Spermidine antagonizes the inhibitory effect of huperzine A on [3H]dizocilpine (MK-801) binding in synaptic membrane of rat cerebral cortex.
Huperzine A, a novel cholinesterase inhibitor, was found to inhibit the N-methyl-D-aspartate (NMDA) receptors in the brain. In this study, the mechanisms of the NMDA receptor inhibition were investigated using [3H]dizocilpine (MK-801) binding in synaptic membrane of rat cerebral cortex. Changing the concentrations of L-glutamate and L-glycine did not alter the potency of huperzine A. Spermidine caused rightward shift of the concentration-response curve of huperzine A, and considerably increased its IC(50) value. Huperzine A did not affect the potency of unlabeled (+)-MK-801 in [3H]MK-801 binding. Saturation binding studies reveal that huperzine A exerts a negative allosteric modulation on the MK-801 binding site within the NMDA receptor-channel. The results suggest that huperzine A is a non-competitive antagonist of the NMDA receptors, acting at one of the polyamine binding sites.
Zhang
Yun-Hai
YH
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Tai-Yuan Road, Shanghai, PR China.
Zhao
Xiao-Yan
XY
Chen
Xue-Qin
XQ
Wang
Yuan
Y
Yang
Hui-Hua
HH
Hu
Guo-Yuan
GY
D000470:Alkaloids; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013095:Spermidine / Q000494:pharmacology*; D013570:Synaptic Membranes / Q000187:drug effects* / Q000378:metabolism
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012717:Sesquiterpenes; C050426:huperzine A; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D005998:Glycine; D013095:Spermidine