The role of IDO1-mediated Tryptophan/Kynurenine metabolism and its association with estrogen level in PTSD within SPS mouse model.

Abstract

Post-Traumatic Stress Disorder (PTSD) is a prevalent mental disorder emerging after traumatic events, and it shows a higher incidence rate in women. Prior research indicated that the overexpression of inflammatory factors can disrupt the IDO1-mediated Tryptophan/Kynurenine (Try/Kyn) metabolism, leading to the manifestation of psychiatric symptoms. This study aimed to verify the hypothesis that IDO1-mediated Try/Kyn metabolism contributes to the behavior abnormalities observed in PTSD using the Single Prolonged Stress (SPS) mice model. Results showed that SPS induced anxiety-like behavior and fear extinction impairment in mice, alongside increased hippocampal IDO1 levels, elevated Kyn/Try ratio, and reduced serotonin (5-HT)/Try ratio; an IDO1 inhibitor reversed these abnormalities, confirming hippocampal IDO1-mediated Try/Kyn pathway as the mechanism for SPS-induced behavioral deficits. In female mice, ovariectomy (OVX), which lowers estradiol (E2), exacerbated SPS-triggered symptoms and hippocampal IDO1 upregulation, effects alleviated by exogenous E2. E2's benefits were blocked by an ERβ antagonist, while an ERβ agonist relieved SPS-induced behavioral deficits and IDO1 overexpression, indicating E2 regulates SPS-related deficits by modulating IDO1 via ERβ. Further exploration revealed the E2-ERβ axis may mitigate deficits in SPS-exposed females by inhibiting the overexpression of NF-κB-mediated inflammatory factors (e.g., TNF-α, IL-6). In male mice, E2 similarly alleviated SPS-induced behavioral deficits, hippocampal IDO1 overexpression, and upregulated NF-κB/downstream inflammatory factors; E2's function was reversed by an ERβ antagonist, confirming the E2-ERβ axis's protective role against SPS in males too. In conclusion, IDO1 and ERβ play crucial roles in the development of PTSD. Therapeutic agents targeting IDO1 and/or ERβ hold promise as potential candidates for the treatment of PTSD.