2-APV and DGAMS are superior to MK-801 in preventing hypoxia-induced injury to developing neurons in vitro.

P K Sher

Index: Pediatr. Neurol. 7(6) , 429-35, (1991)

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Abstract

The relative efficacy of competitive and noncompetitive excitatory amino acid antagonists in preventing hypoxic neuronal injury recently was examined in vitro. Immature (26 days post-conception) fetal mouse cerebral cortical cell cultures were exposed 10 days after plating to 5% oxygen for 24 hrs and returned to normoxia. After hypoxic insult, cultures were either not treated or the medium was supplemented with the competitive excitatory amino acid antagonists 2-amino-5-phosphonovalerate (2-APV), gamma-D-glutamylaminomethylsulphonate (DGAMS), or the noncompetitive antagonist methyl-10,11-dihydro-5-H-dibenzocyclohepten-5,10-imine maleate (MK-801). By 48 hrs after restitution of normoxia, untreated hypoxic cultures evidenced severe neuronal deterioration, elevated LDH concentrations in the medium, depressed benzodiazepine receptor binding, and reduced GABA and glutamate uptake. Enhanced glial cell activity was reflected by modestly elevated glutamine synthetase activity. In hypoxic cultures treated with 2-APV (10 microM) or DGAMS (30 microM), neuronal morphology and biochemical profiles were both improved significantly when compared to both untreated hypoxic cultures and also to those treated with MK-801; 2-APV provided greater, although incomplete, protection. MK-801, at the highest nonneurotoxic concentration (25 nM), did not improve neuronal viability when compared to untreated controls. These results suggest that competitive excitatory amino acid antagonists are superior to noncompetitive antagonists in preventing hypoxic neuronal injury to developing neurons in vitro. MK-801, at low concentrations, produced significant neurotoxicity without improving cell survival.