title: Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus.
abstract: The metabolism of tryptophan along the kynurenine pathway yields several neuroactive intermediates, including kynurenic acid, which is one of the few known endogenous N-methyl-d-aspartate receptor inhibitors; in parallel with this, it is an alpha7 nicotinic acetylcholinergic receptor antagonist. On the basis of these properties, kynurenic acid might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, the use of kynurenic acid as a neuroprotective agent is practically excluded because kynurenic acid hardly crosses the blood-brain barrier. We recently synthetized a new compound, glucosamine-kynurenic acid, which is presumed to cross the blood-brain barrier more easily. In this study, the effects of systemically administered kynurenic acid and glucosamine-kynurenic acid on CA3 stimulation-evoked population spike activity in region CA1 of the rat hippocampus were compared. The effect of kynurenic acid or glucosamine-kynurenic acid was augmented by probenecid (200 mg/kg), which inhibits kynurenic acid excretion from the cerebrospinal fluid. The results showed that, while kynurenic acid administered i.p. or i.v. in doses of 17, 34, 68 or 136 micromol/kg did not cause any observable change in the animals, 136 micromol/kg glucosamine-kynurenic acid (either i.p. or i.v.) resulted in the sudden death of all the animals. The dose of 68 micromol/kg i.v., but not i.p., resulted in a sudden stoppage of breath, but the animals could be reanimated. As small a dose of glucosamine-kynurenic acid as 17 micromol/kg i.p. resulted in a reduction in population spike amplitudes; this effect was further augmented by probenecid, whereas neither 17 micromol/kg nor higher doses of pure kynurenic acid had a similar effect. The results presented here suggest that glucosamine-kynurenic acid passes the blood-brain barrier much more readily than does kynurenic acid.
authors.affiliation: Department of Comparative Physiology, University of Szeged, Hungary.
authors.forename: Hermina
authors.initials: H
authors.lastname: Robotka
authors.forename: Hajnalka
authors.initials: H
authors.lastname: Németh
authors.forename: Csaba
authors.initials: C
authors.lastname: Somlai
authors.forename: László
authors.initials: L
authors.lastname: Vécsei
authors.forename: József
authors.initials: J
authors.lastname: Toldi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005944:Glucosamine / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010865:Pilot Projects; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014528:Uricosuric Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D014528:Uricosuric Agents; D007736:Kynurenic Acid; D005944:Glucosamine; D011339:Probenecid