The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-ĸB induced IDO expression

Abstract

Aim: Indoleamine 2, 3-dioxygenase (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin Ⅵ (ASA Ⅵ) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA Ⅵ in LPS-treated mice and further explored its molecular mechanism by insight into the microglial kynurenine pathway. Methods: To produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA Ⅵ (10 mg/kg, 20mg/kg, 40mg/kg and 80mg/kg, i.p.) thirty minutes prior to LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR and ELISA. The TLR4/NF-ĸB signaling pathway and the expression of IDO, GluA2, and CamKIIβ were measured by western blotting. Results: ASA Ⅵ demonstrated significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhabited by ASA Ⅵ in a dose-dependent manner. TLR4/NF-κB signaling pathway also was suppressed by ASA Ⅵ in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA Ⅵ inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex as a result of LPS administration. Conclusion: Our results propose a promising antidepressant effect for ASA Ⅵ possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA Ⅵ could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.

Inflammation Disturbed the Tryptophan Catabolites in Hippocampus of Post-operative Fatigue Syndrome Rats via Indoleamine 2,3-Dioxygenas Enzyme and the Improvement Effect of Ginsenoside Rb1

“…NF-κB is a protein complex that controls the transcription of DNA ( Kim et al, 2006 ). Inflammatory cytokines can induce overexpression of the IDO enzyme via signal transducer and activator of transcription protein (STAT)-independent pathways involving p38MAPK and NF-κB ( Fujigaki et al, 2006 ; Huang et al, 2020 ; Zhang et al, 2020 ). Our experiments showed a similar tendency of cytokines, pp38, NF-κB/pp65, and IDO to have upregulated expressions and increased nucleus/cytoplasm ratios on post-operative days 1 and 3, then gradually recovered to normal levels as in the CG, which illustrated the activity of the p38MAPK-NF-κB/p65 pathway promoting the overexpression of the IDO enzyme.…”

Microglia as a Potential Target for Antidepressant: A Systematic Review on Preclinical studies

“…TLR-4, a microglia-expressed first-line molecule to initiate the innate immune response, mediates the release of proinflammatory mediators via the NF-κB pathway 56,57 . Inhibition of the TLR4/NF-κB pathway causes a decrease in TNF-α and IL-1β levels, thereby preventing the conversion of microglia to M1 phenotype 24,30 . Inhibition of microglia will then cause a decrease in the release of HMGB1 (high mobility group box-1), damage associated molecular pattern (DAMP), an alarmin protein that may trigger a proinflammatory immune response through the activation of the TLR4/NF-κB pathway 25,30,34 .…”