Studies on the Machanism of Memory Disturbances in Senescence-Accelerated Mouse and the Application to Screening of Nootropics

衰老加速小鼠(SAM)已被建立为加速衰老的小鼠模型。与对照组(SAMR1)相比，P8品系(SAMP8)也观察到随年龄增长的记忆障碍。为了建立筛选有效的抗衰老和改善记忆药物的方法学，我们用SAMP8观察了中药对记忆障碍的影响。以改善外周微循环障碍的东药丹金甲醇提取物500 mg/kg/d给4月龄小鼠灌胃给药，每周5次，连续3周。用Morris水迷宫评价大鼠的空间再认能力。与车辆控制相比，该提取改善了空间识别。此外，提取物对小鼠的运动活动没有影响，但缩短了小鼠在水浴中的不动时间。因此，丹参的甲醇提取物中含有改善大脑功能的活性化学物质。然后，我们测定了用该提取物处理的SAMP8大鼠脑内[~(3 H)H]MK-801与NMDA受体的结合和[~(3 H)H]N-硝基-精氨酸([~(3 H)]NNA)与一氧化氮合酶的结合。治疗后大脑皮层[~(3 H)]MK-801结合量和脑干[~(3 H)]NNA结合量增加，提示痰金对突触神经传递和神经递质受体介导的脑内跨膜信号转导有一定作用。我们仍在研究以下几点：1)活性化学物质的鉴定，2)作用的细胞和分子机制，3)临床应用于精神和智力障碍患者。我们认为SAMP8是研究增龄性记忆障碍机制和筛选治疗药物的有用动物模型。

Senescence-accelerated mouse (SAM) has been esstablihed as a murine model showing accelerating aging. Memory impairment with aging is also observed in P8 strain (SAMP8) in contrast to the control (SAMR1). To establish the methodology screening effective drugs with anti-aging and memory improvement, we investigated effects of herbs on memory disturbance using SAMP8. The methanol extract from Tan-jin, an oriental medicine with improving effects on peripheral microcirculation disturbances at 500 mg/kg/day was orally administrated five time a week for 3 weeks into 4-month-old mice. Spatial recognition ability was evaluated by the Morris water maze methods. The extract ameliorated spatial recognition compared to the vehicle control. In addition, the extract did not affect locomotor activity but shortened the immobility time in the water bath. Therefore the methanol extract from Tan-jin contains active chemicals improving the brain functions. We then measured [^3H]MK-801 binding (to NMDA receptors) and [^3H]N^G-nitro-arginine ([^3H]NNA) binding (to nitric oxide synthase) in regional brains of SAMP8 treated with the extract. The treatment increased the [^3H]MK-801 binding in cerebral cortex and [^3H]NNA binding in brain stem, suggesting that Tan-jin is effective on synaptic neurotransmission and neurotransmittor receptor-mediated transmembrane signaling in the brain. We still are investigating following points : 1) identification of active chemicals, 2) the cellular and moleular mechanism of the action, 3) clinical application to patients with mental and intellectual disturbances. We can propose that SAMP8 is an useful animal model studying the mechanism of age-related memory impairment and screening the therapeutic drugs.