU - Rueda, Carlos
AU - Zornow, Mark H.
N1 - Funding Information:
This study was supported in part by the National Institute of Health grant 2 RO1 NS 29403 to Dr. Zornow, and a stipend from the Max Kade Foundation to Dr. Koinig.
PY - 2001/4/20
Y1 - 2001/4/20
N2 - 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°C in the control, and lubeluzole treated groups, while the animals in the hypothermia group were cooled to 30°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.
AB - 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°C in the control, and lubeluzole treated groups, while the animals in the hypothermia group were cooled to 30°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.
KW - Global cerebral ischemia
KW - Glutamate
KW - Lubeluzole
KW - Microdialysis
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U2 - 10.1016/S0006-8993(01)02204-1
DO - 10.1016/S0006-8993(01)02204-1
M3 - Article
C2 - 11306016
AN - SCOPUS:0035917854
SN - 0006-8993
VL - 898
SP - 297
EP - 302
JO - Brain Research
JF - Brain Research
IS - 2
ER -