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Studies on new drugs for delayed and progressive learning and memory impairment using kappa-opioid related drugs

使用κ阿片类药物相关药物治疗延迟性和进行性学习记忆障碍的新药研究

基本信息

批准号：
16590442
负责人：
HIRAMATSU Masayuki
金额：
$ 2.24万
依托单位：
Meijo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

We have reported that kappa-opioid receptor agonist such as dynorphin A improved learning and memory impairment in several animal models with cholinergic dysfunction. Nociceptin is an endogenous ligand for the opioid receptor-like 1 (ORL1) receptor and has some structural homology with the dynorphin A. We have suggested that the ameliorating effect of low doses nociceptin in learning and/or memory impairment may not be mediated by ORL1 receptor. In the hippocampus of ORL1 receptor knockout mouse, expression of kappa_1 opioid receptor mRNA decreased, while mRNA expression of dynorphin and nociceptin precursor protein significantly increased. These changes were presented in beta-amyloid peptide (25-35)-treated mice. The mRNA expression levels of dynorphin precursor protein in the hippocampus 1 week after beta-amyloid peptide (25-35) administration significantly decreased in ORL1 receptor knockout mouse. We used restraint water-immersion stress model and lipopolysaccharide (LPS) to induce delayed and progressive learning and memory impairment to test the effect of dynorphin A and nociceptin. After water-immersion stress, short-term memory was impaired 5 days after stress exposure and the passive avoidance learning was impaired 7 days after stress exposure. These impairments were significantly ameliorated by the antidepressant, desipramine and the acetylcholine esterase inhibitor, tacrine. In addition, they were also ameliorated by antioxidants such as catechin by repeated administration. Further, delayed impairment of learning and memory induced by LPS was also ameliorated by repeated administration of catechin. We need to elucidate the mechanisms of dynorphin A related peptides in these animal models.

我们已经报道了κ-阿片受体激动剂如强啡肽A在几种胆碱能功能障碍的动物模型中改善了学习和记忆障碍。孤啡肽是阿片受体样1（ORL 1）受体的内源性配体，与强啡肽A具有一定的结构同源性。提示低剂量孤啡肽对学习记忆障碍的改善作用可能不是通过ORL 1受体介导的。在ORL 1受体敲除小鼠海马中，kappa_1阿片受体mRNA表达降低，强啡肽和痛敏素前体蛋白mRNA表达显著增加。这些变化出现在β-淀粉样肽（25-35）治疗的小鼠中。在ORL 1受体敲除小鼠中，β-淀粉样肽（25-35）给药后1周，海马中强啡肽前体蛋白的mRNA表达水平显著降低。采用束缚浸水应激模型和脂多糖（LPS）诱导大鼠延迟性和进行性学习记忆障碍，观察强啡肽A和痛敏素的作用。水浸应激后，短期记忆在应激暴露后5天受损，被动回避学习在应激暴露后7天受损。抗抑郁药地昔帕明和乙酰胆碱酯酶抑制剂他克林可显著改善这些损害。此外，通过重复给药，抗氧化剂如儿茶素也可改善这些症状。此外，儿茶素的重复给药也改善了LPS诱导的学习和记忆的延迟性损害。我们需要阐明强啡肽A相关肽在这些动物模型中的作用机制。

项目成果

期刊论文数量（40）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alpha 7-type nicotinic acetylcholine receptor and prodynorphin mRNA expression after administration of (-)-nicotine and U-50,488H in beta-amyloid peptide (25-35)-treated mice.

在 β-淀粉样肽 (25-35) 处理的小鼠中给予 (-)-尼古丁和 U-50,488H 后，α 7 型烟碱乙酰胆碱受体和强啡肽原 mRNA 表达。

DOI：
发表时间：
2004
期刊：
Ann. New York Acad. Sci. 1025
影响因子：
0
作者：
Masayuki Hiramatsu;Minako Watanabe;Shogo Baba;Ryoji Kojima;Toshitaka Nabeshima
通讯作者：
Toshitaka Nabeshima

Pharmacological characterization of the ameliorating effect on short-term memory impairment and antinociceptive effect of KT-90 in mice.

KT-90 对小鼠短期记忆障碍的改善作用和抗伤害作用的药理学表征。