Neuroprotctive effects of CNS-specific prostacyclin receptro ligands

中枢神经系统特异性前列环素受体配体的神经保护作用

• 批准号: 11670155
• 负责人: SATOH Takumi
• 金额: $ 2.3万
• 依托单位: Osaka Bioscience Institute
• 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 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670155/
• 关键词: Prostacyclin; Prostaglandin; 15R-TIC; Apoptosis; Neuronal death; Hippocampus; Septum

Prostacyclin (PGI2) is a critical regulator of the cardiovascular system. Our previous studies demonstrated that a novel subtype of PGI2 receptor, which is clearly distinct from a peripheral subtype in terms of ligand specificity, is expressed in the rostral region of the brain. CNS-specific PGI2 receptor ligands prevented the neuronal death. They prevented apoptotic cell death of hippocampal neurons induced oxidative stress. The effective concentrations well correlated with the binding potency for the CNS-specific PGI2 receptor. They also promoted neuronal survival of septal cholinergic neurons in culture. In vivo, 15R-TIC protected CA1 pyramidal neurons against ischemic damage in gerbils and prevented neuronal injury induced by focal ischemia in mice. During the PET study, we found that peripherally-injedted 15R-TIC accumulated in the in the rostral region of the brain. These results indicate that CNS-specific PGI2 ligands have neuronal survival-promoting activity both in vitro and in vivo, and may represent a new type of therapeutic drug for neurodegeneration.

前列环素 (PGI2) 是心血管系统的重要调节剂。我们之前的研究表明，PGI2 受体的一种新亚型在大脑的喙区表达，其配体特异性与外周亚型明显不同。 CNS 特异性 PGI2 受体配体可防止神经元死亡。它们阻止了氧化应激引起的海马神经元凋亡细胞死亡。有效浓度与 CNS 特异性 PGI2 受体的结合效力密切相关。它们还促进了培养物中间隔胆碱能神经元的神经元存活。在体内，15R-TIC 可以保护沙鼠 CA1 锥体神经元免受缺血性损伤，并防止小鼠局灶性缺血引起的神经元损伤。在 PET 研究中，我们发现外周注射的 15R-TIC 在大脑的头侧区域积聚。这些结果表明，CNS特异性PGI2配体在体外和体内均具有促进神经元存活的活性，可能代表一种新型的神经退行性疾病治疗药物。

项目成果

Suzuki M., Kato K., Watanabe Yu., Satoh T., Matsumura K., Watanabe Y.and Noyori R.: "15-Deoxy-16-(m-tolyl)-17, 18, 19, 20-tetranoisocarbacyclin : a simple TIC derivative with potent anti-apoptotic activity for neuronal cells"J.Chem.Soc.Chem.Comm.. 307-308

Suzuki M.、Kato K.、Watanabe Yu.、Satoh T.、Matsumura K.、Watanabe Y.和 Noyori R.：“15-脱氧-16-(间甲苯基)-17, 18, 19, 20-四异碳环素

Suzuki M.,Kato K.,Watanabe Yu.,Satoh T.,Matsumura K.,Watanabe Y.and Noyori R.: "15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranoisocarbacyclin : a simple TIC derivative with potent anti-apoptotic activity for neuronal cells"J.Chem.Soc.Chem.Comm.. 307-308 (1999)

铃木 M.、加藤 K.、渡边 Yu.、佐藤 T.、松村 K.、渡边 Y. 和野依 R.：“15-脱氧-16-(间甲苯基)-17,18,19,20-四异碳环素

Suzuki M., Doi H., Kato K., Bjorkman B., Watanabe Y.and Noyori R.: "Rapid methylation for a synthesis of a 11C-labeled tolylisocarbacyclin imaging the IP2 receptor in a living human brain"Tetrahedron. 56. 8263-8278 (2000)

Suzuki M.、Doi H.、Kato K.、Bjorkman B.、Watanabe Y. 和 Noyori R.：“快速甲基化合成 11C 标记的 tolylisocarbacyclin，对活人大脑中的 IP2 受体进行成像”四面体。

Cui Y., Kataoka Y., Satoh T., Yamagata A., Shirakawa N., Watanabe Yu., Suzuki M., Kataoka K.and Watanabe Y.: "Protective effects of prostaglansin I2 analogs ischemic delayed neuronal damage in gerbils"Biochem.Biophys.Res.Comm.. 265. 301-304 (1999)

Cui Y.、Kataoka Y.、Satoh T.、Yamagata A.、Shirakawa N.、Watanabe Yu.、Suzuki M.、Kataoka K. 和 Watanabe Y.：“前列腺素 I2 类似物对沙鼠缺血性迟发性神经元损伤的保护作用”

Watanabe Yu.,Matsumura K.,Takechi H.,Kato K.,Morii H.,Bjorkman M.,Langstrom B.,Noyori R.,Suzuki M.and Watanabe Y.: "A novel subtype of prostacyclin receptor in the central nervous system"J.Neurochem.. 72. 2583-2592 (1999)

Watanabe Yu.、Matsumura K.、Takechi H.、Kato K.、Morii H.、Bjorkman M.、Langstrom B.、Noyori R.、Suzuki M. 和 Watanabe Y.：“中枢前列环素受体的一种新亚型