Astrocytic monoamine oxidase B (MAOB)-gamma-aminobutyric acid (GABA) axis as a molecular brake on repair following spinal cord injury

Authors
Lee, Hye YeongLee, Jung MooLee, Hye-LanPark, JiyeonAn, HeeyoungPark, Eun KyungHwang, Sae YeonYoon, Sol lipHwang, Gwang YongKim, Keung NyunNam, Min-HoLee, Seung EunKang, HyunjiWon, JounghaJang, Bo KoLee, Elijah HwejinChoi, SunyeongPark, Mingu GordonKim, Sang WookPark, Ki DukLee, SeunghwanLee, C. JustinHa, Yoon
Issue Date
2025-09
Publisher
Nature Publishing Group | Sichuan University
Citation
Signal Transduction and Targeted Therapy, v.10, no.1
Abstract
Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system (CNS) injury. The glial scar has been proposed as a major contributor to this failure in the regenerative process. However, its underlying molecular and cellular mechanisms remain unclear. Here, we report that monoamine oxidase B (MAOB)-dependent excessive gamma-aminobutyric acid (GABA) release from reactive astrocytes suppresses the CNS repair system by reducing brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) expression in severe spinal cord injury (SCI) animal models. Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery. Notably, the selective MAOB inhibitor, KDS2010, facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model. Its dose-dependent effects were further validated in a monkey SCI model. Moreover, KDS2010 demonstrated a tolerable safety profile and dose-proportional pharmacokinetics in healthy humans during a phase 1 clinical trial. This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury. Our findings identify the astrocytic MAOB-GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.
Keywords
CHONDROITIN SULFATE PROTEOGLYCANS; STEM-CELL THERAPY; REACTIVE ASTROCYTES; NEUROTROPHIC FACTOR; AXON REGENERATION; ADVERSE EVENTS; BRAIN; BDNF; MOUSE; RELEASE
ISSN
2095-9907
URI
https://pubs.kist.re.kr/handle/201004/153311
DOI
10.1038/s41392-025-02398-2
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KIST Article > Others
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