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首页> 外文期刊>Life sciences >THE MUSCARINIC M1 AGONIST XANOMELINE INCREASES SOLUBLE AMYLOID PRECURSOR PROTEIN RELEASE FROM CHINESE HAMSTER OVARY-M1 CELLS
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THE MUSCARINIC M1 AGONIST XANOMELINE INCREASES SOLUBLE AMYLOID PRECURSOR PROTEIN RELEASE FROM CHINESE HAMSTER OVARY-M1 CELLS

机译：MUSCARINIC M1促性药黄嘌呤增加中国仓鼠卵巢M1细胞的可溶性淀粉样前体蛋白释放

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摘要

The functionally selective M1 agonist xanomeline, which is currently undergoing clinical trials as a therapy for Alzheimer's disease, was compared to the muscarinic agonist carbachol for effects on secretion of soluble amyloid precursor protein (APPs) from Chinese hamster ovary cells transfected with the human mi receptor (CHO-m1). Release of APPs from CHO-m1 cells was increased maximally (4-10 fold) by 100 mu M carbachol (EC(50) = 11 mu M) and by 100 nM xanomeline (EC(50) = 10 nM) Stimulation of APPs secretion by xanomeline and carbachol was blocked by preincubation with 1 mu M atropine. Carbachol did not stimulate APPs secretion from non-transfected CHO cells. Pilocarpine at 1 mM also increased APPs release. The efficacy of carbachol, xanomeline and pilocarpine for stimulating APPs secretion did not differ significantly. Activation of protein kinase C (PKC) in mi transfected cell lines by 1 mu M phorbol dibutyrate (PDBu) increased APPs release, and this was inhibited 97% by the PKC inhibitor bisindolemalemide. The PKC inhibitor decreased xanomeline and carbachol - stimulated APPs secretion by only 25-30%. These results demonstrate that xanomeline increased APPs release by activation of mi muscarinic receptors and support the possibility that cholinergic replacement therapy for Alzheimer's Disease may reduce amyloid deposition. [References: 22]
机译：将具有功能选择性的M1激动剂xanomeline（目前正在作为阿尔茨海默氏病的一种疗法）进行临床试验，将其与毒蕈碱激动剂卡巴胆碱进行比较，以研究转染人mi受体的中国仓鼠卵巢细胞中可溶性淀粉样前体蛋白（APPs）的分泌（CHO-m1）。从CHO-m1细胞中释放APP的最大幅度增加了（4-10倍）100μM卡巴胆碱（EC（50）= 11μM）和100 nM Xanomeline（EC（50）= 10 nM）刺激APP分泌通过与1μM阿托品预孵育来阻断Xanomeline和卡巴胆碱的作用。卡巴胆碱不会刺激未转染的CHO细胞分泌APP。 1 mM的毛果芸香碱也增加了APP的释放。卡巴胆碱，塞诺美林和毛果芸香碱对APPs分泌的刺激作用无明显差异。 1μM佛波醇二丁酸酯（PDBu）激活mi转染的细胞系中的蛋白激酶C（PKC），可增加APPs的释放，而PKC抑制剂双吲哚马来酰亚胺可抑制97％。 PKC抑制剂仅将Xanomeline和卡巴胆碱刺激的APPs分泌降低25-30％。这些结果表明，Xanomeline通过激活毒蕈碱受体而增加了APP的释放，并支持阿尔茨海默氏病的胆碱能替代疗法可减少淀粉样蛋白沉积的可能性。 [参考：22]

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