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首页> 美国卫生研究院文献>Science Advances >Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease
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Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

机译：新开发的可逆MAO-B抑制剂规避了不可逆抑制剂在阿尔茨海默氏病中的缺点

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摘要

Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.
机译：单胺氧化酶B（MAO-B）由于与活性星形胶质细胞中异常的γ-氨基丁酸（GABA）产生有关，最近已成为阿尔茨海默病（AD）的潜在治疗靶标。尽管短期使用不可逆的MAO-B抑制剂（例如司来吉兰）可以改善AD患者的认知障碍，但长期治疗却显示出令人失望的结果。我们显示，长期使用司来吉兰治疗无法降低APP / PS1小鼠（AD的动物模型）的异常星形细胞GABA水平和挽救记忆障碍，因为GABA合成酶，二胺氧化酶（DAO）的补偿性基因活性增加。我们开发了一种有效，高度选择性和可逆的MAO-B抑制剂KDS2010（IC50 = 7.6 nM；比MAO-A的选择性高12,500倍），克服了不可逆MAO-B抑制剂的缺点。用KDS2010进行的长期治疗不会诱导补偿机制，从而显着减弱了星形胶质GABA水平和星形胶质增生，增强了突触传递，并挽救了APP / PS1小鼠的学习和记忆障碍。

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