In a groundbreaking advance that could revolutionize treatments for spinal cord injuries, researchers have unveiled the molecular mechanism responsible for the failure of spinal cord regeneration. This discovery sheds light on the inhibitory processes that halt neural repair and introduces a promising therapeutic candidate capable of overcoming these longstanding biological barriers. For decades, spinal cord injuries resulting from traumatic incidents such as falls or road accidents have posed formidable challenges, often leading to irreversible paralysis and sensory deficits. The newly identified molecular pathway provides hope for effective interventions aimed at restoring motor function after such devastating injuries.
At the heart of this revelation lies the enzyme monoamine oxidase B (MAOB), expressed in astrocytes—the star-shaped glial cells within the spinal cord. MAOB drives the aberrant production of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter whose excess presence effectively “brakes” the regenerative processes. Unlike the traditionally understood glial scar or barrier, which physically obstructs axonal regrowth, this MAOB–GABA axis works at the molecular level, suppressing critical growth factor signaling pathways necessary for neural repair. By dampening these reparative signals, the brain-to-body communication pathway remains severed, leaving patients with chronic disabilities.
The study, led by Director C. Justin Lee of the Institute for Basic Science (IBS) alongside collaborators at Yonsei University College of Medicine, meticulously elucidated the biochemical cascade in a series of sophisticated animal models. They demonstrated that the surplus GABA produced by reactive astrocytes represses the expression of brain-derived neurotrophic factor (BDNF) and its receptor TrkB—both essential mediators of neuronal survival and axonal proliferation. Without adequate BDNF signaling, injured neurons lack the impetus to regrow, resulting in permanent functional impairment.
This discovery represents a paradigm shift, moving beyond the simplistic notion that neural recovery is hindered solely by structural impediments to address the subtle, molecular forms of inhibition. Previous therapeutic strategies largely focused on mitigating inflammation or alleviating secondary symptoms, with limited longevity or efficacy in functional restoration. The MAOB–GABA axis emerges not just as a contributor but as a central regulator impeding spinal cord regeneration, redefining the biological framework underpinning axonal repair failure.
To confirm the pivotal role of MAOB in this pathological mechanism, the research team employed genetic and pharmacological manipulations in rodent models. Suppression of MAOB within spinal astrocytes led to marked axonal regrowth and recovery of hindlimb motor function, while enhanced MAOB expression exacerbated tissue damage and functional loss. These results underscore the critical, direct link between MAOB activity and the inhibition of structural and behavioral recovery following spinal cord injury.
Capitalizing on these insights, the researchers turned to KDS2010, a selective and reversible MAOB inhibitor with prior validation of safety in Phase I clinical trials involving healthy individuals. Administration of KDS2010 in spinal cord-injured animals profoundly improved locomotor abilities and neurological outcomes. Behavioral assessments recorded fewer hindlimb slips during ladder-walking tasks, reflecting restored motor coordination. Histological evaluation corroborated these findings, showing reduced lesion sizes and increased remyelination of axons, which is crucial for electrical signal conduction and neuronal function.
Strikingly, these therapeutic benefits extended beyond rodent models into non-human primates, where KDS2010 treatment similarly preserved spinal tissue integrity and enhanced neural protection. The cross-species efficacy strengthens the translational potential of this treatment, bridging the gap between laboratory studies and human clinical applicability. The capacity of KDS2010 to modulate the astrocytic MAOB–GABA axis introduces a novel, mechanism-based intervention that directly targets neural regeneration pathways.
“This study identifies a fundamental molecular brake on spinal cord repair and offers a targeted strategy to overcome this obstacle,” explained Director C. Justin Lee. “By focusing on the inhibition of MAOB, we can lift the biochemical ‘brake’ imposed by GABA, facilitating the reconnection of neural circuits essential for motor recovery.” Such an approach contrasts sharply with existing symptom-based therapies, promising a transformative impact on patient outcomes.
Professor Ha Yoon of Yonsei University College of Medicine emphasized the clinical promise of these findings: “Given KDS2010’s proven safety profile in Phase I trials, the next logical step is to advance towards Phase II studies focused on spinal cord injury patients. Moreover, the broader implications of MAOB-mediated GABA release in other neurological conditions are compelling and could open new avenues for treatment development.” This prospect positions the MAOB–GABA pathway not only as a target for spinal repair but as a potential cornerstone in treating a spectrum of neurodegenerative and neurotraumatic disorders.
The investigation leveraged multi-institutional collaboration, integrating biochemistry, neurobiology, and translational medicine from research centers including IBS, Yonsei University, Seoul National University, and the Korea Institute of Science and Technology (KIST), supported by Korea’s Ministry of Science and ICT and the National Research Foundation. Published in the prestigious journal Signal Transduction and Targeted Therapy, the work highlights the impactful convergence of basic research and clinical innovation, with a high journal impact factor reflecting its significance.
This research challenges long-held assumptions about the limited capacity for spinal cord regeneration and opens a promising therapeutic horizon. By elucidating the molecular machinery of repair inhibition and demonstrating a safe, effective means to counteract it, the study galvanizes hope for millions worldwide affected by spinal cord injuries. The therapeutic inhibition of MAOB with agents such as KDS2010 represents a precise, targeted intervention poised to reshape neurorehabilitation.
Continuing efforts will focus on further dissecting the intricate signaling networks downstream of GABA-mediated inhibition and refining MAOB inhibitors’ pharmacodynamics and pharmacokinetics. Understanding whether similar mechanisms operate in other central nervous system injuries or neurodegenerative contexts could expand the clinical impact of this discovery. As the field moves toward clinical trials, it is imperative to monitor efficacy while assessing long-term functional recovery and potential neurological side effects.
In summary, this research illuminates a critical molecular barrier previously obscured in spinal cord injury pathology. Targeting the astrocytic MAOB–GABA axis offers a compelling new strategy to unlock neural regeneration, restore motor function, and ultimately improve quality of life for patients globally. The advent of KDS2010 heralds a new era of precision medicine in spinal cord injury, transforming decades of scientific insight into tangible therapeutic breakthroughs.
Subject of Research: Animals
Article Title: Astrocytic monoamine oxidase B (MAOB)–gamma-aminobutyric acid (GABA) axis as a molecular brake on repair following spinal cord injury
News Publication Date: 10-Sep-2025
Web References: http://dx.doi.org/10.1038/s41392-025-02398-2
Image Credits: Institute for Basic Science
Keywords: Spinal cord injuries, Nerve injuries, Traumatic injury, Diseases and disorders, Astrocytes, Glia, Cells, Cell biology, Life sciences, GABA, Neurotransmitters, Neurochemistry, Biochemistry, Inflammation, Symptomatology
