Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils

Gábor Gigler, G. Szénási, Annamária Simó, György Lévay, L. Hársing, K. Sas, L. Vécsei, J. Toldi

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Abstract

Excessive stimulation of N-methyl-D-aspartate (NMDA) receptors during ischemia contributes to apoptotic and excitotoxic nerve cell death. Kynurenic acid is a selective antagonist at the glycine co-agonist site of the NMDA receptor complex at low concentration, and it is a broad-spectrum excitatory amino acid receptor blocker at high concentration. Kynurenic acid provides neuroprotection in animal models of cerebral ischemia only at very high doses as it hardly crosses the blood-brain barrier. The neuroprotective effect of L-kynurenine sulfate, a precursor of kynurenic acid, was therefore studied because L-kynurenine readily crosses the blood-brain barrier. L-kynurenine sulfate was administered 15 min before permanent focal cerebral ischemia produced by electrocoagulation of the distal middle cerebral artery in mice. L-kynurenine sulfate induced a small decrease in the surface area of the brain infarction (10%, P <0.05) at 30 mg/kg i.p., and it caused strong reductions in infarct size (24-25%, P <0.01) at 100 and 300 mg/kg i.p. Treatment of gerbils with L-kynurenine sulfate at 300 mg/kg i.p. 2 h before a 3-min bilateral carotid occlusion decreased (40%, P <0.01) the pyramidal cell loss in the CA1 area of the hippocampus. Furthermore, L-kynurenine sulfate inhibited the ischemia-induced hypermotility (77%, P <0.001), and decreased (50%, P <0.01) the ischemia-induced deterioration of spontaneous alternation, a measure of spatial memory, without altering the rectal temperature. In conclusion, the administration of L-kynurenine can elevate the brain concentration of kynurenic acid to neuroprotective levels, suggesting the potential clinical usefulness of L-kynurenine for the prevention of neuronal loss.

Original languageEnglish
Pages (from-to)116-122
Number of pages7
JournalEuropean Journal of Pharmacology
Volume564
Issue number1-3
DOIs
Publication statusPublished - Jun 14 2007

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Kynurenine
Gerbillinae
Neuroprotective Agents
Brain Ischemia
Sulfates
Kynurenic Acid
Ischemia
N-Methyl-D-Aspartate Receptors
Blood-Brain Barrier
Brain Infarction
Electrocoagulation
Pyramidal Cells
Middle Cerebral Artery
Glutamate Receptors
Glycine
Hippocampus
Cell Death
Animal Models
Neurons
Temperature

Keywords

  • Focal cerebral ischemia
  • Global cerebral ischemia
  • Kynurenic acid
  • L-kynurenine sulfate
  • Neuroprotection

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

@article{7459b216c3af4baea9074b70b33eb402,
title = "Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils",
abstract = "Excessive stimulation of N-methyl-D-aspartate (NMDA) receptors during ischemia contributes to apoptotic and excitotoxic nerve cell death. Kynurenic acid is a selective antagonist at the glycine co-agonist site of the NMDA receptor complex at low concentration, and it is a broad-spectrum excitatory amino acid receptor blocker at high concentration. Kynurenic acid provides neuroprotection in animal models of cerebral ischemia only at very high doses as it hardly crosses the blood-brain barrier. The neuroprotective effect of L-kynurenine sulfate, a precursor of kynurenic acid, was therefore studied because L-kynurenine readily crosses the blood-brain barrier. L-kynurenine sulfate was administered 15 min before permanent focal cerebral ischemia produced by electrocoagulation of the distal middle cerebral artery in mice. L-kynurenine sulfate induced a small decrease in the surface area of the brain infarction (10{\%}, P <0.05) at 30 mg/kg i.p., and it caused strong reductions in infarct size (24-25{\%}, P <0.01) at 100 and 300 mg/kg i.p. Treatment of gerbils with L-kynurenine sulfate at 300 mg/kg i.p. 2 h before a 3-min bilateral carotid occlusion decreased (40{\%}, P <0.01) the pyramidal cell loss in the CA1 area of the hippocampus. Furthermore, L-kynurenine sulfate inhibited the ischemia-induced hypermotility (77{\%}, P <0.001), and decreased (50{\%}, P <0.01) the ischemia-induced deterioration of spontaneous alternation, a measure of spatial memory, without altering the rectal temperature. In conclusion, the administration of L-kynurenine can elevate the brain concentration of kynurenic acid to neuroprotective levels, suggesting the potential clinical usefulness of L-kynurenine for the prevention of neuronal loss.",
keywords = "Focal cerebral ischemia, Global cerebral ischemia, Kynurenic acid, L-kynurenine sulfate, Neuroprotection",
author = "G{\'a}bor Gigler and G. Sz{\'e}n{\'a}si and Annam{\'a}ria Sim{\'o} and Gy{\"o}rgy L{\'e}vay and L. H{\'a}rsing and K. Sas and L. V{\'e}csei and J. Toldi",
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T1 - Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils

AU - Gigler, Gábor

AU - Szénási, G.

AU - Simó, Annamária

AU - Lévay, György

AU - Hársing, L.

AU - Sas, K.

AU - Vécsei, L.

AU - Toldi, J.

PY - 2007/6/14

Y1 - 2007/6/14

N2 - Excessive stimulation of N-methyl-D-aspartate (NMDA) receptors during ischemia contributes to apoptotic and excitotoxic nerve cell death. Kynurenic acid is a selective antagonist at the glycine co-agonist site of the NMDA receptor complex at low concentration, and it is a broad-spectrum excitatory amino acid receptor blocker at high concentration. Kynurenic acid provides neuroprotection in animal models of cerebral ischemia only at very high doses as it hardly crosses the blood-brain barrier. The neuroprotective effect of L-kynurenine sulfate, a precursor of kynurenic acid, was therefore studied because L-kynurenine readily crosses the blood-brain barrier. L-kynurenine sulfate was administered 15 min before permanent focal cerebral ischemia produced by electrocoagulation of the distal middle cerebral artery in mice. L-kynurenine sulfate induced a small decrease in the surface area of the brain infarction (10%, P <0.05) at 30 mg/kg i.p., and it caused strong reductions in infarct size (24-25%, P <0.01) at 100 and 300 mg/kg i.p. Treatment of gerbils with L-kynurenine sulfate at 300 mg/kg i.p. 2 h before a 3-min bilateral carotid occlusion decreased (40%, P <0.01) the pyramidal cell loss in the CA1 area of the hippocampus. Furthermore, L-kynurenine sulfate inhibited the ischemia-induced hypermotility (77%, P <0.001), and decreased (50%, P <0.01) the ischemia-induced deterioration of spontaneous alternation, a measure of spatial memory, without altering the rectal temperature. In conclusion, the administration of L-kynurenine can elevate the brain concentration of kynurenic acid to neuroprotective levels, suggesting the potential clinical usefulness of L-kynurenine for the prevention of neuronal loss.

AB - Excessive stimulation of N-methyl-D-aspartate (NMDA) receptors during ischemia contributes to apoptotic and excitotoxic nerve cell death. Kynurenic acid is a selective antagonist at the glycine co-agonist site of the NMDA receptor complex at low concentration, and it is a broad-spectrum excitatory amino acid receptor blocker at high concentration. Kynurenic acid provides neuroprotection in animal models of cerebral ischemia only at very high doses as it hardly crosses the blood-brain barrier. The neuroprotective effect of L-kynurenine sulfate, a precursor of kynurenic acid, was therefore studied because L-kynurenine readily crosses the blood-brain barrier. L-kynurenine sulfate was administered 15 min before permanent focal cerebral ischemia produced by electrocoagulation of the distal middle cerebral artery in mice. L-kynurenine sulfate induced a small decrease in the surface area of the brain infarction (10%, P <0.05) at 30 mg/kg i.p., and it caused strong reductions in infarct size (24-25%, P <0.01) at 100 and 300 mg/kg i.p. Treatment of gerbils with L-kynurenine sulfate at 300 mg/kg i.p. 2 h before a 3-min bilateral carotid occlusion decreased (40%, P <0.01) the pyramidal cell loss in the CA1 area of the hippocampus. Furthermore, L-kynurenine sulfate inhibited the ischemia-induced hypermotility (77%, P <0.001), and decreased (50%, P <0.01) the ischemia-induced deterioration of spontaneous alternation, a measure of spatial memory, without altering the rectal temperature. In conclusion, the administration of L-kynurenine can elevate the brain concentration of kynurenic acid to neuroprotective levels, suggesting the potential clinical usefulness of L-kynurenine for the prevention of neuronal loss.

KW - Focal cerebral ischemia

KW - Global cerebral ischemia

KW - Kynurenic acid

KW - L-kynurenine sulfate

KW - Neuroprotection

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