Spinal cord injuries caused by external injuries such as road accidents and falls often lead to permanent loss of motor and sensory functions. This is because the central pathway that connects the spinal cord – the brain, and the “brake” mechanism that stops repairing the rest of the body har. For the first time, the molecular mechanism behind this braking system has been revealed.
A research team led by C. Justin Lee of the Center for Cognitive and Social Studies at the Institute of Basic Sciences (IBS) in collaboration with Professor Ha Yoon of the Yonsei University College of Medicine to identify the inhibitory neurotransmitter GABA produced by astocytes in the spinal cord via Enzyme monoamine oxidase B, as a ridiculous block (Maobinal Block). Furthermore, they demonstrated the potential for treatment targeting this pathway by showing that MAOB inhibition promotes spinal cord repair.
Until now, failure to recover after spinal cord injury has been largely attributed to the formation of so-called glial barriers. This barrier is formed by the rapid proliferation of astrocytes and other glial cells around the lesion, protecting sites of damage during the acute phase, but later preventing axonal regeneration. However, the exact molecular mechanisms that hinder regeneration remained unknown. As a result, existing treatments for spinal cord injury have focused primarily on suppressing inflammation or reducing symptoms rather than directly addressing nerve repair.
Based on their previous studies, the team investigated whether similar mechanisms occur in spinal cord injuries as they showed that reactive astrocytes produce GABA via MAOB, exacerbating neurodegenerative diseases such as Alzheimer’s disease. They found that GABA suppresses the expression of BDNF (an important neurotrophic factor) and its receptor TRKB. Both are essential for nerve regeneration. As a result, GABA production acts as a molecular brake, shutting down growth signals, blocking axon regrowth and functional recovery after damage.
To verify this, the researchers used animal models in which MAOB expression in spinal cord astrocytes was suppressed or enhanced. With inhibition of MAOB, axons regenerated and restored hindlimb motor function, and increased MAOB expression led to severe tissue loss and little functional recovery. These findings confirmed that the Maob–Gaba pathway directly prevents spinal cord regeneration.
The team also tested the MAOB inhibitor KDS2010 in an animal model of spinal cord injury. Treated mice showed significant improvement in movement, including fewer hindlimb slips in ladder wall tests, and showed robust axonal regeneration at the site of injury. Histological analysis revealed a decrease in the lesion space and an increase in regenerative axons. Importantly, similar benefits were confirmed in non-human primates with significantly improved tissue conservation and neuroprotection. The safety and tolerability of KDS2010 has already been tested in Phase I clinical trials in healthy adults, highlighting its potential as a treatment candidate.
“This study presents strategies to identify and overcome direct molecular pathways that inhibit nerve regeneration after spinal cord injury. Unlike existing treatments, this offers a fundamentally new therapeutic approach.”
KDS2010 has already demonstrated its safety in phase I clinical trials and plans to proceed with a Phase II trial to assess its efficacy in patients with spinal cord injury. Furthermore, we aim to investigate whether the MAOB-GABA pathway plays a role in other neurological disorders, expanding potential applications to a more comprehensive therapeutic platform. ”
Professor Hayoon, Yonsei University College of Medicine
This study was conducted through a multicenter collaboration that includes the Korean Institute of Science and Technology (KIST), and neurobiology, with support from IBS, Uwaru University, Seoul National University, the Korean Institute of Science and Technology (KIST), and the Korean National Research Foundation. The findings were published on September 11th at Signal Transduction and Targeted Therapy (Impact Factor 52.7, 2024 JCR).
sauce:
Institute of Basic Science
Journal Reference:
Lee, H. Y., et al. (2025). Astrocyte monoamine oxidase B (MAOB) – gamma aminobutyric acid (GABA) axis as a molecular brake during repair after spinal cord injury. Signaling and targeted therapy. doi.org/10.1038/S41392-025-02398-2
