Bikjdaouene Leila, Escames Germaine, Camacho Encarnación, León Josefa, Ferrer José M R, Espinosa Antonio, Gallo Miguel A, De Dios Luna Juan, Acuña-Castroviejo Darío
Departamento de Fisiología, Instituto de Biotecnología, Universidad de Granada, Granada, Spain.
J Pineal Res. 2004 May;36(4):267-77. doi: 10.1111/j.1600-079X.2004.00127.x.
We have previously proven that some synthetic kynurenines behave as antagonists of the N-methyl-d-aspartate receptor inhibiting neuronal subtype of nitric oxide synthase activity. We now investigate the anticonvulsant activity of four of these kynurenines in pentylenetetrazole (PTZ)-treated rats. The rats were treated with each kynurenine (10-160 mg/kg, s.c.) 30 min before PTZ administration (100 mg/kg, s.c.). Then, latency, duration and intensity of the first seizure and the percent animal survival were noted. PTZ-induced death was counteracted by high doses of kynurenines. Latency of the first seizure was significantly increased and its intensity reduced at the same doses, whereas the duration of the first seizure significantly decreased with doses of 20 mg/kg in most of the kynurenines tested. Three hours after PTZ administration, the surviving animals were sacrificed and the levels of brain amino acids and nitrite were measured. PTZ administration increased glutamate, glutamine, serine and taurine levels in different brain areas. High doses of kynurenines generally counteracted the effects of PTZ on excitatory amino acids, but they also reduced inhibitory aminoacids. However, the most consistent effect of kynurenines was the dose-dependent reduction of brain nitrite levels induced by PTZ. These results reveal a new family of anticonvulsant drugs that affect mainly to nitric oxide production in the brain.
我们之前已经证明，一些合成犬尿氨酸可作为N-甲基-D-天冬氨酸受体的拮抗剂，抑制一氧化氮合酶活性的神经元亚型。我们现在研究其中四种犬尿氨酸在戊四氮（PTZ）处理的大鼠中的抗惊厥活性。在给予PTZ（100 mg/kg，皮下注射）前30分钟，给大鼠分别注射每种犬尿氨酸（10 - 160 mg/kg，皮下注射）。然后，记录首次癫痫发作的潜伏期、持续时间和强度以及动物存活率。高剂量的犬尿氨酸可对抗PTZ诱导的死亡。在相同剂量下，首次癫痫发作的潜伏期显著延长，强度降低，而在大多数测试的犬尿氨酸中，20 mg/kg剂量时首次癫痫发作的持续时间显著缩短。给予PTZ 3小时后，处死存活的动物并测量脑氨基酸和亚硝酸盐水平。给予PTZ会增加不同脑区的谷氨酸、谷氨酰胺、丝氨酸和牛磺酸水平。高剂量的犬尿氨酸通常可对抗PTZ对兴奋性氨基酸的影响，但它们也会降低抑制性氨基酸。然而，犬尿氨酸最一致的作用是剂量依赖性降低PTZ诱导的脑亚硝酸盐水平。这些结果揭示了一类主要影响脑内一氧化氮生成的新型抗惊厥药物。
