Targeting Kynurenine Aminotransferase II in Psychiatric Diseases: Promising Effects of an Orally Active Enzyme Inhibitor

Wu, Hui‐Qiu; Okuyama, Masahiro; Kajii, Yasushi; Pocivavsek, Ana; Bruno, John P.; Schwarcz, Robert

doi:10.1093/schbul/sbt157

Cited by 68 publications

(75 citation statements)

References 48 publications

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“…Kynurenic acid, in turn, acts as an antagonist of NMDA receptors, creating a hypoglutamatergic state with decreased brain-derived neurotrophic factor (BDNF) and ultimately potentiating the dopaminergic hyperfunction in the limbic system that is responsible for the development of positive symptoms characteristic of SZ. 15,[58][59][60] In our study, we found that positive symptoms appear to be most robustly linked to inflammation, with more severe symptomatology correlated to higher levels of CRP. Thus, a pro-inflammatory state with activation of the kynurenine pathway may be one possible explanation for the association of CRP with SZ.…”

Section: Discussionsupporting

confidence: 52%

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

et al. 2015

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The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural-immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g=0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P<0.001, 24 between-group comparisons, n=82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g=0.01, 95% CI -0.20 to 0.22, P=0.803, 8 within-group comparisons, n=713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.

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Section: Discussionsupporting

confidence: 52%

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

et al. 2015

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“…A possible explanation is that KAT I (despite the name) may not be a major source of kynurenate in the brain. Indeed, it appears that workers in the field have recently emphasized the importance of KAT II as the major source of kynurenate in the brain (Potter et al 2010;Sathyasaikumar et al 2011;Wu et al 2014). Nevertheless, there is some evidence that KAT I/ GTK may have a neuroprotective role.…”

Section: Glutamine Transaminases and Cysteine S-conjugate β-Lyasesmentioning

confidence: 99%

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

et al. 2015

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In mammals, two major routes exist for the metabolic conversion of L-glutamine to α-ketoglutarate. The most widely studied pathway involves the hydrolysis of L-glutamine to L-glutamate catalyzed by glutaminases, followed by the conversion of L-glutamate to α-ketoglutarate by the action of an L-glutamate-linked aminotransferase or via the glutamate dehydrogenase reaction. However, another major pathway exists in mammals for the conversion of L-glutamine to α-ketoglutarate (the glutaminase II pathway) in which L-glutamine is first transaminated to α-ketoglutaramate (KGM) followed by hydrolysis of KGM to α-ketoglutarate and ammonia catalyzed by an amidase known as ω-amidase. In mammals, the glutaminase II pathway is present in both cytosolic and mitochondrial compartments and is most prominent in liver and kidney. Similarly, two routes exist for the conversion of L-asparagine to oxaloacetate. In the most extensively studied pathway, L-asparagine is hydrolyzed to L-aspartate by the action of asparaginase, followed by transamination of L-aspartate to oxaloacetate. However, another pathway also exists for the conversion of L-asparagine to oxaloacetate (the asparaginase II pathway). In this pathway, L-asparagine is first transaminated to α-ketosuccinamate (KSM), followed by hydrolysis of KSM to oxaloacetate by the action of ω-amidase. One advantage of both the glutaminase II and the asparaginase II pathways is that they are irreversible, and thus are important in anaplerosis by shuttling 5-C (α-ketoglutarate) and 4-C (oxaloacetate) units into the TCA cycle. In this review, we briefly mention the importance of the glutaminase II and asparaginase II pathways in microorganisms and plants. However, the major emphasis of the review is related to the importance of these pathways (especially the common enzyme component of both pathways--ω-amidase) in nitrogen and sulfur metabolism in mammals and as a source of anaplerotic carbon moieties in rapidly dividing cells. The review also discusses a potential dichotomous function of ω-amidase as having a role in tumor progression. Finally, the possible role of KGM as a biomarker for hyperammonemic diseases is discussed.

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“…As ɑ7nACh and NMDA receptors, which likely serve as preferential targets of KYNA in the mammalian brain in vivo (26, 27), are critical to neurogenesis and play central roles in modulating neuronal migration and integration during brain maturation (72–76), we suspect that prolonged inhibition of these receptors, particularly during developmental periods, may be causally related to the behavioral phenotypes seen in adult Kmo −/− mice. Using biochemical, electrophysiological and behavioral outcome measures, experiments currently in progress in our laboratories are designed, inter alia , to investigate the impact of prenatal insults in both Kmo −/− and heterozygous ( Kmo +/− ) animals (77) and to evaluate genetic and pharmacological approaches to experimentally down-regulate brain KYNA levels in Kmo −/− mice (78, 79). However, caution is indicated when extrapolating studies with knock-out mice to pathological conditions in humans (80) and when assuming direct correlations between central and peripheral measures of KP metabolism (19).…”

Section: Discussionmentioning

confidence: 99%

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

Erhardt

Pocivavsek

Repici

et al. 2017

Biological Psychiatry

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BACKGROUND Kynurenine 3-monooxygenase (KMO) converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway - which is implicated as dysfunctional in various psychiatric disorders - towards enhanced synthesis of kynurenic acid (KYNA), an antagonist of both α7 nicotinic acetylcholine and NMDA receptors. Possibly as a result of reduced KMO activity, elevated central nervous system levels of KYNA have been found in patients with psychotic disorders, including schizophrenia (SZ). METHODS In the present study, we investigated adaptive – and possibly regulatory – changes in mice with a targeted deletion of Kmo (Kmo−/−) and characterized the KMO-deficient mice using six behavioral assays relevant for the study of SZ. RESULTS Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of SZ- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. KYNA levels were also increased in these brain regions in Kmo−/− mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo−/− mice exhibited impairments in contextual memory and spent less time than controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light-dark box. After a D-amphetamine challenge (5 mg/kg, i.p.), Kmo−/− mice showed potentiated horizontal activity in the open field paradigm. CONCLUSIONS Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.

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Targeting Kynurenine Aminotransferase II in Psychiatric Diseases: Promising Effects of an Orally Active Enzyme Inhibitor

Cited by 68 publications

References 48 publications

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

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