Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent
Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent
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DOI：
10.1073/pnas.0508575102
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发表时间：
2005-11-22
影响因子：
11.1
通讯作者：
Lahiri, DK
中科院分区：
文献类型：
--
作者：
Greig, NH;Utsuki, T;Lahiri, DK
与乙酰胆碱酯酶一样，丁酰胆碱酯酶（BChE）使神经递质乙酰胆碱（ACh）失活，因此是阿尔茨海默病（以胆碱能缺陷为特征）的可行治疗靶点。有效的，可逆的，脑靶向BChE抑制剂（胱氨酸类似物）是基于结合域结构开发的，以帮助阐明该酶在中枢神经系统中的作用。在大鼠中，胱氨酸类似物引起脑BChE的长期抑制和细胞外乙酰胆碱酯酶水平升高，对乙酰胆碱酯酶无抑制作用。在大鼠脑切片中，选择性BChE抑制增强了长时程增强。这些化合物还能改善老年大鼠的认知能力（迷宫导航）。在培养的人SK-N-SH神经母细胞瘤细胞中，细胞内和细胞外的β -淀粉样蛋白前体蛋白和分泌的β -淀粉样肽水平降低，但不影响细胞活力。过度表达人类突变淀粉样蛋白前体蛋白的转基因小鼠的治疗也导致β -淀粉样肽脑水平低于对照组。选择性的，可逆的脑BChE抑制可能代表阿尔茨海默病的治疗，改善认知和调节疾病的神经病理标志物。
Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular beta-amyloid precursor protein, and secreted beta-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that over-expressed human mutant amyloid precursor protein also resulted in lower beta-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.