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Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

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Title
Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease
Author(s)
Park J.-H.; Ju Y.H.; Choi J.W.; Song H.J.; Jang B.K.; Woo J.; Chun H.; Kim H.J.; Shin S.J.; Yarishkin O.; Jo S.; Park M.; Yeon S.K.; Kim S.; Kim J.; Nam M.-H.; Londhe A.M.; Kim J.; Cho S.J.; Cho S.; Lee C.; Hwang S.Y.; Kim S.W.; Oh S.-J.; Cho J.; Pae A.N.; Justin Lee C.; Park K.D.
Publication Date
2019-03
Journal
SCIENCE ADVANCES, v.5, no.3, pp.eaav0316
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Abstract
Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant -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 (IC 50 = 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. Copyright © 2019 The Authors, some rights reserved
URI
https://pr.ibs.re.kr/handle/8788114/5886
DOI
10.1126/sciadv.aav0316
ISSN
2375-2548
Appears in Collections:
Center for Cognition and Sociality(인지 및 사회성 연구단) > 1. Journal Papers (저널논문)
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