Background: G1 is a specific agonist of G protein‐coupled estrogen receptor 1 (GPER1), which binds and activates GPER1 to exert various neurological functions. However, the preventive effect of G1 on post‐traumatic stress disorder (PTSD) and its mechanisms are unclear.Objective: To evaluate the protective effect of G1 against synaptic and mitochondrial impairments and to investigate the mechanism of G1 to improve PTSD from brain‐derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling.Methods: This study initially detected GPER1 expression in the hippocampus of single prolonged stress (SPS) mice, utilizing both Western blot and immunofluorescence staining. Subsequently, the effects of G1 on PTSD‐like behaviors, synaptic, and mitochondrial functions in SPS mice were investigated. Additionally, the involvement of BDNF/TrkB signaling involved in the protection was further confirmed using GPER1 antagonist and TrkB inhibitor, respectively.Results: The expression of GPER1 was reduced in the hippocampus of SPS mice, and G1 treatment given for 14 consecutive days significantly improved PTSD‐like behaviors in SPS mice compared with model group. Electrophysiological local field potential (LFP) results showed that G1 administration for 14 consecutive days could reverse the abnormal changes in the gamma oscillation in the CA1 region of SPS mice. Meanwhile, G1 administration for 14 consecutive days could significantly improve the abnormal expression of synaptic proteins, increase the expression of mitochondria‐related proteins, increase the number of synapses in the hippocampus, and ameliorate the damage of hippocampal mitochondrial structure in SPS mice. In addition, G15 (GPER1 inhibitor) and ANA‐12 (TrkB inhibitor) blocked the ameliorative effects of G1 on PTSD‐like behaviors and aberrant expression of hippocampal synaptic and mitochondrial proteins in SPS mice and inhibited the reparative effects of G1 on structural damage to hippocampal mitochondria, respectively.Conclusion: G1 improved PTSD‐like behaviors in SPS mice, possibly by increasing hippocampal GPER1 expression and promoting BDNF/TrkB signaling to repair synaptic and mitochondrial functional impairments. This study would provide critical mechanism for the prevention and treatment of PTSD.

Objective: This systematic review and meta-analysis aim to comprehensively evaluate the efficacy of propranolol in the prevention and treatment of post-traumatic stress disorder (PTSD), with a focus on its improvement of core PTSD symptoms.Methods: A literature search was conducted across multiple databases (including PubMed, Cochrane, Web of Science, and Embase), with the search cutoff date in October 2024. The studies included randomized controlled trials (RCTs) investigating pharmacological treatments for PTSD. PTSD symptoms were assessed using standardized clinical scales, including the Clinician-Administered PTSD Scale (CAPS) and the PTSD Checklist (PCL). The primary outcome was the improvement in PTSD symptoms.Results: Seven studies met the inclusion criteria for the meta-analysis. The studies showed low heterogeneity, with a chi-squared value of 2.56 (df = 6, p = 0.86) and I² = 0%. The overall effect test indicated significant improvement in PTSD symptoms after propranolol intervention (Z = 2.32, p = 0.02). These findings suggest that propranolol has a statistically significant effect on reducing the severity of PTSD symptoms, with a moderate effect size according to Cohen’s criteria.Conclusion: This systematic review and meta-analysis provide preliminary evidence supporting the possible role of propranolol in alleviating PTSD symptoms. Future researches are needed to further clarify the therapeutic potential, mechanisms of action, and long-term safety of propranolol in PTSD treatment.