Gigler Gábor, Szénási Gábor, Simó Annamária, Lévay György, Hársing László Gábor, Sas Katalin, Vécsei László, Toldi József
Division of Preclinical Research, EGIS Pharmaceuticals PLC, Budapest, Hungary.
Eur J Pharmacol. 2007 Jun 14;564(1-3):116-22. doi: 10.1016/j.ejphar.2007.02.029. Epub 2007 Feb 23.
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.
缺血期间N-甲基-D-天冬氨酸（NMDA）受体的过度刺激会导致凋亡性和兴奋性毒性神经细胞死亡。犬尿氨酸在低浓度时是NMDA受体复合物甘氨酸共激动剂位点的选择性拮抗剂，在高浓度时是一种广谱兴奋性氨基酸受体阻滞剂。犬尿氨酸仅在非常高的剂量下才对脑缺血动物模型具有神经保护作用，因为它很难穿过血脑屏障。因此，对犬尿氨酸的前体L-犬尿氨酸硫酸盐的神经保护作用进行了研究，因为L-犬尿氨酸很容易穿过血脑屏障。在小鼠大脑中动脉远端电凝导致永久性局灶性脑缺血前15分钟给予L-犬尿氨酸硫酸盐。腹腔注射30mg/kg的L-犬尿氨酸硫酸盐可使脑梗死面积略有减小（10%，P<0.05），腹腔注射100mg/kg和300mg/kg时可使梗死面积显著减小（24-25%，P<0.01）。在沙土鼠双侧颈动脉闭塞3分钟前2小时腹腔注射300mg/kg的L-犬尿氨酸硫酸盐，可使海马CA1区锥体细胞损失减少（40%，P<0.01）。此外，L-犬尿氨酸硫酸盐可抑制缺血诱导的运动亢进（77%，P<0.001），并减少（50%，P<0.01）缺血诱导的自发交替行为恶化（一种空间记忆指标），且不改变直肠温度。总之，给予L-犬尿氨酸可使大脑中犬尿氨酸浓度升高至神经保护水平，提示L-犬尿氨酸在预防神经元丢失方面可能具有临床应用价值。
