Häntzschel A, Andreas K
Institute of Pharmacology and Toxicology, Faculty of Medicine, Technical University Dresden, Germany.
Pharmacol Toxicol. 1998 Feb;82(2):80-8. doi: 10.1111/j.1600-0773.1998.tb01402.x.
The hexachlorophene-induced cytotoxic brain oedema is an experimental model of brain damage, suitable for testing cerebroprotective substances (Andreas 1993). In order to examine whether glutamate receptors are involved in mediating functional disorders due to neurotoxic brain damage, we have studied the protective effects of several competitive and non-competitive antagonists using adult male Wistar rats in a simple "ladder-test" for assessing coordinative motor behaviour. Hexachlorophene-induced brain damage was verified by histological examination of the cerebellum with vacuolation of white matter, astrocyte hypertrophy and astrocyte proliferation taken as signs of neurotoxic injury. The non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine maleate (MK-801) decreased the motor disturbance on the first and second day of the "ladder-test" when applied in the doses 0.1 mg/kg and 0.2 mg/kg intraperitoneally for 3 weeks during the hexachlorophene treatment. Acute MK-801 administration (0.1 mg/kg intraperitoneally) after 3 weeks hexachlorophene exposure improved the coordinative motor response only on the first day. When testing the competitive NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) in the dose 1.0 mg/kg intraperitoneally the motor disturbance was lowered significantly earlier than in spontaneous remission. Similar effects were observed with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the dose of 0.8 mg/kg intraperitoneally, an antagonist interacting both with the strychnine-insensitive binding site for glycine within the NMDA receptor complex and with the kainate(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor complex. Concurrent MK-801 administration decreased the vacuolation of white matter. The results suggest that NMDA receptors and non-NMDA receptors are involved in development of functional disorders induced by hexachlorophene.
六氯酚诱导的细胞毒性脑水肿是一种脑损伤的实验模型，适用于测试脑保护物质（安德烈亚斯，1993年）。为了研究谷氨酸受体是否参与介导神经毒性脑损伤所致的功能障碍，我们使用成年雄性Wistar大鼠，通过一个简单的“阶梯试验”来评估协调运动行为，研究了几种竞争性和非竞争性拮抗剂的保护作用。通过对小脑进行组织学检查来证实六氯酚诱导的脑损伤，以白质空泡化、星形胶质细胞肥大和星形胶质细胞增殖作为神经毒性损伤的标志。非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂马来酸氯氮平（MK-801）在六氯酚治疗期间以0.1mg/kg和0.2mg/kg的剂量腹腔注射3周，在“阶梯试验”的第一天和第二天可减轻运动障碍。在六氯酚暴露3周后急性腹腔注射MK-801（0.1mg/kg）仅在第一天改善了协调运动反应。当以1.0mg/kg的剂量腹腔注射竞争性NMDA受体拮抗剂2-氨基-5-膦酰基戊酸（AP-5）时，运动障碍的减轻明显早于自然缓解。以0.8mg/kg的剂量腹腔注射6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）也观察到类似效果，该拮抗剂既与NMDA受体复合物内对士的宁不敏感的甘氨酸结合位点相互作用，也与红藻氨酸（+/-）-α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体复合物相互作用。同时给予MK-801可减少白质空泡化。结果表明，NMDA受体和非NMDA受体参与了六氯酚诱导的功能障碍的发生。
