@article{11534fff2b04444d89418f411e53ddc4,
title = "Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer{\textquoteright}s disease",
abstract = " Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer{\textquoteright}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.",
author = "Park, {Jong Hyun} and Ju, {Yeon Ha} and Choi, {Ji Won} and Song, {Hyo Jung} and Jang, {Bo Ko} and Junsung Woo and Heejung Chun and Kim, {Hyeon Jeong} and Shin, {Su Jeong} and Oleg Yarishkin and Seonmi Jo and Mijeong Park and Yeon, {Seul Ki} and Siwon Kim and Jeongyeon Kim and Nam, {Min Ho} and Londhe, {Ashwini M.} and Jina Kim and Cho, {Sung Jin} and Suengmok Cho and Changho Lee and Hwang, {Sung Yeoun} and Kim, {Sang Wook} and Oh, {Soo Jin} and Jeiwon Cho and Pae, {Ae Nim} and {Justin Lee}, C. and Park, {Ki Duk}",
note = "Funding Information: We thank H. Hwang for in vitro ADME/Tox tests. We also acknowledge a number of colleagues for critical feedback on the manuscript. This work was supported by the National Research Council of Science & Technology (NST) grant by the Korean government (MSIP) (no. CRC-15-04-KIST to K.D.P.), the Drug Development Project (KDDF-2105-09-06 to K.D.P.) of Korea Drug Development Fund, the National Research Foundation of Korea (NRF-2018M3A9C8016849 to K.D.P.), the Main Research Program (E0164503-01 to K.D.P.) of the Korea Food Research Institute (KFRI), the Creative Research Initiative Program, the Korean National Research Foundation (2015R1A3A2066619 to C.J.L.), the KIST Institutional Grant (2E26662 to C.J.L.), and the KU-KIST Graduate School of Science and Technology program (R1435281 to C.J.L.). Publisher Copyright: Copyright {\textcopyright} 2019 The Authors, some rights reserved.",
year = "2019",
doi = "10.1126/sciadv.aav0316",
language = "English",
volume = "5",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "3",
}