GypenosideXVII alleviates fear and anxiety like behavior in rats arising from post-traumatic stress disorder through the PERK/CHOP signaling pathway

Abstract Objective Recent investigations suggest GP-17 may be effective in managing conditions like insomnia, depression, and Alzheimer's disease, primarily due to the qualities of anti-inflammatory, antioxidative, and neuroprotective.Studies reveal pathological imaging changes in the mPFC of PTSD patients, with animal experiments showing PERK-mediated activation of ER stress in the mPFC. To explore the potential role of GP-17 in the pathogenesis of PTSD.We carried out this study to assess the effects of Gypenoside XVII on PTSD-like behaviors and to further investigate the mechanisms underlying this process.The Single Prolonged Stress (SPS) model is extensively employed as a method to replicate post-traumatic stress disorder (PTSD). Method This research utilized standardized animal behavior tests, including the Open Field Test for anxiety-related behavior and the Conditioned Fear Test for fear-related responses, to explore the potential of Gypenoside XVII in reducing PTSD-like symptoms. Fear extinction was assessed using the Fear Extinction Test, highlighting deficits in fear extinction.The rats' medial prefrontal cortex subjected to SPS treatment was extracted, followed by the application of Western blotting and TUNEL apoptosis staining methods to investigate the mechanisms through which Gypenoside XVII mitigates PTSD-like behaviors.Additionally,through cellular experiments, we validated that GP-17 exerts its anti-apoptotic mechanism on BV2 cells by suppressing the endoplasmic reticulum(ER) stress signaling pathway. Results Gypenoside XVII was found to alleviate SPS-induced PTSD-like behaviors and mitigate deficits in fear extinction.In the brains of SPS model rats, PERK phosphorylation was markedly increased, driving the downstream activation of eif2a phosphorylation. This led to the over-activation of ATF4, which subsequently initiated CHOP transcription and triggered the apoptotic process. Intraperitoneal injection of Gypenoside XVII reversed these changes. Moreover, Tunicamycin (Tu) induces ER stress in BV2 cells, contributing to PERK phosphorylation and resulting in CHOP-induced apoptosis. Gypenoside XVII was able to inhibit the apoptosis triggered by the Overexpression of CHOP, a downstream component of the PERK signaling pathway in BV2 cells. Conclusions In this study, we observed that Gypenoside XVII can improve anxiety and fear extinction deficits in SPS model rats while inhibiting apoptosis in the mPFC brain tissue, likely by suppressing the activation of the PERK/CHOP signaling pathway induced by SPS in the mPFC. By targeting ER stress and inhibiting cortical cell apoptosis post-PTSD, Gypenoside XVII provides a new avenue for clinical treatment strategies.