Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus.
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.
Robotka
Hermina
H
Department of Comparative Physiology, University of Szeged, Hungary.
Németh
Hajnalka
H
Somlai
Csaba
C
Vécsei
László
L
Toldi
József
J
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
D018691:Excitatory Amino Acid Antagonists; D014528:Uricosuric Agents; D007736:Kynurenic Acid; D005944:Glucosamine; D011339:Probenecid