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Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease
- Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease
- Park, Jong-Hyun; Ju, Yeon Ha; Choi, Ji Won; Song, Hyo Jung; Jang, Bo Ko; Woo, Junsung; Chun, Heejung; Kim, Hyeon Jeong; Shin, Su Jeong; Yarishkin, Oleg; Jo, Seonmi; Park, Mijeong; Yeon, Seul Ki; Kim, Siwon; Kim, Jeongyeon; Nam, Min-Ho; Londhe, Ashwini M.; Kim, Jina; Cho, Sung Jin; Cho, Suengmok; Lee, Changho; Hwang, Sung Yeoun; Kim, Sang Wook; Oh, Soo-Jin; Cho, Jeiwon; Pae, Ae Nim; Lee, C. Justin; Park, Ki Duk
- Ewha Authors
- Issue Date
- Journal Title
- SCIENCE ADVANCES
- SCIENCE ADVANCES vol. 5, no. 3
- AMER ASSOC ADVANCEMENT SCIENCE
- SCIE; SCOPUS
- Document Type
- 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.
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