Cellular and pharmacological studies for protection ofneuronal and endothelial cells

保护神经元和内皮细胞的细胞和药理学研究

• 批准号: 13470482
• 负责人: MURAYAMA Toshihiko
• 金额: $ 8.06万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470482/
• 关键词: Neuronal cells; Endothelial cells; Arachidonic acid; Phospholipase A2; Oxidative stress; Cell death; Alkaloids; 天然アルカロイド; 酸化ストレス; 血管収縮; アポトーシス; 一酸化窒素

We investigated the pharmacological and biochemical mechanisms of neuronal and endothelial cells functions in the present study. The results were : 1) In PC12 cells, 1,2,3,4-tetrahydroisoquinoline, an endogenous neurotoxin for dopaminergic neurons, caused the delayed cell death. The mRNAs of IL6 and cytosolic phospholipase A2 levels in PCI2 cells were regulated by TIQ treatment 2) S-Nitroso-cysteine, a stable and endogenous NO compound, is incorporated by the L-type amino acid transporter in PC 12 cells. The effects of S-nitroso-cysteine appeared to be mediated by S-nitrosylation of functional proteins such as cytosolic phospholipase A2 and Ca2+-channels in PC 12 cells. The effects of S-nitroso-cysteine were inhibited by specific amino acids such as L-leucine. 3) Secretory type of phospholipase A2 is expressed in neuronal cells, and the activity was regulated by the SH group-reactive agents such as phenylarsine oxide. The activity of secretory phospholipase A2 in membrane may be regula … More ted by the membrane-associated and redox-level regulating proteins such as protein disulfide isomerase. 4) Inhibition of superoxise dismutase caused an increase of arachidonic acid release and mRNA and protein levels of cytosolic phospholipase A2 in PC12 cells. Several ceramide analogs and sphyngosine-1-phosphate analogs regulated arachidonic acid metabolism in neuronal cells. 5) Activation of vanilloid receptor 1 by the central injection of capsaicin and anandamide and the activation of opioid receptor-like 1 (ORL1) receptor by nociceptin caused gastric acid secretion through mechanisms involving the vagus nerve in rats. Activation of kappa-opioid receptor system in the CNS coupled with glutamate and gamma-amino butyric acid receptor systems in the CNS, and thus stimulated gastric acid secretion in rats. 6) Aconite alkaloids such as mesaconitine showed activation of Ca2+ influx and NO synthase and thus caused relaxation in rat aorta. In rat small artery, Ca2+ influx induced by mesaconitine caused relaxation via the production of endothelium-derived hyperpolarizing factor. Mitragynine-related indole alkaloids showed the opioid agonistic activities, and the OH-group in the 7-position was important for the activation of opioid receptors. Less

我们在本研究中研究了神经元和内皮细胞功能的药理学和生化机制。结果表明：1）多巴胺能神经元内源性神经毒素1，2，3，4-四氢异喹啉可引起PC12细胞延迟性死亡。TIQ处理可调节PC12细胞IL 6和胞浆磷脂酶A2的mRNA水平。2）S-亚硝基半胱氨酸是一种稳定的内源性NO化合物，通过L-型氨基酸转运蛋白掺入PC12细胞。S-亚硝基半胱氨酸的作用似乎是通过对PC 12细胞胞浆磷脂酶A2和Ca~（2+）通道等功能蛋白的S-亚硝基化来介导的。S-亚硝基半胱氨酸的作用可被特定的氨基酸如L-亮氨酸所抑制。3)分泌型磷脂酶A2在神经细胞中表达，其活性受SH基团反应剂如氧化苯胂调节。细胞膜分泌型磷脂酶A_2的活性可能是受细胞膜磷脂酶A_2活性的调节。 ...更多信息 由膜相关和氧化还原水平调节蛋白如蛋白质二硫键异构酶引起。4)抑制超氧化物歧化酶可引起PC12细胞花生四烯酸释放增加，胞浆磷脂酶A2 mRNA和蛋白水平升高。几种神经酰胺类似物和鞘氨醇-1-磷酸类似物调节神经元细胞中的花生四烯酸代谢。5)辣椒素和大麻素的中枢注射激活香草酸受体1和痛敏素激活阿片受体样1（ORL 1）受体通过涉及迷走神经的机制引起胃酸分泌。中枢神经系统中κ-阿片受体系统的激活与中枢神经系统中谷氨酸和γ-氨基丁酸受体系统的激活耦合，从而刺激大鼠胃酸分泌。6)乌头碱类生物碱如中乌头碱可激活大鼠主动脉内Ca~（2+）内流和NO合成酶，从而引起主动脉舒张。在大鼠小动脉中，新乌头碱诱导的Ca 2+内流通过产生内皮源性超极化因子引起舒张。Mitragynine相关吲哚生物碱具有阿片受体激动活性，其7位OH基团对阿片受体的激活起重要作用。少

项目成果

Takayama, H. et al.: "Studies on the synthesis and opioid agonistic activities of Mitragynine-related indole alkaloids"J.Med.Chem.. 45. 1949-1956 (2002)

Takayama, H. 等人：“帽柱木碱相关吲哚生物碱的合成和阿片样物质激动活性的研究”J.Med.Chem.. 45. 1949-1956 (2002)

Ohsawa, K., Mori. A., Horie, S., Saito, T., Okuma, Y., Nomura, Y., and Murayama, T.: "Arachidonic acid release and prostaglandin F2 a formation induced by phenylarsine oxide in PC 12 cells : possible involvement of secretory phospholipase A2 activity"Bioc

大泽，K.，森。

Komasaka, M., Horie, S., Watanabe, K., Murayama, T.: "Antisecretory effect of somatostatin on gastric acid via inhibition of histamine release in isolated mouse stomach"Eur. J. Pharmacol.. 452. 235-243 (2002)

Komasaka, M.、Horie, S.、Watanabe, K.、Murayama, T.：“生长抑素通过抑制离体小鼠胃中组胺释放对胃酸的抗分泌作用”Eur。

Minowa, S., Tsuchiya, S., Horie, S., Watanabe, K., Murayama, T.: "centrally injected capsaicin, an agonist of vanilloid receptors, on gastric acid secretion in ats"Eur. J. Pharmacol.. 428. 349-356 (2001)

Minowa, S.、Tsuchiya, S.、Horie, S.、Watanabe, K.、Murayama, T.：“中央注射辣椒素（香草酸受体激动剂）对 ats 胃酸分泌的影响”Eur。

Someya, A., Horie, S., Murayama, T.: "Arachidonic acid release and prostaglandin F2 a formation induced by anandamide and capsaicin in PC12 cells"Eur. J. Pharmacol.. 450. 131-139 (2002)

Someya, A.、Horie, S.、Murayama, T.：“PC12 细胞中由花生四烯酸释放和前列腺素 F2a 诱导的花生四烯酸释放和前列腺素 F2a 形成”Eur。