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 α7 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 μmol/kg did not cause any observable change in the animals, 136 μmol/kg glucosamine-kynurenic acid (either i.p. or i.v.) resulted in the sudden death of all the animals. The dose of 68 μmol/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 μmol/kg i.p. resulted in a reduction in population spike amplitudes; this effect was further augmented by probenecid, whereas neither 17 μmol/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.