Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus

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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.

Original languageEnglish
Pages (from-to)75-80
Number of pages6
JournalEuropean Journal of Pharmacology
Volume513
Issue number1-2
DOIs
Publication statusPublished - Apr 18 2005

Fingerprint

Kynurenic Acid
Glucosamine
Hippocampus
Blood-Brain Barrier
Probenecid
Kynurenine

Keywords

  • (Rat)
  • Glucosamine-kynurenic acid
  • Hippocampus
  • Kynurenic acid
  • Neuroprotection
  • Probenecid

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

@article{34d6f4e7f85f41d79dbd8a8da17a8a77,
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 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.",
keywords = "(Rat), Glucosamine-kynurenic acid, Hippocampus, Kynurenic acid, Neuroprotection, Probenecid",
author = "H. Robotka and H. N{\'e}meth and C. Somlai and L. V{\'e}csei and J. Toldi",
year = "2005",
month = "4",
day = "18",
doi = "10.1016/j.ejphar.2005.02.043",
language = "English",
volume = "513",
pages = "75--80",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "1-2",

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TY - JOUR

T1 - Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus

AU - Robotka, H.

AU - Németh, H.

AU - Somlai, C.

AU - Vécsei, L.

AU - Toldi, J.

PY - 2005/4/18

Y1 - 2005/4/18

N2 - 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.

AB - 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.

KW - (Rat)

KW - Glucosamine-kynurenic acid

KW - Hippocampus

KW - Kynurenic acid

KW - Neuroprotection

KW - Probenecid

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VL - 513

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JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

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