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

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 (IC50 = 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.

SUBMITTER: Park JH

PROVIDER: S-EPMC6426469 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Park Jong-Hyun JH Ju Yeon Ha YH Choi Ji Won JW Song Hyo Jung HJ Jang Bo Ko BK Woo Junsung J Chun Heejung H Kim Hyeon Jeong HJ Shin Su Jeong SJ Yarishkin Oleg O Jo Seonmi S Park Mijeong M Yeon Seul Ki SK Kim Siwon S Kim Jeongyeon J Nam Min-Ho MH Londhe Ashwini M AM Kim Jina J Cho Sung Jin SJ Cho Suengmok S Lee Changho C Hwang Sung Yeoun SY Kim Sang Wook SW Oh Soo-Jin SJ Cho Jeiwon J Pae Ae Nim AN Lee C Justin CJ Park Ki Duk KD

Science advances 20190320 3

Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-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 ...[more]

PMID: 30906861

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Project description:Aim: Differentiation of cardiac fibroblasts (Fb) into myofibroblasts (MyoFb) is responsible for connective tissue buildup in myocardial remodeling. We examined reversibility of MyoFb differentiation. Methods and Results: Adult rat cardiac Fb were cultured on a plastic substratum providing mechanical stress, with conditions to obtain different Fb phenotypes. Fb spontaneously differentiated to proliferating MyoFb (p-MyoFb) with stress fiber formation decorated with alpha-smooth muscle actin (M-NM-1-SMA). Transforming growth factor-M-NM-21 (TGF-M-NM-21) promoted terminal differentiation into M-NM-1-SMA positive MyoFb showing near absence of proliferation i.e. non-p-MyoFb (2-fold increase in cell number after 12 days vs 11-fold for p-MyoFb). SD-208, a TGF-M-NM-2-receptor-I kinase blocker, inhibited p-MyoFb differentiation as shown by stress fiber absence, low levels of M-NM-1-SMA protein expression, and high levels of proliferation (32-fold increase after 12 days). Fb seeded in collagen matrices induced no contraction, whereas p-MyoFb and non-p-MyoFb induced 2.5- and 4-fold contraction. Fb produced low levels of collagen and secreted high levels of IL-10. Non-p-MyoFb showed high collagen production and high MCP-1 and TIMP-1 secretion. Transcriptome analysis indicated differential gene expression between all phenotypes. Dedifferentiation of p-MyoFb, but not of non-p-MyoFb, was induced by SD-208 despite maintained stress, shown by stress fiber de-polymerization in 30% of p-MyoFb vs in 8% of non-p-MyoFb. Stress fiber de-polymerization could be induced by mechanical strain release in p-MyoFb and non-p-MyoFb (2 day culture in unrestrained 3-D collagen matrices). Only p-MyoFb showed true dedifferentiation after long-term 3-D culture. Conclusions: Both reduction in mechanical strain and TGF-M-NM-2-receptor-I kinase inhibition can reverse p-MyoFb differentiation but not in non-p-MyoFb. Fibroblasts isolated from each rat heart (n= 4) were cultured in specific conditions to obtain different fibroblast phenotypes: 1) spontaneously differentiation into proliferating myofibroblasts (code RC), 2) terminal differentiation into non-proliferating myofibroblasts with TGF-M-NM-21 (code RT) and 3) inhibition of myofibroblast differentiation with SD-208, a TGF-M-NM-2-receptor-I kinase blocker (code RS). RNA concentration and purity from a total of 12 samples were determined spectrophotometrically using the Nanodrop ND-1000 (Nanodrop Technologies) and RNA integrity was assessed using a Bioanalyser 2100 (Agilent). Using the Ambion WT Expression Kit, per sample, an amount of 100 ng of total RNA spiked with bacterial poly-A RNA positive controls (Affymetrix) was converted to double stranded cDNA in a reverse transcription reaction. Next the sample was converted and amplified to antisense cRNA in an in vitro transcription reaction which was subsequently converted to single stranded sense cDNA. Finally, samples were fragmented and labeled with biotin in a terminal labeling reaction according to the Affymetrix WT Terminal Labeling Kit. A mixture of fragmented biotinylated cDNA and hybridisation controls (Affymetrix) was hybridised on Affymetrix GeneChipM-BM-. Rat Gene 2.0 ST array followed by staining and washing in a GeneChipM-BM-. fluidics station 450 (Affymetrix) according to the manufacturerM-bM-^@M-^Ys procedures. To assess the raw probe signal intensities, chips were scanned using a GeneChipM-BM-. scanner 3000 (Affymetrix).

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

Publications

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

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