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

衰老加速小鼠易感8 （SAMP8）表现出明显的学习和记忆障碍，而SAMP10表现出脑萎缩和与衰老相关的抑郁行为。2月龄小鼠海马GDNF mRNA表达在SAMP8和SAMP10株中低于同年龄SAMR1株。SAMP8和SAMP10中CA1区存活神经元数量随年龄增长而减少。这些发现表明，年轻SAMP8和SAMP10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。我们通过SAMP8与正常小鼠JF1的杂交，研究了SAMP8学习记忆障碍的遗传特征。SAMP8回交代学习缺陷发生率和QTL分析结果表明，至少有一个主要基因可能与SAMP8的学习缺陷有关。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，阻断l型钙通道，抑制钙调素依赖途径。我们发现CV-159对缺血性脑损伤有保护作用。这可能是通过阻断l型钙通道和抑制钙调素依赖功能介导的。我们试图分离出在短暂性脑缺血反应中其水平发生改变的基因。我们发现海马磷脂酰肌醇4-激酶（PI4-K）在脑缺血后表达降低，证明PI4-K对缺血神经元死亡具有保护作用。应用短时间的缺血可以产生缺血耐受性。我们发现，在预处理大鼠中，半暗区CREB磷酸化的增强速度更快。结果表明，半暗区CREB磷酸化的立即增强阻止了预处理动物梗死的扩散。

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.