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

Title
Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease
Authors
Park, Jong-HyunJu, Yeon HaChoi, Ji WonSong, Hyo JungJang, Bo KoWoo, JunsungChun, HeejungKim, Hyeon JeongShin, Su JeongYarishkin, OlegJo, SeonmiPark, MijeongYeon, Seul KiKim, SiwonKim, JeongyeonNam, Min-HoLondhe, Ashwini M.Kim, JinaCho, Sung JinCho, SuengmokLee, ChanghoHwang, Sung YeounKim, Sang WookOh, Soo-JinCho, JeiwonPae, Ae NimLee, C. JustinPark, Ki Duk
Ewha Authors
조제원
Issue Date
2019
Journal Title
SCIENCE ADVANCES
ISSN
2375-2548JCR Link
Citation
SCIENCE ADVANCES vol. 5, no. 3
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Indexed
SCIE; SCOPUS WOS
Document Type
Article
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 gamma-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. Longterm 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.
DOI
10.1126/sciadv.aav0316
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일반대학원 > 뇌·인지과학과 > Journal papers
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