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

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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.