Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats
Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats
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DOI：
10.1016/j.neulet.2006.02.077
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发表时间：
2006-06-12
影响因子：
2.5
通讯作者：
Ohizumi, Asushi
中科院分区：
文献类型：
--
作者：
Matsuzaki, Kentaro;Yamakuni, Tohru;Ohizumi, Asushi
阿尔茨海默病（Alzheimer's disease，AD）是一种以认知和记忆功能减退为特征的进行性神经退行性疾病。β-淀粉样肽（AP）的产生和积累是AD发病机制的核心。最近的研究表明，PKA/CREB依赖的信号通路和长时程增强在培养的海马神经元中被亚致死浓度的A β（1-42）抑制。在这里，我们研究了在培养的大鼠海马神经元中，川陈皮素对A β诱导的CREB磷酸化抑制的影响。亚致死浓度的A β（1-42）或A β（1-40）可降低谷氨酸诱导的CREB磷酸化，而用诺必利预处理可逆转A β诱导的CREB磷酸化降低。还使用八臂径向迷宫在慢性A β（1-40）输注的AD模型大鼠中检查了诺贝尔碱对学习能力损伤的影响。在AD模型大鼠中，诺贝尔碱对A β（1-40）诱导的学习能力障碍具有保护作用。这些结果表明，诺贝尔碱有可能成为一种新的先导化合物，用于药物开发的AD。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and memory deterioration. Production and accumulation of P-amyloid peptide (AP) is central to the pathogenesis of AD. Recent studies have demonstrated that PKA/CREB-dependent signaling pathway and long-term potentiation are inhibited by sublethal concentrations of A beta(1-42) in cultured hippocampus neurons. Here, we examined the effects of nobiletin on the A beta-induced inhibition of CREB phosphorylation in cultured rat hippocampus neurons. A sublethal concentration of A beta(1-42) or A beta(1-40) decreased glutamate-induced CREB phosphorylation, whereas pretreatment with nobiletin reversed the A beta-induced decrease in CREB phosphorylation. The effects of nobiletin on impairment of learning ability were also examined in chronically A beta(1-40) infused AD model rats using the eight-arm radial maze. In the AD model rats, nobiletin showed protective effects on A beta(1-40)-induced impairment of learning ability. These results suggest that nobiletin has the potential for becoming a novel lead compound for drug development for AD. (c) 2006 Elsevier Ireland Ltd. All rights reserved.