权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Preparation of animal model with higher brain dysfunction : studies on evaluation methods of active chemicals

高级脑功能障碍动物模型的制备：活性化学物质评价方法的研究

基本信息

批准号：
12357015
负责人：
NOMURA Yasuyuki
金额：
$ 26.6万
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：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12357015/
关键词：
Senescence-accelerated mouse (SAM)quantitative trait Loci analysis (QTL)learning deficiency GDNF neurotrophic factor phosphatididylinositol 4-kinase CREB brain ischemia Phosphatidylinositol 4-kinase senescence accelerated mouse (SAM) /

项目摘要

Senescence-accelerated mouse prone 8 (SAMP8) shows marked impairment of learning and memory, whereas SAMP10 shows brain atrophy and aging-associated depressive behavior. Hippocampal GDNF mRNA expression in 2-month-old SAMP8 and SAMP10 strains was less than in SAMR1 specimens of the same age. The number of surviving neurons in the CA1 region decreased with age in SAMP8 and SAMP10. These findings suggest that low GDNF expression in young SAMP8 and SAMP10 may be involved in hippocampal dysfunctions, such as age-related learning impairment and neuronal death. We investigated genetic characteristic of learning and memory impairment in SAMP8 by cross-mating between SAMP8 and normal mice, JF1. Results of the incidence of learning deficit in backcross generation and quantitative trait Loci analysis (QTL) suggest that at least one major gene may involves in learning impairment of SAMP8. CV-159, dihydropyridine derivative, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pryridinedicarboxylic acid methyl 6-(5-phenyl-3- pyrazolyloxyl ester that blocks the L-type calcium channel and inhibits the calmodulin-dependent pathway. We found that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type calcium channel and inhibiting calmodulin-dependent function. We have attempted to isolate the genes whose levels were changed in response to transient cerebral ischemia. We found that hippocampal expression of phosphatididylinositol 4-kinase (PI4-K) was decreaed after the brain ischemia, and demonstrated the protective role of PI4-K on ischemia-induced neuronal death. Application of a brief period of ischemia has been known to produce ischemic tolerance. We found that the phosphorylation of CREB in the penumbra region was more rapidly enhanced in the preconditioned rats. The result suggests that the immediate enhancement in the phosphorylation of CREB in penumbra region prevented the spread of infarction in the preconditioned animal.

衰老加速型小鼠倾向8（SAMP 8）显示出明显的学习和记忆障碍，而SAMP 10显示出脑萎缩和衰老相关的抑郁行为。海马GDNF mRNA表达在2月龄SAMP 8和SAMP 10株低于SAMR 1相同年龄的标本。在SAMP 8和SAMP 10中，CA 1区存活的神经元数量随着年龄的增长而减少。这些发现表明，年轻SAMP 8和SAMP 10中GDNF的低表达可能参与海马功能障碍，如年龄相关的学习障碍和神经元死亡。通过SAMP 8与正常小鼠JF 1杂交，研究SAMP 8学习记忆障碍的遗传特征。回交后代学习障碍发生率和数量性状基因座分析结果表明，SAMP 8的学习障碍可能与至少一个主效基因有关。CV-159，二氢吡啶衍生物，1，4-二氢-2，6-二甲基-4-（3-硝基苯基）-3，5-吡啶二羧酸甲基6-（5-苯基-3-吡唑氧基）酯，可阻断L型钙通道并抑制钙调蛋白依赖性途径。我们发现CV-159可以保护缺血性脑损伤。这可能是通过阻断L型钙通道和抑制钙调素依赖性功能介导的。我们试图分离出那些在短暂性脑缺血中水平发生变化的基因。我们发现脑缺血后海马磷脂酰肌醇4-激酶（PI 4-K）表达减少，证明PI 4-K对缺血诱导的神经元死亡具有保护作用。已经知道应用短暂的缺血可以产生缺血耐受。我们发现，CREB的磷酸化的半影区更迅速地增强预处理大鼠。结果表明，在预处理动物中，半暗带区CREB磷酸化的立即增强阻止了梗死的扩散。