Neuroprotective Effect of L-kynurenine Sulfate Administered Before Focal Cerebral Ischemia in Mice and Global Cerebral Ischemia in Gerbils.
From: Division of Preclinical Research, EGIS Pharmaceuticals PLC, Budapest, Hungary.
European journal of pharmacology
- Publish Date: Jun 2007
- ISSN: 0014-2999
- Volume: 564
- Issue: 1-3
- Pages: 116-22
- Medium: Print
- Language: English
- Citation (JAMA): Gigler Gábor, Szénási Gábor, Simó Annamária, et al. Neuroprotective Effect of L-kynurenine Sulfate Administered Before Focal Cerebral Ischemia in Mice and Global Cerebral Ischemia in Gerbils.. Eur. J. Pharmacol. Jun 2007;564:116-22
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.
Mesh Headings (Keywords): Amino Acids, Animals, Behavior, Animal, Blood-Brain Barrier, Body Temperature, Brain, Brain Ischemia, Disease Models, Animal, Dose-Response Relationship, Drug, Electrocoagulation, Gerbillinae, Kynurenine, Male, Maze Learning, Memory, Mice, Motor Activity, Neuroprotective Agents, Species Specificity
Check for Full Text / PubMed Unique Identifier (PMID): 17407777
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