Dent G W, Rule B L, Tam S W, De Souza E B
Central Nervous System Diseases Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880.
Brain Res. 1993 Aug 20;620(1):7-15. doi: 10.1016/0006-8993(93)90264-n.
Linopirdine [DuP 996; 3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one] represents a novel class of compounds which enhance depolarization-activated (but not basal) release of acetylcholine, dopamine and serotonin in brain slices and improve learning and memory in rodents. The effects of linopiridine on local cerebral glucose metabolism were studied by the quantitative autoradiographic 2-deoxy-D-[1-14C]glucose method. Linopirdine administration in naive rats (0.01, 0.1, or 1.0 mg/kg, s.c.) did not significantly alter cerebral glucose metabolism in any of the regions analyzed. Since linopirdine protects against hypoxia-induced passive avoidance deficits in rats, we also examined the effects of linopirdine on cerebral metabolism after the rats were exposed to 30 min of hypoxia. Glucose metabolism was not significantly altered after hypoxic exposure, except for a small increase in some brain regions. Linopirdine administered after hypoxia decreased glucose metabolism in the hippocampus, limbic cortex, ventral hippocampal commissure, medial septum, striatum, subthalamic nucleus, zona incerta, lateral habenula, cerebral cortex, cerebellar vermis and a few thalamic nuclei. Statistically significant effects of linopirdine on glucose metabolism were observed in 22 of 56 brain regions sampled. In hypoxia-exposed rats, linopirdine altered glucose metabolism in brain regions that are implicated in learning and memory and are affected in Alzheimer's disease. Several of the affected regions are associated with the cholinergic system and may play a role in the cognitive enhancing properties of linopirdine.
利诺吡啶[DuP 996；3,3 - 双(4 - 吡啶基甲基)-1 - 苯基吲哚啉 - 2 - 酮]代表一类新型化合物，可增强脑片中乙酰胆碱、多巴胺和5 - 羟色胺的去极化激活（而非基础）释放，并改善啮齿动物的学习和记忆。采用定量放射自显影2 - 脱氧 - D - [1 - 14C]葡萄糖法研究了利诺吡啶对局部脑葡萄糖代谢的影响。给未处理的大鼠皮下注射利诺吡啶（0.01、0.1或1.0 mg/kg）后，在所分析的任何脑区中，脑葡萄糖代谢均未发生显著改变。由于利诺吡啶可预防大鼠缺氧诱导的被动回避缺陷，我们还研究了大鼠暴露于30分钟缺氧环境后利诺吡啶对脑代谢的影响。缺氧暴露后，除部分脑区有小幅增加外，葡萄糖代谢未发生显著改变。缺氧后给予利诺吡啶可降低海马、边缘叶皮质、腹侧海马连合、内侧隔核、纹状体、丘脑底核、未定带、外侧缰核、大脑皮质、小脑蚓部和一些丘脑核团的葡萄糖代谢。在采样的56个脑区中的22个观察到利诺吡啶对葡萄糖代谢有统计学意义的影响。在缺氧暴露的大鼠中，利诺吡啶改变了与学习和记忆相关且在阿尔茨海默病中受影响的脑区的葡萄糖代谢。一些受影响的区域与胆碱能系统有关，可能在利诺吡啶的认知增强特性中发挥作用。
