New Drug for PTSD?
Did you know that patients with post-traumatic stress disorder (PTSD) often struggle to forget traumatic memories, even long after the danger has passed? This failure to extinguish fear memories has long puzzled scientists and posed a major hurdle for treatment, especially since current medications targeting serotonin receptors offer limited relief for only a subset of patients.
In a new discovery, scientists at the Institute for Basic Science (IBS) and Ewha Womans University have uncovered a new brain mechanism driving PTSD and a promising drug that may counteract its effects. Led by Dr. C. Justin LEE at the IBS Center for Cognition and Sociality and Professor LYOO In Kyoon at Ewha Womans University, the team has shown that excessive GABA (gamma-aminobutyric acid) produced by astrocytes, which are star-shaped support cells in the brain, impairs the brain’s ability to extinguish fear memories. This deficit is a core feature of PTSD and helps explain why traumatic memories can persist long after the threat has passed.
Crucially, the researchers found that a brain-permeable drug called KDS2010, which selectively blocks the monoamine oxidase B enzyme responsible for this abnormal GABA production, can reverse PTSD-like symptoms in mice. The drug has already passed Phase 1 safety trials in humans, making it a strong candidate for future PTSD treatments.
PTSD remains difficult to treat, with current medications targeting serotonin pathways providing limited relief for many patients. The new study focused on the medial prefrontal cortex (mPFC), a region of the brain critical for regulating fear, and found that PTSD patients had unusually high levels of GABA and reduced cerebral blood flow in this area. These findings emerged from brain imaging studies of more than 380 participants. GABA levels decreased in patients who showed clinical improvement, pointing to the chemical’s central role in recovery.
To uncover the origin of this excess GABA, the researchers examined postmortem human brain tissue and used PTSD-like mouse models. They discovered that astrocytes, not neurons, were producing abnormal amounts of GABA via the enzyme monoamine oxidase B (MAOB). This astrocyte-derived GABA impaired neural activity, blocking the brain’s ability to forget traumatic memories.
Excessive GABA produced by astrocytes in the medial prefrontal cortex (mPFC) is a key factor in Post-Traumatic Stress Disorder (PTSD), leading to the inability to forget traumatic memories. This astrocytic GABA (gamma-aminobutyric acid) impairs neural activity, which can be targeted by monoamine oxidase B (MAOB) inhibitors, such as the drug KDS2010. Research has shown that blocking MAOB normalizes astrocytic GABA levels, restores blood flow in the mPFC, and
improves fear extinction in PTSD mouse models, with KDS2010 currently in Phase 2 clinical trials for PTSD.
Excessive astrocytic GABA disrupts the brain’s ability to extinguish fear memories, a core feature of PTSD. This dysregulation is observed in the medial prefrontal cortex (mPFC), a brain region crucial for fear regulation. High levels of astrocyte-derived GABA inhibit neuronal activity and reduce cerebral blood flow (CBF) in the mPFC. Studies found that elevated prefrontal GABA levels in PTSD patients were associated with symptom severity and improved with clinical recovery.
The research identified astrocytic monoamine oxidase B (MAOB) as the enzyme responsible for producing excessive GABA in the mPFC of individuals with PTSD. Targeting astrocytic MAOB offers a new therapeutic path for PTSD. A selective, reversible MAOB inhibitor called KDS2010 has been shown to normalize astrocytic GABA, restore mPFC blood flow, and improve fear extinction in PTSD mouse models. KDS2010 is a strong candidate for clinical trials in PTSD.
The drug has successfully completed Phase 1 trials and is currently in Phase 2 clinical trials to evaluate its effectiveness in treating PTSD. This research provides a novel therapeutic strategy for PTSD by directly targeting the underlying astrocytic GABA mechanism.
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