Herbal Neuroprotection Meets Stress-Induced Neuropathology: Bojungikgi-Tang Modulates the Hypothalamic–Pituitary–Adrenal Axis and GABAergic Pathways in Post-Traumatic Stress Disorder

<b>Background</b>: Post-traumatic stress disorder (PTSD) is a mental disorder that can develop after experiencing or witnessing a traumatic event. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in neurotransmitters (gamma-aminobutyric acid (GABA) and glutamate) are the main pathologies of PTSD. In particular, altered GABAergic neurotransmission and reduced GABA activity are linked to PTSD. Given the low efficacy and side effects of serotonin reuptake inhibitors-the most common treatment for PTSD-a safer and more effective treatment is urgently needed. Bojungikgi-tang (BJIGT) is well-known herbal prescription in East Asia, which used to boost immunity and to alleviated symptoms such as chronic fatigue, poor appetite, and indigestion. However, its role in PTSD remains largely unexamined. This study aimed to investigate the effects of BJIGT in single-prolonged stress with shock (SPSS)-induced PTSD male mice for 2 weeks. <b>Methods</b>: To assess PTSD-like behaviors, we conducted open field, forced swimming, Y-maze, and contextual fear conditioning tests. To investigate the underlying mechanisms, we performed ELISA, Western blot, and immunohistochemistry. <b>Results</b>: BJIGT significantly ameliorated PTSD-like behaviors, including emotional and cognitive decline. Additionally, it restored serum corticosterone levels, regulated neuronal functions (c-Fos, DCX, and Prox1), and GABAergic neurotransmission-related factors (vGAT, GAD67, and parvalbumin) in the hippocampus of PTSD mice. Notably, in SPSS-induced PTSD mice, BJIGT effectively ameliorated pathological changes by modulating JNK-CaMKII and Pin1-β-catenin intracellular signaling. <b>Conclusions</b>: These findings revealed that BJIGT effectively improved PTSD-like emotional and cognitive decline by regulating the HPA axis and GABAergic neurotransmission in SPSS-induced PTSD mice, thereby promising to be an effective strategy for the treatment of PTSD.