Ohta H, Nishikawa H, Kimura H, Anayama H, Miyamoto M
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Neuroscience. 1997 Aug;79(4):1039-50. doi: 10.1016/s0306-4522(97)00037-7.
To investigate the influence of cerebral hypoperfusion on learning behaviours, we developed a novel rat cerebral hypoperfusion model, in which the bilateral internal carotid arteries were permanently ligated to reduce the cerebral blood flow, and examined its behavioural and histopathological consequences in comparison to those occurring after bilateral common carotid ligation. In the Morris water maze task, rats with common carotid ligation exhibited a learning deficit, whereas rats with internal carotid ligation exhibited normal learning. Both models exhibited significant learning impairments in the eight-arm radial maze task, although the impairment was less severe in internal carotid-ligated rats than in common carotid-ligated rats. The cerebral blood flow of rats with common carotid ligation was reduced significantly both two and 10 days after ligation, and was still below normal three months after ligation. A milder, but significant reduction in the cerebral blood flow was observed in internal carotid-ligated rats. Shrinkage of the optic nerves and a circadian activity rhythm desynchronized to the light/dark cycle were exhibited by the rats with common carotid ligation, whereas these parameters remained unaffected in the rats with internal carotid ligation, suggesting that permanent ligation of common carotid arteries but not internal carotid arteries impairs visual functions. The main pathological changes observed in the brain following common carotid ligation were rarefaction and gliosis of the white matter and neuronal loss in the hippocampal CA1 region. On the other hand, the rats with internal carotid ligation had no significant brain damage. Chronic treatment with idebenone (1.5 and 15 mg/kg/day), a cerebral energy metabolism enhancer, over a three-month period, commencing five days after ligation, ameliorated the impairment of water maze learning in rats with common carotid ligation. The treatment also significantly improved the learning impairment in the radial maze task of internal carotid-ligated rats. Idebenone had no effect on the histopathological changes that followed cerebral hypoperfusion. It is concluded that cerebral hypoperfusion induced by permanent internal carotid ligation impairs the working memory without causing pathological damage to the brain tissues and the visual system, and the learning impairment can be ameliorated by a cerebral energy metabolism enhancer. These findings have the clinical implication that a reduction in blood flow may be an important factor that causes or exacerbates cognitive decline in dementias.
为研究脑灌注不足对学习行为的影响，我们建立了一种新型大鼠脑灌注不足模型，通过永久性结扎双侧颈内动脉以减少脑血流量，并与双侧颈总动脉结扎后的行为和组织病理学结果进行比较。在莫里斯水迷宫任务中，颈总动脉结扎的大鼠表现出学习缺陷，而颈内动脉结扎的大鼠学习正常。在八臂放射状迷宫任务中，两种模型均表现出明显的学习障碍，尽管颈内动脉结扎大鼠的障碍程度低于颈总动脉结扎大鼠。颈总动脉结扎大鼠在结扎后2天和10天脑血流量均显著降低，结扎后3个月仍低于正常水平。颈内动脉结扎大鼠的脑血流量有轻度但显著的降低。颈总动脉结扎的大鼠出现视神经萎缩和昼夜活动节律与光/暗周期不同步，而颈内动脉结扎的大鼠这些参数未受影响，这表明永久性结扎颈总动脉而非颈内动脉会损害视觉功能。颈总动脉结扎后在脑中观察到的主要病理变化是白质稀疏和胶质增生以及海马CA1区神经元丢失。另一方面，颈内动脉结扎的大鼠没有明显的脑损伤。从结扎后5天开始，用艾地苯醌（1.5和15毫克/千克/天）进行为期3个月的慢性治疗，艾地苯醌是一种脑能量代谢增强剂，可改善颈总动脉结扎大鼠水迷宫学习的损伤。该治疗还显著改善了颈内动脉结扎大鼠在放射状迷宫任务中的学习障碍。艾地苯醌对脑灌注不足后的组织病理学变化没有影响。结论是，永久性颈内动脉结扎诱导的脑灌注不足损害工作记忆，但不会对脑组织和视觉系统造成病理损害，脑能量代谢增强剂可改善学习障碍。这些发现具有临床意义，即血流量减少可能是导致或加剧痴呆症认知衰退的一个重要因素。
