Preservation of redox, polyamine, and glycine modulatory domains of the N-methyl-D-aspartate receptor in Alzheimer's disease.
This study used [3H]dizocilpine ([3H]MK-801) binding to the N-methyl-D-aspartate (NMDA) receptor to examine redox, polyamine, and glycine modulatory sites in membranes derived from the superior frontal and the superior temporal cortex of patients with Alzheimer's disease. In control subjects the competitive polyamine site antagonist arcaine inhibited [3H]dizocilpine binding in a dose-dependent fashion and this curve was shifted to the right by the addition of 50 microM spermidine. Arcaine inhibition of binding was more potent in the temporal cortex than in the frontal cortex, in both the absence and presence of 50 microM spermidine. In Alzheimer's disease, arcaine inhibition of [3H]dizocilpine binding (in both the absence and the presence of spermidine) was not different from control in either of the two brain areas examined. The sulfhydryl redox site of the NMDA receptor was assessed using the oxidizing agent 5,5'-dithio-bis(2-nitrobenzoic acid), which inhibited binding in a dose-dependent fashion. This inhibition was similar in patients with Alzheimer's disease and control subjects. Glycine-stimulated [3H]dizocilpine binding was also unaffected in patients with Alzheimer's disease. However, in the temporal cortex there was a significant age-associated decline in [3H]dizocilpine binding in the presence of 100 microM glutamate (Rs = -0.71) and 100 microM glutamate plus 30 microM glycine (Rs = -0.90). There was also an age-related increase in arcaine IC50 (which reflects an age-related decrease in arcaine affinity) in the frontal cortex, determined both in the absence (Rs = 0.83) and the presence (Rs = 0.79) of spermidine. These data indicate that the NMDA receptor and its modulatory redox, polyamine, and glycine subsites are intact in patients with Alzheimer's disease and that the modulatory activity of polyamine and glycine sites decline with aging.
Palmer
A M
AM
Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania.
Burns
M A
MA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000704:Analysis of Variance; D001645:Biguanides / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013095:Spermidine / Q000494:pharmacology*; D013702:Temporal Lobe / Q000378:metabolism
D001645:Biguanides; D016194:Receptors, N-Methyl-D-Aspartate; C006624:arcaine; D016291:Dizocilpine Maleate; D004228:Dithionitrobenzoic Acid; D005998:Glycine; D013095:Spermidine