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 Cho; Changho Lee; Sung Yeoun Hwang; Sang Wook Kim; Soo Jin Oh; Jeiwon Cho; Ae Nim Pae; C. Justin Lee; Ki Duk Park

doi:10.1126/sciadv.aav0316

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

Department of Pharmacy

Research output: Contribution to journal › Article › peer-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 language	English
Article number	eaav0316
Journal	Science Advances
Volume	5
Issue number	3
DOIs	https://doi.org/10.1126/sciadv.aav0316
Publication status	Published - 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.

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10.1126/sciadv.aav0316

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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., ... Park, K. D. (2019). Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease. Science Advances, 5(3), [eaav0316]. https://doi.org/10.1126/sciadv.aav0316

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 ; Justin Lee, C. ; Park, Ki Duk. / Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease. In: Science Advances. 2019 ; Vol. 5, No. 3.

@article{9d2fd2f419614b649588a1839fdc5eda,

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",

}

Park, JH, Ju, YH, Choi, JW, Song, HJ, Jang, BK, Woo, J, Chun, H, Kim, HJ, Shin, SJ, Yarishkin, O, Jo, S, Park, M, Yeon, SK, Kim, S, Kim, J, Nam, MH, Londhe, AM, Kim, J, Cho, SJ, Cho, S, Lee, C, Hwang, SY, Kim, SW, Oh, SJ, Cho, J, Pae, AN, Justin Lee, C & Park, KD 2019, 'Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease', Science Advances, vol. 5, no. 3, eaav0316. https://doi.org/10.1126/sciadv.aav0316

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; Justin Lee, C.; Park, Ki Duk.

In: Science Advances, Vol. 5, No. 3, eaav0316, 2019.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

AU - Park, Jong Hyun

AU - Ju, Yeon Ha

AU - Choi, Ji Won

AU - Song, Hyo Jung

AU - Jang, Bo Ko

AU - Woo, Junsung

AU - Chun, Heejung

AU - Kim, Hyeon Jeong

AU - Shin, Su Jeong

AU - Yarishkin, Oleg

AU - Jo, Seonmi

AU - Park, Mijeong

AU - Yeon, Seul Ki

AU - Kim, Siwon

AU - Kim, Jeongyeon

AU - Nam, Min Ho

AU - Londhe, Ashwini M.

AU - Kim, Jina

AU - Cho, Sung Jin

AU - Cho, Suengmok

AU - Lee, Changho

AU - Hwang, Sung Yeoun

AU - Kim, Sang Wook

AU - Oh, Soo Jin

AU - Cho, Jeiwon

AU - Pae, Ae Nim

AU - Justin Lee, C.

AU - Park, Ki Duk

N1 - 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.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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U2 - 10.1126/sciadv.aav0316

DO - 10.1126/sciadv.aav0316

M3 - Article

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AN - SCOPUS:85063344007

VL - 5

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 3

M1 - eaav0316

ER -

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

Abstract

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