Genetic and hormonal regulation of tryptophan kynurenine metabolism: implications for vascular cognitive impairment, major depressive disorder, and aging.

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-gamma). The effect of IFN-gamma on iNOS might be mediated by kynurenine derivatives of tryptophan because (1) IFN-gamma 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. IFN-gamma production is controlled by (IFN-gamma) + 874(T/A) genotypes, suggesting the association of a high promoter T allele with the high rate of IFN-gamma production and, consequently, with activated IDO and enhanced production of kynurenines. Although IDO is strictly an IFN-gamma-induced gene product, tumor necrosis factor alpha (TNF-alpha) can synergistically increase the transcriptional activation of the IDO gene in response to IFN-gamma. The combination of high promoter T of (IFN-gamma) + 874(T/A) with high promoter A of (TNF-alpha) -308(G/A) might "superinduce" IDO and cause (or contribute to) inflammation of brain microvessels detected as white matter hyperintensities and leading to VCI development. Hormonal induction of tryptophan dioxygenase and the ability of hormones to potentiate IFN-gamma-induced activation of IDO might contribute to the development of inflammatory changes in major depressive disorder and in aging. The IFN-gamma-IDO-iNOS hypothesis of VCI suggests new ways of preventing (identifying population at risk by analysis of IFN-gamma and TNF-alpha genetic polymorphism) and treating VCI (using IDO inhibitors and melatonin and bupropion [Wellbutrin] as agents suppressing IFN-gamma and TNF-alpha production).