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

Abstract

AimPost-operative fatigue syndrome (POFS) is a common complication that prolongs the recovery to normal function and activity after surgery. The aim of the present study was to explore the mechanism of central fatigue in POFS and the anti-fatigue effect of ginsenoside Rb1.MethodWe investigated the association between inflammation, indoleamine 2,3-dioxygenase (IDO) enzyme, and tryptophan metabolism in the hippocampus of POFS rats. A POFS rat model was induced by major small intestinal resection. Rats with major small intestinal resection were administered ginsenoside Rb1 (15 mg/kg) once a day from 3 days before surgery to the day of sacrifice, or with saline as corresponding controls. Fatigue was assessed with the open field test (OFT) and sucrose preference test (SPT). ELISA, RT-PCR, Western blot, immunofluorescence, and high-performance liquid chromatography (HPLC) were used to test the inflammatory cytokines; p38MAPK, NF-κB/p65, and IDO enzyme expressions; and the concentrations of tryptophan, kynurenine, and serotonin, respectively.ResultOur results showed that POFS was associated with increased expressions of inflammatory cytokines and p38MAPK and higher concentrations of kynurenine and tryptophan on post-operative days 1 and 3; a lower serotonin level on post-operative day 1; and an enhanced translocation of NF-κB/p65 and the IDO enzyme on post-operative days 1, 3, and 5. Ginsenoside Rb1 had an improvement effect on these.ConclusionInflammatory cytokines induced by large abdominal surgery disturb tryptophan metabolism to cause POFS through the activation of the p38MAPK–NF-κB/p65–IDO pathway in the hippocampus. Ginsenoside Rb1 had an anti-fatigue effect on POFS by reducing inflammation and IDO enzyme.

Tryptophan metabolism and kynurenine metabolites in cancer: systemic nutritional and metabolic implications

“…We recently reported that in patients with chronic kidney disease undergoing hemodialysis, IDO activity was significantly associated with fatigue and IL-6 levels [25]. Also considering another study on rats after major abdominal surgery the increase of inflammatory cytokines in the hippocampus and the consequent upregulation of the kynurenine pathway mediated by the overexpression of the IDO enzyme through the p38MAPK-NF-κB/p65 pathway results in fatigue behaviors especially in the early phase after surgery [26]. Taken together, this evidence show a close relation among central fatigue, Kyn and Trp levels and inflammation.…”

Research Progress on Anti‐Inflammatory Mechanisms of Black Ginseng

“…[26] Additionally, Rb3 can inhibit the phosphorylation level of p38MAPK and p65 NF-кB, reduce the expression of total AKT, significantly reduce the protein expression levels of IL-1β, IL-6, and IL-8, and reduce the expression of total-AKT simultaneously, resulting in the reduction of inflammatory response caused by LPS by inhibiting the MAPK/AKT signaling pathway. [27] Liu et al [28] used ginsenoside Rb1 in the treatment of postoperative fatigue syndrome (POFS). ELISA and real-time PCR were used to evaluate the levels of inflammatory cytokines in serum and the hippocampus, respectively.…”

The role of the immune system in posttraumatic stress disorder

“…Pro-inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO), which converts tryptophan, the primary amino acid of serotonin, into kynurenine [122]. Hence, increased IDO activity in response to inflammation leads to serotonin depletion in the brain, as observed in animal models [163,164]. In human studies, IFN-α therapy led to increased kynurenine and decreased tryptophan levels that were associated with symptoms of depression and anxiety, as well as cognitive problems, including memory disturbances and confusion [165,166].…”