Importance of kynurenine 3-monooxygenase for spontaneous firing and pharmacological responses of midbrain dopamine neurons: Relevance for schizophrenia

Abstract

Kynurenine 3-monooxygenase (KMO) is an essential enzyme of the kynurenine pathway, converting kynurenine into 3-hydroxykynurenine. Inhibition of KMO increases kynurenine, resulting in elevated levels of kynurenic acid (KYNA), an endogenous N-methyl-d-aspartate and α*7-nicotinic receptor antagonist. The concentration of KYNA is elevated in the brain of patients with schizophrenia, possibly as a result of a reduced KMO activity. In the present study, using in vivo single cell recording techniques, we investigated the electrophysiological characteristics of ventral tegmental area dopamine (VTA DA) neurons and their response to antipsychotic drugs in a KMO knock-out (K/O) mouse model. KMO K/O mice exhibited a marked increase in spontaneous VTA DA neuron activity as compared to wild-type (WT) mice. Furthermore, VTA DA neurons showed clear-cut, yet qualitatively opposite, responses to the antipsychotic drugs haloperidol and clozapine in the two genotypes. The anti-inflammatory drug parecoxib successfully lowered the firing activity of VTA DA neurons in KMO K/O, but not in WT mice. Minocycline, an antibiotic and anti-inflammatory drug, produced no effect in this regard. Taken together, the present data further support the usefulness of KMO K/O mice for studying distinct aspects of the pathophysiology and pharmacological treatment of psychiatric disorders such as schizophrenia.

Exhaustion of CD4+ T-cells mediated by the Kynurenine Pathway in Melanoma

“…In addition, CD4+ T-cells were less proliferative in culture with VE600wt MCLs compared with VE600E MCLs, which may reflect the critical role of elevated KYNA on the induction of CD4+ T-cell exhaustion in co-culture set-up. Additionally, the lower mRNA KMO expression in CD4+ T-cells and elevated level of KYNA upon co-culture may propose KMO as an enzyme that is crucial for determining the levels of KYNA, which has also been reported elsewhere 34 .…”

“…Our analysis run was based on the 2016_01_28 data run and included 368 metastatic SKCM samples. T-cell signature genes shown in previous studies 34 were used for clustering metastatic SKCM samples to T-cell signature high and low groups. For cluster analysis, we applied Ward’s method using the Euclidean distance, and a correlation coefficient was used for genes with the same method.…”

Comparative psychopharmacology of autism and psychotic-affective disorders suggests new targets for treatment

“…Concentrations of KYNA in cerebrospinal fluid are substantially increased among subjects with schizophrenia, across many studies ([111–114], meta-analysis in [115]); comparable increases are also found among subjects with bipolar disorder with (but not without) psychosis, and KYNA levels are associated directly with psychotic symptoms in both disorders [105]. Treatment with antipsychotics reduces levels on KYNA, from studies in rodents [116, 117].…”

Tryptophan Metabolism: A Versatile Area Providing Multiple Targets for Pharmacological Intervention

“…A glance at Figure 4 will show that KMO inhibition should result in the following important changes in KP metabolite formation in liver, plasma, brain and/or CSF: (1) accumulation of Kyn; (2) consequent to the increase in this substrate, production of KA by the KAT A and of AA by the kynureninase A reactions is increased; (3) decreased formation of 3-HK; (4) a consequent decrease in production of subsequent metabolites from the main oxidative route, namely 3-HAA, QA and PA and from the transamination arm leading to XA formation by KAT B. These changes, which have important implications for drug development for a variety of disease states, can be seen from published data of the effects of the KMO inhibitors m -nitrobenzoylalanine in rats [181, 182] and mice [183] and 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro-61-8048) in mice [184], and of the effects of targeted deletion of the KMO gene in mice [185, 186]. These changes are desirable for achieving protection against the patho-physiological disturbances encountered in many disease states.…”