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因子。我们先前的研究表明，一个新的PGI2受体亚型在大脑的吻侧区域表达，该亚型在配基特异性方面明显不同于外周亚型。中枢神经系统特异性的PGI2受体配体可阻止神经元死亡。它们可防止氧化应激引起的海马神经元细胞凋亡。有效浓度与中枢神经系统特异性PGI2受体的结合能力有很好的相关性。它们还能促进培养的隔区胆碱能神经元存活。在体实验中，15R-TIC对沙土鼠CA1区锥体神经元的缺血性损伤有保护作用，对小鼠局灶性脑缺血所致的神经元损伤也有保护作用。在PET研究中，我们发现外周损伤的15R-TIC积聚在大脑吻区。这些结果表明，中枢神经系统特异性PGI2配体在体外和体内都具有促进神经元存活的活性，可能是一种新型的治疗神经退行性变的药物。

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

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”

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)

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)