Developmental study on anti-dementia drugs by using neuropeptides related to memory disturbance

记忆障碍相关神经肽抗痴呆药物的开发研究

• 批准号: 11672197
• 负责人: UKAI Makoto
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672197/
• 关键词: Endomorphin; Opioid; Opioid receptor antagonist; Anti-dementia drug; Short-term memory; Long-term memory; Neuropeptide; Dementia; オピオイド受容体拮抗薬; ドパミン受容体; 受動的回避学習; 生理活性ペプチド; 自発的交替行動

The effects of the μ-opioid receptor agonists endomorphin-1 and -2 on short- and long-term memory were examined. In addition, the present study was designed to find novel therapeutic drugs for dementia. The μ-opioid receptor antagonist β-funaltrexamine significantly antagonized the endomorphins-induced disturbance of short- and long-term memory. Although the disturbance of short-term memory with endomorphm-1 was significantly improved by the μ1-opioid receptor antagonist naloxonazine, such drug was without any significant effects on the endomorphin-2-induced disturbance of short-term memory. Naloxonazine and the cholmesterase inhibit or physostigmine ameliorated the disturbance of long-term memory. The dopamine D2 receptor agonist RU24213 did not significantly influence the disturbance of short- and long-term memory induced by endomorpnms, the dopamine D2 receptor antagonist (-)-sulpiride significantly antagonized the endomorphins-induced disturbance of short- and long-term memory. From the above results, μ1-opioid receptor, dopamine D2 receptor and cholinergic neurotransmission play a major role in the memory disturbance with endomorpnins. Furthermore, it is possible that μ1-opioid receptor antagonists are useful as novel anti-dementia drugs.

观察μ-阿片受体激动剂内啡肽-1和内啡肽-2对大鼠短期和长期记忆的影响。此外，本研究旨在寻找新的治疗痴呆症的药物。μ-阿片受体拮抗剂β-富纳曲胺对内啡肽引起的短期和长期记忆障碍具有显著的拮抗作用。μ1-阿片受体拮抗剂纳洛唑嗪虽能明显改善内啡肽-1对短期记忆的干扰，但对内啡肽-2对短期记忆的干扰无明显作用。纳洛唑嗪和胆碱酯酶抑制剂或芥子碱可改善长期记忆障碍。多巴胺D2受体激动剂RU24213对内啡肽诱导的短时和长时记忆障碍无显著影响，多巴胺D2受体拮抗剂(-)-舒必利对内啡肽诱导的短时和长时记忆障碍有显著拮抗作用。综上所述，μ -阿片受体、多巴胺D2受体和胆碱能神经传递在内啡肽引起的记忆障碍中起主要作用。此外，μ1-阿片受体拮抗剂有可能成为新型抗痴呆药物。

项目成果

Makoto Ukai, Yoshiko Watanabe and Tsutomu Kameyama: "Effects of endomorphins-1 and 2, endogenous μ-opioid recept or agonists, on spontaneous alternation performance in mice"Eur. J. Pharmacol.. 395. 211-215 (2000)

Makoto Ukai、Yoshiko Watanabe 和 Tsutomu Kameyama：“内吗啡肽 1 和 2、内源性 μ-阿片受体或激动剂对小鼠自发交替行为的影响”Eur. J. Pharmacol.. 395. 211-215 (2000)

Takayoshi Mamiya: "Morphine tolerance and dependence in the nociceptin receptor knockout mice"J.Neural Transm.. 108. 1349-1361 (2001)

Takayoshi Mamiya：“伤害感受肽受体敲除小鼠的吗啡耐受性和依赖性”J.Neural Transm.. 108. 1349-1361 (2001)

鵜飼 良: "生理活性peptideによる脳機能障害治療薬の開発研究"応用薬理. 57. 138-139 (1999)

Ryo Ukai：“使用生物活性肽治疗脑功能障碍的药物的开发研究”应用药理学 57. 138-139 (1999)。

鵜飼 良: "Endomorphinsと学習・記憶"名城大学総合研究所紀要. 4. 175-176 (1999)

Ryo Ukai：“内吗啡肽与学习和记忆” 名城大学研究所通报 4. 175-176 (1999)。

間宮隆吉: "Effects of κ-opioid receptor agonists on the learned helplessness model of depression in mice"名城大学総合研究所紀要. 7:(印刷中). (2002)

Ryukichi Mamiya：“κ-阿片受体激动剂对小鼠习得性无助模型的影响”名城大学研究所公告 7：（出版中）。