| First Author | Park JH | Year | 2019 |
| Journal | Sci Adv | Volume | 5 |
| Issue | 3 | Pages | eaav0316 |
| PubMed ID | 30906861 | Mgi Jnum | J:288513 |
| Mgi Id | MGI:6432209 | Doi | 10.1126/sciadv.aav0316 |
| Citation | Park JH, et al. (2019) Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease. Sci Adv 5(3):eaav0316 |
| abstractText | 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. 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. |
