Berg M, Bruhn T, Johansen F F, Diemer N H
Cerebral Ischaemia Research Group, University of Copenhagen, Denmark.
Pharmacol Toxicol. 1993 Nov;73(5):262-8. doi: 10.1111/j.1600-0773.1993.tb00582.x.
We have studied the effect of two glutamate receptor antagonists on seizures and hippocampal neurone loss in the rat after systemic kainic acid administration. Intraperitoneal injection of the novel AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid) receptor antagonist NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione) (30 mg/kg x 3 and 15 mg/kg x 3) administered 30 and 15 min. before and simultaneously with injection of kainic acid (5 mg/kg) intraperitoneally, dramatically enhanced the toxicity of kainic acid leading to death of all animals. When the NBQX dose was reduced to 8 mg/kg x 3, all animals survived and neurone damage in the hippocampus did not differ from control animals. When NBQX (30 mg/kg x 3) was administered 30- or 60 min after injection of kainic acid (8 mg/kg) intraperitoneally, no changes were observed concerning survival rates, seizure generation and neurone loss. Post-kainic acid treatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg and 1.0 mg/kg), 30 and 60 min. after intraperitoneally injection of kainic acid 8 mg/kg, abolished seizures in all animals and the neurone damage in the hippocampus was completely prevented. The results emphasize the importance of the NMDA-receptor activation for seizure generation and subsequent brain damage after intraperitoneally kainic acid. The paradoxical, unexpected effects of NBQX contrast to the protective effect of this compound after cerebral ischaemia and hypoglycaemia, conditions which are also characterized by glutamate-mediated damage. One possible explanation of the lowered seizure threshold to kainic acid after NBQX could be that NBQX is blocking AMPA receptors on interneurones more efficiently than on pyramidal cells.
我们研究了两种谷氨酸受体拮抗剂对全身注射海藻酸后的大鼠癫痫发作和海马神经元损失的影响。腹腔注射新型AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）受体拮抗剂NBQX（6-硝基-7-氨磺酰基苯并[f]喹喔啉-2,3-二酮）（30mg/kg×3次和15mg/kg×3次），在腹腔注射海藻酸（5mg/kg）前30分钟和15分钟以及同时给药，显著增强了海藻酸的毒性，导致所有动物死亡。当NBQX剂量降至8mg/kg×3次时，所有动物存活，海马中的神经元损伤与对照动物无差异。当腹腔注射海藻酸（8mg/kg）后30分钟或60分钟给予NBQX（30mg/kg×3次）时，在存活率、癫痫发作和神经元损失方面未观察到变化。在腹腔注射8mg/kg海藻酸后30分钟和60分钟，用非竞争性NMDA受体拮抗剂MK-801（0.5mg/kg和1.0mg/kg）进行海藻酸后处理，可消除所有动物的癫痫发作，并完全预防海马中的神经元损伤。结果强调了NMDA受体激活在腹腔注射海藻酸后癫痫发作和随后脑损伤中的重要性。NBQX的矛盾、意外作用与该化合物在脑缺血和低血糖后（这两种情况也以谷氨酸介导的损伤为特征）的保护作用形成对比。NBQX后对海藻酸癫痫阈值降低的一种可能解释是，NBQX比锥体细胞更有效地阻断中间神经元上的AMPA受体。
