Genetic and Hormonal Regulation of Tryptophan—Kynurenine Metabolism Implications for Vascular Cognitive Impairment, Major Depressive Disorder, and Aging

摘要

Impairment of cognition that is caused by (or associated with) vascular factors has been termed vascular cognitive impairment (VCI). The hallmark of VCI is an impairment of brain executive, or planning, functions caused by inflammatory changes of brain microvessels. VCI is characterized by impairment of the executive function and is distinct from Alzheimer's-type and multi-infarct dementias, although VCI might overlap with Alzheimer's disease. This review focuses on the possible contribution of the kynurenine pathway of tryptophan (Try) catabolism to the inflammatory changes in brain microvessels. One mechanism of brain microvessel inflammation is activation of the inducible nitric oxide synthase (iNOS) by the proinflammatory cytokine interferon gamma (IFN-y). The effect of IFN-y on iNOS might be mediated by kynurenine derivatives of tryptophan because (1) IFN-y stimulates the rate-determining enzyme of the Try–kynurenine pathway, indoleamine- 2,3-dioxygenase (IDO) and (2) some kynurenines (e.g., quinolinic and picolinic acids) can stimulate iNOS.