Inhibition of indoleamine 2,3-dioxygenase by 1-methyl-D-tryptophan (1-MT) rescued PTSD-like symptoms via downregulation of neuroinflammation and NMDA receptor

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating mental health condition stemming from exposure to traumatic events. Current treatment for PTSD is limited to the selective serotonin reuptake inhibitors, which are often associated with severe side effects and result in poor treatment adherence and limited effectiveness. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO) may play a significant role in the development of stress-related disorders. As a result, targeting and inhibiting IDO could offer a promising new approach for treating conditions like PTSD. Therefore, 1-Methyl-D-tryptophan (1-MT), an IDO inhibitor, was tested in rats exhibiting PTSD-like symptoms. The rat model for PTSD was created using foot shock stress (FSS) as a method to simulate traumatic experiences. Following the induction of PTSD, the potential benefits of 1-MT were assessed by performing a series of tests, including sucrose preference, freezing behaviour, light-dark transition, and open field tests. Additionally, biochemical evaluation, ELISA, western blotting, and immunohistochemistry were utilized to investigate the pharmacological effects of 1-MT. 1-MT significantly reduced PTSD symptoms, as shown by improvements in behavioural parameters, cortisol levels, and oxidative stress markers, specifically GSH and MDA. 1-MT effectively treated the expression levels of IDO, TNF-α, and the phosphorylation of NF-κB in both the hippocampus and the PFC. By inhibiting IDO and reducing neuroinflammation, it further lessened the overexpression of N-Methyl-D-Aspartate (NMDA) receptor subunit NR1. Overall findings strongly suggest that 1-MT could serve as a potential therapeutic agent to treat PTSD by alleviating the TNF-α/NF-κB/IDO signaling pathway.

Keywords: 1-Methyl-D-tryptophan; Cortisol; IDO; Neuroinflammation; PTSD.