Shifts in the balance of brain tryptophan metabolism due to age and systemic administration of lipopolysaccharide

Abstract

The kynurenine (KYN) pathway, which is initiated by indoleamine 2, 3-dioxygenase (IDO), is a key tryptophan (TRP) metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. Because activation of the KYN pathway by proinflammatory cytokines induces depressive symptoms, shifts in the balance of TRP metabolism to the KYN pathway are closely related to the etiology of depression. In the present study, the influence of age on the effect of the inflammation response system (IRS) on brain TRP metabolism was investigated. Male ICR mice (PND21) were reared for 4 weeks (younger group) or until they reached 1 year of age (older group), and given an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). The TRP, KYN, and 5-HT levels were measured in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei. An increase in TRP and 5-HT levels was observed with age in all brain regions, whereas age was associated with decreases in KYN levels in the dorsal raphe nuclei. In all brain regions, LPS increased TRP levels, while it increased KYN levels in the prefrontal cortex and amygdala. Reduced KYN/5-HT ratios in all regions were observed with age, whereas increased KYN/5-HT ratios were observed with LPS in all regions except the dorsal raphe nuclei. Thus, age shifted the balance between the KYN and 5-HT pathways toward the 5-HT pathway, and countered the effects of LPS, which shifted the balance to the KYN pathway. These effects are relevant to the etiology of psychiatric disorders in elderly people.