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1. 发明授权

US6043224A Compositions and methods for treatment of neurological disorders and neurodegenerative diseases 失效
标题翻译：用于治疗神经障碍和神经变性疾病的组合物和方法
公开(公告)号：US6043224A
公开(公告)日：2000-03-28
申请号：US924505
申请日：1997-09-05
申请人： Robert K. K. Lee , Richard J. Wurtman
发明人： Robert K. K. Lee , Richard J. Wurtman
IPC分类号： A61K31/00 , A61K31/05 , A61K31/137 , A61K31/18 , A61K31/198 , A61K31/34 , A61K31/365 , A61K31/436 , A61K31/465 , A61K31/5383 , A61K31/5575 , A61K38/13 , A61K38/19 , A61K3/705
CPC分类号： A61K31/7076 , A61K31/00 , A61K31/05 , A61K31/137 , A61K31/18 , A61K31/198 , A61K31/34 , A61K31/365 , A61K31/436 , A61K31/465 , A61K31/5383 , A61K31/5575 , A61K38/13 , A61K38/193 , Y10S514/878 , Y10S514/879
摘要： It has been discovered that the stimulation of .beta.-adrenergic receptors, which activate cAMP formation, give rise to increased APP and GFAP synthesis in astrocytes. Hence, the in vitro or in vivo exposure of neuronal cells to certain compositions comprising .beta.-adrenergic receptor ligands or agonists, including, e.g., norepinephrine, isoproterenol and the like, increases APP mRNA transcription and consequent APP overproduction. These increases are blocked by .beta.-adrenergic receptor antagonists, such as propranolol. The in vitro or in vivo treatment of these cells with 8Br-cAMP, prostaglandin E.sub.2 (PG E.sub.2), forskolin, and nicotine ditartrate also increased APP synthesis, including an increase in mRNA and holoprotein levels, as well as an increase in the expression of glial fibrillary acidic protein (GFAP). Compositions and methods are disclosed of regulating APP overexpression and mediating reactive astrogliosis through cAMP signaling or the activation of .beta.-adrenergic receptors. It has further been found that the increase in APP synthesis caused by 8Br-cAMP, PG E.sub.2, forskolin, or nicotine ditartrate is inhibited by immunosuppressants or anti-inflammatory agents, such as cyclosporin A, and FK-506 (tacrolimus), as well as ion-channel modulators, including ion chelating agents such as EGTA, or calcium/calmodulin kinase inhibitors, such as KN93. The present invention has broad implications in the alleviation, treatment, or prevention of neurological disorders and neurodegenerative diseases, including Alzheimer's Disease.
摘要翻译：已经发现，激活cAMP形成的β-肾上腺素能受体的刺激在星形胶质细胞中产生增加的APP和GFAP合成。因此，神经元细胞体外或体内暴露于包含β-肾上腺素能受体配体或激动剂（包括例如去甲肾上腺素，异丙肾上腺素等）的某些组合物会增加APP mRNA转录和随后的APP过量产生。这些增加被β-肾上腺素能受体拮抗剂如普萘洛尔阻断。用8Br-cAMP，前列腺素E2（PG E2），毛喉素和烟碱尼泊金酯处理这些细胞的体外或体内治疗也增加了APP合成，包括mRNA和蛋白水平的增加，以及表达增加胶质纤维酸性蛋白（GFAP）。公开了通过cAMP信号传导或β-肾上腺素能受体活化调节APP过表达和介导反应性星形胶质细胞增生的组合物和方法。还发现免疫抑制剂或抗炎剂如环孢菌素A和FK-506（他克莫司）抑制了由8Br-cAMP，PG E2，毛喉素或烟碱尼泊金酯引起的APP合成的增加，以及作为离子通道调节剂，包括离子螯合剂如EGTA或钙/钙调蛋白激酶抑制剂，例如KN93。本发明在减轻，治疗或预防神经障碍和神经变性疾病（包括阿尔茨海默病）方面具有广泛的意义。

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