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Development of model animals and cells for neuronal disease

神经元疾病模型动物和细胞的开发

基本信息

批准号：
09357019
负责人：
NOMURA Yasuyuki
金额：
$ 22.59万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

The senescence accelerated mouse (SAM) is known as a murine model of aging. SAM consists of senescence accelerated-prone mouse (SAMP) and senescence accelerated-resistant mouse (SAMR). Previously, we reported that SAMP8 and SAMP10 exhibit age-related learning impairments . In this study, we investigated the changes in emotional behavior and in neurotansmitter receptor in SAMP10, and the effect of onion extract on learning ability in Morris's water maze test.1) SAMP10 at 8 months showed an increases of immobility in a forced swimming test compared with SAMR1. Treatment with desipramine (25 mg/kg, I.p., 3 days) in SAMP10 caused a decrease in immobility.2) In the cortex from SAMP1O, [ィイD13ィエD1H]quinpirol binding to D2/D3 dopamine receptors increased significantly. In the hippocampus from SAMP10, [ィイD13ィエD1H]hydroxy DPAT binding to 5-HTィイD11AィエD1 receptors increased.3) In Morris's water maze task, in a control strain of SAMR1 at 8 months, the escape latency and path length decreased with increasing trial days, in contrast, the escape latency and path length did not change in SAMP8. Treatment with onion extract (5 ml/kg, p.o., 2 months) in SAMP8 improved the learning and memory in the task.4) In the control rats pretreated with the vehicle, transient forebrain ischemia-induced delayed neuronal death in the hippocampal CA 1 region was observed 7 days after reperfusion. Pretreatment with glial cell line-derived neurotrophic factor (1 μg), which was directly microinjected into the right hippocampal CA1 region, gave significant protection against the neuronal death. CV-159 (a dihydropyridine derivative) that blocks the L-type CaィイD12+ィエD1 channel and inhibits the calmodulin-dependent pathway. CV-159 gave protection against delayed neuronal death in the CA1 region after 15-min transient forebrain ischemia.

衰老加速小鼠（SAM）被称为衰老的鼠模型。SAM包括加速衰老易感小鼠（SAMP）和抗加速衰老小鼠（SAMR）。之前，我们报道过SAMP 8和SAMP 10表现出与年龄相关的学习障碍。在这项研究中，我们研究了SAMP 10的情绪行为和神经递质受体的变化，以及洋葱提取物对Morris水迷宫测试中学习能力的影响。1）与SAMR 1相比，8个月时的SAMP 10在强迫游泳测试中表现出增加的不动性。用地昔帕明（25 mg/kg，I. p.，2）在SAMP 10的皮层中，[β-D13-β-D1 H]喹吡罗与D2/D3多巴胺受体的结合显著增加。在Morris水迷宫实验中，8个月时SAMR 1对照组的逃避潜伏期和路径长度随实验天数的增加而缩短，而SAMP 8组的逃避潜伏期和路径长度无明显变化。用洋葱提取物（5 ml/kg，p.o.，2个月）SAMP 8组大鼠在任务中的学习和记忆能力得到改善。4）在对照组中，再灌注7天后观察到短暂前脑缺血诱导的海马CA 1区迟发性神经元死亡。将胶质细胞源性神经营养因子（glialcellline-derivedneurotrophicfactor，GFNF）1 μg直接注射于大鼠右侧海马CA 1区，可明显抑制海马CA 1区神经元的死亡。CV-159（一种二氢吡啶衍生物），阻断L型Ca ~（2+）D12+ Ca ~（2+）D1通道并抑制钙调蛋白依赖性途径。CV-159对15分钟短暂前脑缺血后CA 1区迟发性神经元死亡具有保护作用。