Himori N, Watanabe H, Akaike N, Kurasawa M, Itoh J, Tanaka Y
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
J Pharmacol Methods. 1990 Jul;23(4):311-27. doi: 10.1016/0160-5402(90)90059-t.
During anesthesia in mice, both common carotid arteries were tied loosely with an overhand knot suture (an occluder), while two snares (releasers) were placed in the knot so that it could be repeatedly tightened to occlude the arteries and loosened again to allow for reperfusion while the mice were conscious and unrestrained. The incidence of mortality as well as impairment of brain metabolism depended upon the length of cerebral ischemia. Cortical electroencephalogram (EEG) clearly reflected the regional ischemia as evidenced by electrical quiescence. Less mortality was observed with ischemic mice treated with dextrorphan (30 mg/kg p.o.). On day 1 (24 hr after ischemia), there were impairments in complex motor coordination, multichoice swim performance, and step-through or thermal pain-motivated avoidance responses. Thereafter, the battery of tests progressively improved. This improvement depended on the period of resumption of cerebral blood flow; the 7-day, postischemic lapse significantly reduced the deficit observed. Reduction in the degree of habituation of exploratory activity was also clearly observed following ischemic insult. Dextrorphan (1-30 mg/kg i.p.) given to ischemic mice was effective in the habituation and step-through-type passive avoidance test paradigms. In conclusion, 1) the decline in cognition as observed with ischemic mice is due to the temporal and reversible derangement of their neuronal networks; 2) excessively released glutamate is probably of major pathogenic importance in the consequences of cerebral ischemia based on the positive results of the N-methyl-D-aspartate receptor antagonist, dextrorphan; 3) the simple technique could be useful in elucidating the pathophysiologic mechanisms of ischemically elicited derangement of the cerebral organization; and 4) the model could be used to assess the efficiency of drugs with high clinical predictivity.
在对小鼠进行麻醉期间，用活结缝线（一种封堵器）将双侧颈总动脉轻轻结扎，同时在结中放置两个圈套（松开器），以便在小鼠清醒且不受限制时能够反复收紧以阻塞动脉，然后再次松开以实现再灌注。死亡率以及脑代谢损伤的发生率取决于脑缺血的时长。皮层脑电图（EEG）通过电静息清晰地反映了局部缺血情况。用右啡烷（30 mg/kg口服）治疗的缺血小鼠死亡率较低。在第1天（缺血后24小时），复杂运动协调、多项选择游泳表现以及穿梭或热痛激发的回避反应均出现损伤。此后，一系列测试逐渐改善。这种改善取决于脑血流恢复的时期；缺血后7天的延迟显著减少了观察到的缺陷。缺血损伤后还明显观察到探索活动习惯化程度的降低。给予缺血小鼠右啡烷（1 - 30 mg/kg腹腔注射）在习惯化和穿梭型被动回避测试范式中有效。总之，1）缺血小鼠观察到的认知下降是由于其神经网络的暂时和可逆紊乱；2）基于N - 甲基 - D - 天冬氨酸受体拮抗剂右啡烷的阳性结果，过量释放的谷氨酸可能在脑缺血后果中具有主要致病重要性；3）该简单技术可用于阐明缺血引起的脑组织紊乱的病理生理机制；4）该模型可用于评估具有高临床预测性的药物的疗效。
