Astrocytic monoamine oxidase B (MAOB)-gamma-aminobutyric acid (GABA) axis as a molecular brake on repair following spinal cord injury
- Authors
- Lee, Hye Yeong; Lee, Jung Moo; Lee, Hye-Lan; Park, Jiyeon; An, Heeyoung; Park, Eun Kyung; Hwang, Sae Yeon; Yoon, Sol lip; Hwang, Gwang Yong; Kim, Keung Nyun; Nam, Min-Ho; Lee, Seung Eun; Kang, Hyunji; Won, Joungha; Jang, Bo Ko; Lee, Elijah Hwejin; Choi, Sunyeong; Park, Mingu Gordon; Kim, Sang Wook; Park, Ki Duk; Lee, Seunghwan; Lee, C. Justin; Ha, 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
- Appears in Collections:
- KIST Article > Others
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