Targeting Astrocytic GABA Production to Promote Spinal Cord Repair and Neuronal Regeneration

Recent research has uncovered a key molecular mechanism that inhibits neural regeneration following spinal cord injury (SCI). The study, led by the Institute for Basic Science (IBS) in collaboration with Yonsei University, identified an inhibitory pathway centered around the enzyme monoamine oxidase B (MAOB) in astrocytes. This enzyme produces gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, which acts as a molecular 'brake' that prevents axonal regrowth and neural repair after injury.

Spinal cord injuries, often caused by trauma such as accidents or falls, typically result in permanent motor and sensory deficits. One of the major barriers to recovery has been the formation of a glial scar, composed of proliferating astrocytes and other glial cells, which shields the injury site initially but later blocks nerve regeneration. Until now, the precise molecular pathways underpinning this inhibitory effect were unclear.

The research demonstrates that elevated GABA levels, produced via MAOB activity in reactive astrocytes, suppress the expression of brain-derived neurotrophic factor (BDNF) and its receptor TrkB—both critical for neuronal growth and regeneration. This suppression effectively puts the brakes on axonal extension and functional recovery.

Using animal models, the team showed that inhibiting MAOB with a compound called KDS2010 significantly reduced GABA overproduction. This intervention restored neuronal markers like MAP2, preserved neurons at the injury site, and promoted remyelination of damaged axons. Electrophysiological assessments confirmed that GABA-driven inhibitory currents returned to normal, re-establishing the excitatory-inhibitory balance necessary for neural activity.

Further experiments revealed that suppression of MAOB allowed axons to regrow, leading to improved motor functions in rodents, including fewer slips during ladder-walking and enhanced hindlimb movement. These benefits were also observed in non-human primates, showing tissue preservation and neural protection. Importantly, KDS2010 has already been validated for safety in Phase I clinical trials.

The findings suggest that targeting the MAOB-GABA pathway may offer a promising new therapeutic strategy for promoting neural regeneration after SCI. With plans to advance into Phase II clinical trials, researchers are optimistic about translating this approach into effective treatments. The study highlights a novel mechanism of neural repair blockage and opens avenues for treating not only SCI but potentially other neurodegenerative conditions.