Indoleamine 2, 3-dioxygenase is responsible for low stress tolerance after intracerebral hemorrhage

Abstract

In the chronic phase after intracerebral hemorrhage (ICH), the aftereffect-associated lowering of motivation burdens many patients; however, the pathogenic mechanism is unclear. Here, we revealed for the first time that indoleamine 2, 3-dioxygenase (IDO) expression and enzyme activity are increased in the collagenase-induced murine ICH model. IDO is a rate-limiting enzyme situated at the beginning of the kynurenine pathway and converts tryptophan, a source of serotonin (5-hydroxytryptamine; 5-HT), to kynurenine. In this study, we showed that IDO is localized in 5-HTergic neurons. After ICH, the synaptosomal 5-HT level decreased, but this effect was neutralized by subcutaneous injections of 1-methyl tryptophan (MT), a specific IDO inhibitor. These results suggest that ICH-induced IDO weakens the activity of 5-HTergic neurons. Accordingly, we next investigated whether the IDO increase contributes to the depression-like behaviors of ICH mice. The immobility times of tail suspension and forced swimming tests were significantly prolonged after ICH but shortened by the administration of 1-MT. In conclusion, the increased IDO after ICH was found to decrease 5-HT levels and subsequently reduce stress tolerance. These findings indicate that IDO is a novel therapeutic target for the ICH aftereffect-associated lowering of motivation.

Lipopolysaccharide-Induced Delirium-like Behaviour in a Rat Model of Chronic Cerebral Hypoperfusion Is Associated with Increased Indoleamine 2,3-Dioxygenase Expression and Endotoxin Tolerance

“…Previously, Honsi and colleagues (2008) reported time-course upregulated hippocampal IDO expression in mice models of cerebral ischaemia 72 h after the BCCAL [46]. Meanwhile, several studies identified that IDO is upregulated in acute and chronic phases of cerebral ischaemia and chronic brain damage after stroke injury [35,47,48]. Although our study did not suggest memory deficit in CCH rats, increased IDO was associated with poststroke cognitive impairment, depression, and mortality [47,49].…”

“…This condition increases the susceptibility of the microglia to a secondary stimulus and exhibits an exaggerated inflammatory response. Uniquely, under the influence of cytokines, 'primed' microglia express heightened IDO levels, which serve immunoregulatory and tolerogenic functions [34][35][36]. Increased expression of IDO enhances amino acid tryptophan (TRP) degradation via the kynurenine pathway (KP), which can affect the host immune system and CNS.…”

Role of aryl hydrocarbon receptors in infection and inflammation

“…Exogenous ligands, such as 2, 3, 7, 8tetrachlorodibenzo-p-dioxin (TCDD) and various viruses, can activate the AhR signaling pathway in host cells (3)(4)(5). Endogenous AhR ligands, such as Kynurenine (Kyn) and arachidonic acid, induce the translocation of AhR from the cytoplasmic matrix to the nucleus, thereby regulating the transcription of various target genes (6). Activation of AhR leads to the upregulation of cytochrome P450 enzymes, including CYP1A1 and CYP1B1, which play a crucial role in facilitating detoxification and drug metabolism (2).…”