Cellular and pharmacological studies for protection ofneuronal and endothelial cells

我们在本研究中探讨了神经细胞和内皮细胞功能的药理和生化机制。结果表明：1)在PC12细胞中，多巴胺能神经元内源性神经毒素1,2,3,4-四氢异喹啉引起细胞延迟死亡。TIQ处理可调节PCI2细胞中IL6和胞质磷脂酶A2 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，在pc12细胞中被l型氨基酸转运体掺入。在pc12细胞中，s -亚硝基半胱氨酸的作用似乎是通过胞质磷脂酶A2和Ca2+通道等功能蛋白的s -亚硝基化介导的。l -亮氨酸等特定氨基酸可抑制s -亚硝基半胱氨酸的作用。3)分泌型磷脂酶A2在神经元细胞中表达，其活性受SH基团活性物质如氧化苯larsin的调控。膜分泌磷脂酶A2的活性可能受膜相关蛋白和氧化还原水平调节蛋白（如蛋白二硫异构酶）的调控。4)抑制超氧歧化酶导致PC12细胞花生四烯酸释放增加，胞质磷脂酶A2 mRNA和蛋白水平升高。几种神经酰胺类似物和鞘氨醇-1-磷酸类似物调节花生四烯酸在神经元细胞中的代谢。5)大鼠中枢注射辣椒素和阿片样受体1激活和伤害肽激活阿片样受体1 （ORL1）受体通过迷走神经机制引起胃酸分泌。激活中枢神经系统的kappa-阿片受体系统与中枢神经系统的谷氨酸和γ -氨基丁酸受体系统，从而刺激大鼠胃酸分泌。6)中乌头碱等乌头生物碱能激活大鼠主动脉Ca2+内流和NO合酶，引起大鼠主动脉松弛。在大鼠小动脉中，中乌头碱诱导的Ca2+内流通过产生内皮源性超极化因子引起舒张。米特拉吉宁相关吲哚类生物碱具有阿片受体的拮抗活性，7位的oh基团对阿片受体的激活具有重要作用。少

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