title: 6-Hydroxykynurenic acid and kynurenic acid differently antagonise AMPA and NMDA receptors in hippocampal neurones.
abstract: 6-Hydroxykynurenic acid (6-HKA), a derivative of kynurenic acid (KYNA) extracted from Ginkgo biloba leaves, was tested for its putative glutamate receptor (GluR) antagonism in comparison to the scaffold substance. The patch-clamp method together with fast-application techniques were used to estimate inhibition by 6-HKA and KYNA of agonist binding at NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (NMDARs and AMPARs) of CA1 pyramidal neurones. 6-Hydroxykynurenic acid proved to be a low-affinity antagonist. When comparing with KYNA, 6-HKA was less potent at NMDARs (IC(50) = 136 versus 59 microM), but showed a higher affinity to AMPARs (K(B) = 22 versus 172 microM). The replacement of 6-HKA and KYNA by glutamate was investigated on outside-out patches. Both antagonists competitively inhibited AMPAR responses and displayed fast unbinding kinetics, but the derivative was significantly slower displaced than KYNA (tau = 1.63 versus 1.22 ms). Our findings demonstrate that 6-hydroxylation considerably changes the pharmacological profile of KYNA. Among the 6-derivatives of KYNA, 6-HKA shows the highest affinity to AMPARS: Despite its relatively low lipophily, these properties might be of clinical relevance under conditions that compromise the integrity of the blood-brain barrier. Furthermore, 6-HKA should be a useful tool to analyse glutamate-mediated synaptic responses.
authors.affiliation: Experimental Neurobiology, Neurosurgery, Bonn University, Bonn, Germany Institute of Pharmacy, Jena University, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weber
authors.forename: D
authors.initials: D
authors.lastname: Dietrich
authors.forename: I
authors.initials: I
authors.lastname: Gräsel
authors.forename: G
authors.initials: G
authors.lastname: Reuter
authors.forename: G
authors.initials: G
authors.lastname: Seifert
authors.forename: C
authors.initials: C
authors.lastname: Steinhäuser
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology
chemical_list: C428563:6-hydroxykynurenic acid; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D007736:Kynurenic Acid