Interactions of neurotoxins with non-NMDA glutamate receptors: an autoradiographic study.
Neurotoxic substances are discussed to cause neurodegeneration by acting as excitotoxins on glutamate receptors. We investigated the properties of L-beta-oxalyl-amino-alanine (L-BOAA) and 3,4, 6-trihydroxyphenlyalanine (6-OH-Dopa) at the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor and that of L-BOAA and domoic acid at the kainate glutamate receptor in human hippocampus. (3H)AMPA binding in hippocampal subfields was inhibited by L-BOAA and 6-OH-Dopa with mean IC50-values in the low micromolar range. (3H)Kainate binding was inhibited by L-BOAA with similar potency as (3H)AMPA binding and by domoic acid with mean IC50-values in the low nanomolar range. These results support the notion that symptoms like anterograde amnesia and epileptic seizures seen in domoic acid intoxication and limbic symptoms, e.g. cognitive and mood impairment observed in neurolathyrism may be caused by excitotoxic action on non-NMDA receptors. The potent interaction of 6-OH-Dopa with the AMPA-receptor may point to a possible dopaminergic-glutamatergic interaction in the development of neurodegenerative diseases like Parkinson's and Huntington's disease.
Künig
G
G
Department of Psychiatry, University of Würzburg, Federal Republic of Germany.
Niedermeyer
B
B
Krause
F
F
Hartmann
J
J
Deckert
J
J
Ransmayr
G
G
Heinsen
H
H
Beckmann
H
H
Riederer
P
P
D000599:Amino Acids, Diamino; D001345:Autoradiography; D001667:Binding, Competitive; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000378:metabolism
D000599:Amino Acids, Diamino; D004295:Dihydroxyphenylalanine; D007608:Kainic Acid; D009498:Neurotoxins; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015091:beta-Alanine; C100126:oxalyldiaminopropionic acid; C001388:6-hydroxydopa; C012301:domoic acid