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.

前列环蛋白（PGI2）是心血管系统的关键调节剂。我们先前的研究表明，在大脑的鼻部区域中表达了一种新型的PGI2受体亚型，其在配体特异性方面显然与外围亚型不同。 CNS特异性PGI2受体配体阻止了神经元死亡。他们防止了海马神经元的凋亡细胞死亡诱导氧化应激。有效浓度与CNS特异性PGI2受体的结合效力很好地相关。他们还促进了培养中间隔胆碱能神经元的神经元存活。在体内，15R-TIC保护的CA1锥体神经元免受沙鼠的缺血损伤，并预防小鼠局灶性缺血引起的神经元损伤。在宠物研究中，我们发现在大脑的尾部区域中积累了周围侵蚀的15R-TIC。这些结果表明，CNS特异性PGI2配体在体外和体内具有神经元促进活性，并且可能代表一种用于神经变性的新型治疗药物。

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.et al.: "15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarboacyclin as ・・・"Chem.Comm.. 307. 307-308 (1999)

Suzuki M.等人：“15-脱氧-16-(间甲苯基)-17,18,19,20-四去甲异碳环素...”Chem.Comm.. 307. 307-308 (1999)

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”

Satoh T.,Ishikawa Y.,Kataoka Y.,Cui Y.,Yanase H.,Kato K.,Watanabe Yu.,Nakadate K.,Matsumura K.,Hatanaka H.,Kataoka K.,Noyori R.,Suzuki M.and Watanabe Y.: "CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain"Eur.J.Neurosci

佐藤 T.、石川 Y.、片冈 Y.、崔 Y.、柳濑 H.、加藤 K.、渡边 Yu.、中馆 K.、松村 K.、畑中 H.、片冈 K.、野依 R.、铃木 M

Cui Y. et al.: "Protective effects of prostaglandin I_2 analogs on ・・・"Biochem.Biophys.Res.Comm.. (1999)

Cui Y.等：“前列腺素I_2类似物对…的保护作用”Biochem.Biophys.Res.Comm..(1999)