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Journal ArticleDOI

Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals With Schizophrenia

TL;DR: The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.
Abstract: The levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the branched kynurenine pathway (KP) of tryptophan degradation and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, are elevated in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). Because endogenous KYNA modulates extracellular glutamate and acetylcholine levels in the PFC, these increases may be pathophysiologically significant. Using brain tissue from SZ patients and matched controls, we now measured the activity of several KP enzymes (kynurenine 3-monooxygenase [KMO], kynureninase, 3-hydroxyanthranilic acid dioxygenase [3-HAO], quinolinic acid phosphoribosyltransferase [QPRT], and kynurenine aminotransferase II [KAT II]) in the PFC, ie, Brodmann areas (BA) 9 and 10. Compared with controls, the activities of KMO (in BA 9 and 10) and 3-HAO (in BA 9) were significantly reduced in SZ, though there were no significant differences between patients and controls in kynureninase, QPRT, and KAT II. In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ. As examined in rats treated chronically with the antipsychotic drug risperidone, the observed biochemical changes were not secondary to medication. A persistent reduction in KMO activity may have a particular bearing on pathology because it may signify a shift of KP metabolism toward enhanced KYNA synthesis. The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.

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Journal ArticleDOI
TL;DR: With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions on the basis of the kynurenine pathway.
Abstract: The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

1,097 citations

Journal ArticleDOI
TL;DR: An overview of the physiological and pathophysiological roles of tryptophan metabolism is provided, focusing on the clinical potential and challenges associated with targeting this pathway.
Abstract: L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.

664 citations

Journal ArticleDOI
TL;DR: Support for the relevance of a low-level neuroinflammatory process in schizophrenia is provided by the loss of central nervous system volume and microglial activation demonstrated in neuroimaging studies, and the benefit of anti-inflammatory medications found in some studies and the intrinsic anti- inflammatory and immunomodulatory effects of antipsychotics provide further support for the role of inflammation in this debilitating disease.
Abstract: This paper discusses the current evidence from animal and human studies for a central role of inflammation in schizophrenia. In animal models, pre- or perinatal elicitation of the immune response may increase immune reactivity throughout life, and similar findings have been described in humans. Levels of pro-inflammatory markers, such as cytokines, have been found to be increased in the blood and cerebrospinal fluid of patients with schizophrenia. Numerous epidemiological and clinical studies have provided evidence that various infectious agents are risk factors for schizophrenia and other psychoses. For example, a large-scale epidemiological study performed in Denmark clearly showed that severe infections and autoimmune disorders are such risk factors. The vulnerability-stress-inflammation model may help to explain the role of inflammation in schizophrenia because stress can increase pro-inflammatory cytokines and may even contribute to a chronic pro-inflammatory state. Schizophrenia is characterized by risk genes that promote inflammation and by environmental stress factors and alterations of the immune system. Typical alterations of dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission described in schizophrenia have also been found in low-level neuroinflammation and consequently may be key factors in the generation of schizophrenia symptoms. Further support for the relevance of a low-level neuroinflammatory process in schizophrenia is provided by the loss of central nervous system volume and microglial activation demonstrated in neuroimaging studies. Last but not least, the benefit of anti-inflammatory medications found in some studies and the intrinsic anti-inflammatory and immunomodulatory effects of antipsychotics provide further support for the role of inflammation in this debilitating disease.

342 citations

Journal ArticleDOI
TL;DR: Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.
Abstract: High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.

324 citations


Cites background from "Impaired Kynurenine Pathway Metabol..."

  • ...Elevated kynurenic acid has mainly been described in the CSF (Erhardt et al., 2001; Linderholm et al., 2012), in the brains of schizophrenia patients (Schwarcz et al., 2001; Sathyasaikumar et al., 2011) and in animal models of schizophrenia (Olsson et al., 2009)....

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Journal ArticleDOI
TL;DR: The purposes of this special feature are to clarify the key findings on inflammation in schizophrenia, identify major gaps in the literature, and suggest priorities for research in this area.
Abstract: An association between inflammatory abnormalities and schizophrenia has been found repeatedly. The purposes of this special feature are to clarify the key findings on inflammation in schizophrenia, identify major gaps in the literature, and suggest priorities for research in this area. What is inflammation? Inflammation is one of the body’s first lines of defense in response to injury or infection, and increased inflammation is found in many diseases. Acute inflammation is a nonspecific response characterized by warmth, pain, and swelling. Leukocytes migrate to the area of injury and become activated, the blood supply to the area increases, and blood vessels become more permeable, allowing cells and molecules to leave blood vessels and enter the injured tissue. The inflammatory response also involves the complement system, a group of proteins that, when activated, combine to form a complex molecular structure that kills cells, usually bacteria and parasites. Cytokines are key molecules that regulate inflammation; they also have important roles in the immune system. They are produced by a wide variety of immune cells and cells outside of the immune system. The term cytokine derives from their ability to influence the movement of inflammatory cells, but they also have other functions. Chronic inflammation is usually a lower grade response, lacks the grossly visible signs of acute inflammation, and may be systemic rather than localized. Chronic inflammation plays a role in the pathophysiology of many chronic diseases, including cardiovascular and cerebrovascular disease, diabetes, Alzheimer’s disease, and some cancers. The characteristics of chronic inflammation differ somewhat in the brain from what occurs in other tissues. An important component of neuroinflammation is the microglial activation. The brain contains relatively few of the inflammatory cells that are found outside the brain. Microglia, which are related to the peripheral inflammatory cells, serve some of the protective functions such cells play in the rest of the body. Microglia are involved in other brain functions, including the pruning and maintenance of synapses, trafficking of neurotransmitters, and devouring—phagocytosis—of cell fragments and damaged cells. Activated microglia produce inflammatory cytokines and the phagocytose cells or proteins that provoke the inflammatory response. Microglial activation and subsequent proinflammatory cytokine production may disrupt the blood-brain barrier (BBB). An intact BBB usually tightly controls the entry of cytokines and leukocytes into brain tissue. Damage to the BBB impairs its ability to control which inflammatory cells and molecules enter the brain; other substances leak into brain tissue, and the brain is unable to function normally.

280 citations

References
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Journal ArticleDOI
TL;DR: Inhibition of the JNK pathway may provide a new therapy for inflammatory depression and extend to microglia the property that LPS induces IDO expression via an IFNgamma-independent mechanism that depends upon activation of JNK.
Abstract: Inflammation-induced activation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) causes depressive-like behavior in mice following acute activation of the innate immune system by lipopolysaccharide (LPS) Here we investigated the mechanism of IDO expression induced by LPS in primary cultures of microglia derived from neonatal C57BL/6J mice LPS (10 ng/ml) induced IDO transcripts that peaked at 8 h and enzymatic activity at 24 h, resulting in an increase in extracellular kynurenine, the catabolic product of IDO-induced tryptophan catabolism This IDO induction by LPS was accompanied by synthesis and secretion of the proinflammatory cytokines TNFα and IL-6, but without detectable IFNγ expression To explore the mechanism of LPS-induced IDO expression, microglia were pretreated with the c-Jun-N-terminal kinase (JNK) inhibitor SP600125 for 30 min before LPS treatment We found that SP600125 blocked JNK phosphorylation and significantly decreased IDO expression induced by LPS, which was accompanied by a reduction of LPS-induced expression of TNFα and IL-6 Collectively, these data extend to microglia the property that LPS induces IDO expression via an IFNγ-independent mechanism that depends upon activation of JNK Inhibition of the JNK pathway may provide a new therapy for inflammatory depression

77 citations


"Impaired Kynurenine Pathway Metabol..." refers background in this paper

  • ...Notably, these two enzymes, like the entire cerebral KP pathway, are preferentially localized in glial cells, and newly produced kynurenine is readily liberated into the extracellular compartment.(63) Irrespective of the underlying enzymatic and cellular mechanism(s), there are reasons to assume that the observed increase in prefrontal KYNA levels plays a role in the pathophysiology of SZ....

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Journal ArticleDOI
TL;DR: Analysis of major pre- and post-mortem variables showed that none were confounding for these between-group experimental comparisons, and known regulators of one of the key kynurenine-producing enzymes, tryptophan 2,3-dioxygenase (TDO2), were investigated.

75 citations

Journal Article
TL;DR: Treatment of chronic schizophrenics should involve the supply of agents to prevent degeneration of microglia and/or long-term immunotherapy, and morphological signs of the former normal function of immunocompetent and phagocytosing cells.
Abstract: Schizophrenia is a social disease that occurs in 0.5-1% of the population. It shows a high variability in both clinical picture and theory of its pathogenesis. Its clinical manifestations are accompanied by biochemical, immunological and structural changes. A pivotal role in the development of psychotic disorders is attributed to the impaired limbic system. The aim of this study was to find out whether, and if so, to what extent immunocompetent cells of the central nervous system (microglia) are involved in the process of degeneration occuring in these structures. The study was carried out on 12 brains of female chronic schizophrenics. Sections of frontal and temporal cortex were subjected to ultrastructural as well as histochemical and immunohistochemical examinations by light microscopy. In the structures under study, a large number of ramified microglial cells showing on their surface the expression of the major histocompatibility complex class II (MHC II) was observed. Most cells showed degenerative traits (cytoplasm shrinkage, thinning, shortening and fragmentation of their processes) up to apoptotic changes. Perivascular microglia displayed the lowest intensity of degenerative changes. Ultrastructurally, some damaged microglial cells contained phagosomes and/or degenerated mitochondria. Most abnormal microglia showed morphological signs of the former normal function of immunocompetent and phagocytosing cells. Degeneration of microgial cells, resulting most likely from the primary impairment of the neuron-glia communication that damages their immunocompetent function, may lead to the exacerbation of structural damage and psychotic symptoms. Treatment of chronic schizophrenics should involve the supply of agents to prevent degeneration of microglia and/or long-term immunotherapy.

61 citations