Effects of N-methyl-D-aspartate receptor antagonists on carbon monoxide-induced brain damage in mice.
The mechanism of neurodegeneration and the possible therapeutic amelioration were investigated in a model induced by successive carbon monoxide (CO) exposures. Successive CO exposures resulted in a consistent pattern of degeneration of hippocampal CA1 pyramidal cells, which was quantified using an image analyzer. Competitive and noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptors, cyclopentenophenanthrene, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten,5,10-imine maleate and an antagonist of glycine binding sites, 7-chlorokynurenic acid, significantly reduced the CO-induced neurodegeneration. Ifenprodil (a antagonist of polyamine binding sites) and glycine had no effect. From these results, it is clear that NMDA receptor/ion channel complex is involved in the mechanism of CO-induced neurodegeneration, and that glycine binding site antagonist as well as NMDA competitive and noncompetitive antagonists may have neuroprotective properties in neurological disorders associated with overactivation of NMDA receptors.
Ishimaru
H
H
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
Katoh
A
A
Suzuki
H
H
Fukuta
T
T
Kameyama
T
T
Nabeshima
T
T
D000818:Animals; D001665:Binding Sites; D002249:Carbon Monoxide Poisoning / Q000188:drug therapy / Q000473:pathology*; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D005998:Glycine / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D010880:Piperidines / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014665:Vasodilator Agents / Q000627:therapeutic use
D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D014665:Vasodilator Agents; D016291:Dizocilpine Maleate; C010739:ifenprodil; D005998:Glycine