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Usefulness of a new long life system dementia model mouse and the application to creative drugs.

一种新型长寿命系统痴呆模型小鼠的实用性及其在创新药物中的应用。

基本信息

批准号：
09557212
负责人：
MIYAMOTO Atsushi
金额：
$ 5.95万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557212/
关键词：
Brain aging C57BL 6J mice Memory disorders Signal transduction Membrane fluidity NMDA receptor Piracetam neurosteroids 老化細胞情報伝達マウス GABA_A受容体受動的回避試験向知性薬

项目摘要

The importance of age-related memory deficits is well known, and much has recently been done to gain a better understanding of the pathophysiology of learning disorders in order to further improve the therapeutical approach. Various ones of evidence suggest that, with aging, there is an impairment of animals' learning abilities.1) We studied two groups of 30-month-old C57BL/6J mice selected on the basis of their memory performance in the passive avoidance acquisition task (PAAT). By using the PAAT as a test of memory performance, it was found that approximately 50% of aged C57BL/6J mice showed clearly impaired memory performance (AI), whereas about 50% of the aged animals performed clearly unimpaired memory performance (AU) as well as adults (6-month-old). N-methyl-D-aspartate receptor density, as determined by the specific binding of [ィイD13ィエD1H]MK-801 to forebrain membranes, decreased by 27% in AI mice and by 7% in AU mice compared with adult animals. Membrane fluidity, as determined … More by fluorescence probe 1, 6-diphenyl-1,3, 5-hexatriene to forebrain membranes, decreased by 30% in AI mice and by 5% in AU mice compared with adult animals.2) The antiamnesic and memory-enhancing properties of piracetam and other structurally related nootropics have been demonstrated in numerous studies with animals. Subcutaneous injection of piracetam (200 mg/kg once daily) for 8 weeks improved the impaired memory retention and decreased brain membrane fluidity in AI mice, but had no measurable effect on membrane fluidity in AU mice. It is concluded that chronic administration of piracetam to AI animals promoted a partial recovery of the impaired memory retention with aging, which might be explicable in terms of mechanisms involving fluidity of the brain neuronal membranes.3) Numerous studies confirm that serum levels of dehydroepiandrosterone sulfate (DHEAS) decrease with age in both human and mammalian and this can be considered to be a rather specific marker of aging. Subcutaneous infection of pregnenolone sulfate (PS) and DHEAS for 8 weeks improved the impaired memory retention of PAAT in AI mice. PS and DHEAS, major neurosteroids that decreases in blood serum with age, may be of use in treatment of neurodegenerative and memory disorders. Less

与年龄相关的记忆缺陷的重要性是众所周知的，并且最近已经做了很多工作来更好地了解学习障碍的病理生理学，以便进一步改进治疗方法。各种证据表明，随着年龄的增长，动物的学习能力会受到损害。1) 我们研究了两组 30 个月大的 C57BL/6J 小鼠，这些小鼠是根据它们在被动回避习得任务 (PAAT) 中的记忆表现而选择的。通过使用PAAT作为记忆表现测试，发现大约50%的老年C57BL/6J小鼠表现出明显受损的记忆表现（AI），而大约50%的老年动物与成年动物（6个月大）一样表现出明显未受损的记忆表现（AU）。根据 [ィイD13ィD1H]MK-801 与前脑膜的特异性结合测定，与成年动物相比，AI 小鼠中的 N-甲基-D-天冬氨酸受体密度下降了 27%，AU 小鼠中的受体密度下降了 7%。通过前脑膜荧光探针 1, 6-二苯基-1,3, 5-己三烯测定，与成年动物相比，AI 小鼠的膜流动性降低了 30%，AU 小鼠的膜流动性降低了 5%。2) 吡拉西坦和其他结构相关的促智药的抗遗忘和增强记忆特性已在大量动物研究中得到证实。皮下注射吡拉西坦（200 mg/kg，每日一次）8周改善了AI小鼠的记忆力受损和脑膜流动性降低，但对AU小鼠的脑膜流动性没有可测量的影响。结论是，对人工智能动物长期服用吡拉西坦，促进了随着年龄增长而受损的记忆保留的部分恢复，这可能可以用涉及脑神经元膜流动性的机制来解释。 3) 大量研究证实，在人类和哺乳动物中，硫酸脱氢表雄酮 (DHEAS) 的血清水平随着年龄的增长而降低，这可以被认为是一个相当具体的标志物。老化。皮下感染孕烯醇酮硫酸盐 (PS) 和 DHEAS 8 周可改善 AI 小鼠 PAAT 受损的记忆保留。 PS 和 DHEAS 是血清中随年龄增长而减少的主要神经类固醇，可用于治疗神经退行性疾病和记忆障碍。较少的