Comparison of delayed administration of competitive and uncompetitive antagonists in preventing NMDA receptor-mediated neuronal death.
Activation of N-methyl-D-aspartate (NMDA) receptors is thought to mediate toxic damage to central neurons due to hypoxia-ischemia, hypoglycemia, and trauma. We studied identified rat retinal ganglion cell neurons in vitro, a useful system for the study of excitotoxicity, and compared the protective effects of delayed administration of a competitive antagonist, 2-amino-5-phosphonovalerate (APV), and of an uncompetitive antagonist, MK-801, after glutamate-induced injury. We used maximally protective doses of the 2 antagonists. Under these conditions, both antagonists were able to prevent neuronal cell death if they were present within minutes of exposure to an endogenous glutamate-related toxin. In contrast, MK-801, but not APV, protected significantly against NMDA-mediated neurotoxicity when administered 1 to 4 hours after the initial insult. Thus, at least under certain conditions, an uncompetitive NMDA antagonist may offer a distinct advantage over a competitive antagonist when given several hours after a neurologic injury.
Levy
D I
DI
Department of Neurology, Children's Hospital, Boston, MA 02115.
Lipton
S A
SA
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000633:toxicity*; D012160:Retina / Q000187:drug effects*; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D013997:Time Factors
D003986:Dibenzocycloheptenes; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate