Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice.
Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice.
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DOI：
10.1016/j.ejphar.2010.12.013
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发表时间：
2011-03-01
影响因子：
5
通讯作者：
Witt, Ken A.
中科院分区：
文献类型：
--
作者：
Sandoval, Karin E.;Farr, Susan A.;Banks, William A.;Niehoff, Michael L.;Morley, John E.;Crider, Albert M.;Witt, Ken A.
已经提出选择性生长抑素受体亚型激动剂作为减轻与阿尔茨海默病相关的学习和记忆丧失的手段。本研究的第一个目的是评价NNC 26-9100（一种选择性生长抑素亚型-4（sst 4）受体激动剂）的血脑转运和局部脑分布。131 I-NNC 26-9100的进入率Ki = 0.25 μl/g min，与实质成分的相关性为93%。本研究的第二个目的是评价NNC 26-9100长期给药（i.p）对阿尔茨海默病加速衰老小鼠p8（SAMP 8）模型中学习和记忆、脑Aβx-42水平以及sst 4受体和淀粉样前体蛋白（APP）蛋白表达的影响。使用T-迷宫范例（20和200 μg），长期接受NNC 26-9100处理的小鼠显示出学习（第21天）和记忆（第28天）改善。离体组织分析显示，与溶剂对照相比，20μg剂量下Aβx-42水平下降，而sst 4受体或APP蛋白表达未观察到变化。这些发现表明，NNC 26-9100被吸收到与学习和记忆相关的关键大脑区域。此外，NNC 26-9100长期给药可改善学习和记忆，并降低Aβx-42脑水平。这些结果表明，SST 4受体激动剂可能提供一个可行的治疗阿尔茨海默病和其他形式的认知障碍。
Selective somatostatin receptor subtype agonists have been proposed as a means to mitigate learning and memory loss associated with Alzheimer's disease. The first aim of this study evaluated blood-to-brain transport and regional brain distribution of NNC 26-9100, a selective somatostatin subtype-4 (sst4) receptor agonist. The entry rate of 131I-NNC 26-9100 was Ki = 0.25 μl/g min, with a ∼93% association with the parenchymal component. The second goal of this study was to evaluate the effect of chronic NNC 26-9100 administration (i.p) on learning and memory, brain Aβx-42 levels, and protein expression of sst4 receptor and amyloid precursor protein (APP) in the senescence-accelerated mouse p8 (SAMP8) model of Alzheimer's disease. Mice chronically treated with NNC 26-9100 showed improved learning (day-21) and memory (day-28) using the T-maze paradigm (20 and 200 μg). Ex vivo tissue analyses showed a decline in Aβx-42 levels at the 20μg dose, while no alterations were observed in sst4 receptor or APP protein expression compared to vehicle controls. These findings indicate NNC 26-9100 is taken up into key brain regions associated with learning and memory. Furthermore, chronic administration of NNC 26-9100 improved learning and memory and decreased Aβx-42 brain levels. These results suggest sst4 receptor agonists may provide a viable therapy in the treatment of Alzheimer's disease and other forms of cognitive impairment.
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