Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils.
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.
Gigler
Gábor
G
Division of Preclinical Research, EGIS Pharmaceuticals PLC, Budapest, Hungary.
Szénási
Gábor
G
Simó
Annamária
A
Lévay
György
G
Hársing
László Gábor
LG
Sas
Katalin
K
Vécsei
László
L
Toldi
József
J
D000596:Amino Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004564:Electrocoagulation; D005849:Gerbillinae; D007737:Kynurenine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity
D000596:Amino Acids; D018696:Neuroprotective Agents; D007737:Kynurenine