Yoon Sujung, Won Woojin, Lee Suji, Han Kayoung, Ha Eunji, Lee Juheon, Hyeon Seung Jae, Joo Yoonji, Hong Haejin, Lee Hyangwon, Song Yumi, Park Ki Duk, Huber Bertrand R, Lee Junghee, Edden Richard A E, Suh Minah, Ryu Hoon, Lee C Justin, Lyoo In Kyoon
Ewha Brain Institute, Ewha Womans University, Seoul, South Korea.
Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul, South Korea.
Signal Transduct Target Ther. 2025 Jul 28;10(1):240. doi: 10.1038/s41392-025-02317-5.
Post-traumatic stress disorder (PTSD) remains a debilitating psychiatric condition with limited pharmacological treatment options. Identifying novel therapeutic targets is critical for addressing its unmet clinical needs. Through our comprehensive human clinical research, including both cross-sectional and longitudinal studies, we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid (GABA) levels and PTSD symptoms. Notably, elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow (CBF) and symptom severity, normalizing with recovery, highlighting GABA dysregulation as a key mechanism in the disorder. Postmortem and PTSD-like mouse models implicated monoamine oxidase B (MAOB)-dependent astrocytic GABA as a primary driver of this imbalance, exacerbating deficit in fear extinction retrieval. Genetic and pharmacological inhibition of MAOB effectively restored astrocytic GABA and improved fear extinction retrieval in PTSD-like mouse models. Specifically, KDS2010, a recently developed highly selective and reversible MAOB inhibitor, not only restored astrocytic GABA homeostasis but also rescued CBF deficits and reduced tonic GABA and astrogliosis in the prefrontal cortex. Moreover, KDS2010 successfully advanced through Phase 1 clinical trials, showing a favorable safety profile and paving the way for Phase 2 trials to evaluate its therapeutic potential in PTSD. Our findings highlight the pivotal role of astrocytic GABA in PTSD pathophysiology and establish MAOB inhibition as a mechanistically targeted approach to alleviate symptoms. By bridging human and animal studies with translational clinical trials, this work positions KDS2010 as a promising first-in-class therapy, offering a novel paradigm for PTSD treatment.
创伤后应激障碍（PTSD）仍然是一种使人衰弱的精神疾病，药物治疗选择有限。确定新的治疗靶点对于满足其未得到满足的临床需求至关重要。通过我们全面的人体临床研究，包括横断面研究和纵向研究，我们揭示了前额叶γ-氨基丁酸（GABA）水平失调与PTSD症状之间存在令人信服的联系。值得注意的是，PTSD患者前额叶GABA水平升高与脑血流量（CBF）受损和症状严重程度相关，随着恢复而恢复正常，这突出了GABA失调是该疾病的关键机制。尸检和PTSD样小鼠模型表明，单胺氧化酶B（MAOB）依赖性星形胶质细胞GABA是这种失衡的主要驱动因素，加剧了恐惧消退恢复的缺陷。在PTSD样小鼠模型中，对MAOB进行基因和药理学抑制可有效恢复星形胶质细胞GABA，并改善恐惧消退恢复。具体而言，KDS2010是一种最近开发的高选择性和可逆性MAOB抑制剂，不仅恢复了星形胶质细胞GABA稳态，还挽救了CBF缺陷，并减少了前额叶皮质的强直GABA和星形胶质细胞增生。此外，KDS2010成功完成了1期临床试验，显示出良好的安全性，为2期试验评估其在PTSD中的治疗潜力铺平了道路。我们的研究结果突出了星形胶质细胞GABA在PTSD病理生理学中的关键作用，并将MAOB抑制确立为一种缓解症状的机制性靶向方法。通过将人体和动物研究与转化性临床试验相结合，这项工作将KDS2010定位为一种有前途的一流疗法，为PTSD治疗提供了一种新的范例。
