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

Jong Hyun Park, Yeon Ha Ju, Ji Won Choi, Hyo Jung Song, Bo Ko Jang, Junsung Woo, Heejung Chun, Hyeon Jeong Kim, Su Jeong Shin, Oleg Yarishkin, Seonmi Jo, Mijeong Park, Seul Ki Yeon, Siwon Kim, Jeongyeon Kim, Min Ho Nam, Ashwini M. Londhe, Jina Kim, Sung Jin Cho, Suengmok ChoChangho Lee, Sung Yeoun Hwang, Sang Wook Kim, Soo Jin Oh, Jeiwon Cho, Ae Nim Pae, C. Justin Lee, Ki Duk Park

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

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.

Original languageEnglish
Article numbereaav0316
JournalScience Advances
Volume5
Issue number3
DOIs
Publication statusPublished - 2019

Bibliographical 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 © 2019 The Authors, some rights reserved.

All Science Journal Classification (ASJC) codes

  • General

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