Spinal cord injuries caused by trauma such as traffic accidents or falls can lead to the permanent loss of motor and sensory functions. That is because there is a "brake" in the spinal cord, which connects the brain and the whole body, that prevents recovery from injury. A Korean research team has for the first time revealed the molecular-level mechanism by which this brake operates.
Lee Chang-joon, head of the Center for Cognition and Sociality at the Institute for Basic Science (IBS), and Ha Yun, a professor at Yonsei University College of Medicine, said on the 11th that they identified that "the inhibitory neurotransmitter 'GABA' produced by star-shaped astrocytes in the spinal cord through the enzyme MAOB is the key cause that hinders recovery of the injured spinal cord."
By demonstrating the recovery effect of an MAOB inhibitor, the team also suggested the possibility of treating spinal cord injury with drugs. The findings were published the same day in the international journal Signal Transduction and Targeted Therapy.
It is known that the reason spinal cord injuries are difficult to recover from lies in the "glia barrier" that forms at the injury site. Neuroglia are like a rear support unit that supplies substances needed by neurons that transmit signals. The glia barrier refers to the rapid proliferation of various glial cells, including astrocytes, immediately after injury, thickly surrounding the wound.
The glia barrier protects the injury site in the early stage but over time interferes with nerve regrowth. However, the exact mechanism by which this barrier blocks nerve injury recovery has not been identified at the molecular level. For this reason, treatments for spinal cord injury have mostly been limited to suppressing inflammation or alleviating symptoms.
In earlier research, the team showed that reactive astrocytes abnormally generate GABA through MAOB and that this worsens neurodegenerative diseases such as Alzheimer's disease. In this study, by analyzing astrocytes in injured spinal cords, the team found that GABA suppresses the expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor needed for neuronal regeneration, and its receptor TrkB.
As a result, neural growth signals necessary for recovery after injury were blocked, halting the regeneration of nerve fibers and functional recovery. In other words, the pathway in which GABA is generated by MAOB acts as a brake that stops the recovery process of spinal cord injury.
Using animal models in which MAOB expression in spinal astrocytes was suppressed or activated, the researchers compared post-injury recovery. Analysis showed that mice with suppressed MAOB expression experienced regrowth of injured nerve fibers and a marked recovery of hindlimb motor function.
Conversely, mice with increased MAOB expression showed severe damage, with the cross-sectional area of the spinal cord reduced to nearly half of normal, and their motor function hardly recovered. This shows that the MAOB–GABA pathway is the direct cause preventing recovery from spinal cord injury.
The team then administered the MAOB inhibitor KDS2010 to animals with spinal cord injury to confirm its effects. Mice that received the drug showed significant improvement in gait, including fewer hindlimb slips in the ladder-walking test, and new nerve fibers extended from the injury site.
In primates similar to humans, the loss of injured tissue was markedly reduced and nerves were preserved. In particular, a phase 1 clinical trial in healthy adults verified the drug's excellent safety and tolerability. Tolerability refers to the degree to which patients endure side effects and discomfort from drug administration.
Ha Yun, a professor at Yonsei University College of Medicine, said, "KDS2010 is a drug whose safety has already been confirmed in a phase 1 clinical trial, and we plan to verify its therapeutic effect in actual spinal cord injury patients through a phase 2 clinical trial," adding, "We will determine whether the MAOB–GABA pathway is involved in other neurological diseases to broaden its applications and develop it into a more precise and multifaceted treatment platform."