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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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
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
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
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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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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TL;DR: The results suggest that kynurenic acid contributes to the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency in glutamatergic function in this disease.
154 citations
"Impaired Kynurenine Pathway Metabol..." refers background in this paper
...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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...This further supports the notion that distinct, rather than generalized, KP impairments exist in the brain of patients with SZ....
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...Alternatively or quite possibly in addition, kynurenine levels in the SZ brain might be elevated due to increased activity of the biosynthetic enzymes tryptophan 2,3- dioxygenase60 or indoleamine-2,3-dioxygenase.43 Notably, these two enzymes, like the entire cerebral KP pathway, are preferentially localized in glial cells,23,60–62 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.22,64 Within the PFC, astrocyte-derived KYNA controls the levels of acetylcholine and glutamate14,15,20 by initially targeting and thus reducing the activity of a7nAChRs.12 Thus, increased KYNA levels trigger or exacerbate the nicotinergic and glutamatergic deficits, which have been credibly linked to both cognitive dysfunctions and psychotic manifestations in humans (cf Introduction).1–3,65,66 The demonstration of distinct impairments in cerebral KP metabolism in SZ, which are also observed in the basal ganglia,67 raises the prospect that more than one KP enzyme could be targeted to provide clinical benefits in the disease....
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...We have previously proposed that this can be exploited for the treatment of Huntington’s disease and other neurodegenerative disorders by cautiously targeting KMO with specific enzyme inhibitors.40 The present study revealed a significant decrease in KMO activity in the PFC of individuals with SZ....
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...Thus, while the precise nature and causes of the abnormalities are not well understood, and although there is an increased awareness of additional factors,7–9 there is general consensus that changes in cholinergic and glutamatergic function are critically involved in the pathophysiology of SZ.10,11 Recent studies suggest that kynurenic acid (KYNA), a metabolite produced in a dead-end side arm of the kynurenine pathway (KP) of tryptophan degradation (figure 1), might also be involved in prefrontal dysfunctions in SZ....
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TL;DR: This review synthesizes the current knowledge on the neurobiology of psychosis from an array of in vivo brain-imaging studies and consistently replicated associations of psychotic symptoms and cognitive impairment in both structural and functional imaging in schizophrenia but not in bipolar disorder.
Abstract: This review synthesizes our current knowledge on the neurobiology of psychosis from an array of in vivo brain-imaging studies. The evidence base consists of hundreds of studies of patients with schizophrenia and fewer on bipolar disorder but rarely providing direct comparisons between the disorders or integration across methods. Replicated findings in schizophrenia include reduced whole-brain and hippocampal volume as potential vulnerability markers, with further progression at onset; reduced N-acetyl aspartate concentrations in hippocampus and prefrontal cortex; striatal dopamine D(2) receptors upregulation; and alteration in the relation between frontal and temporal activation. These findings are not attributable to medication effects but are of unclear specificity and may apply across the psychosis spectrum. There are consistently replicated associations of psychotic symptoms and cognitive impairment in both structural and functional imaging in schizophrenia but not, as yet, in bipolar disorder. Therefore, it would be premature to dispense with current diagnostic categories because direct comparisons among them are rare, insufficient studies have examined longitudinal changes, and long-term imaging outcome studies in first-episode psychosis have not yet been done. To address these issues and make neuroimaging "clinically relevant," investigators will need to standardize their approaches to data acquisition and analysis, and construct the necessary range of "human brain maps," to implement studies that are sufficiently powered to provide reliable data pertinent to deconstructing psychosis.
144 citations
TL;DR: A remarkable functional segregation of the two pathway branches in the brain is indicated, boding well for the development of selective KAT II or KMO inhibitors for cognitive enhancement and neuroprotection, respectively.
Abstract: In the mammalian brain, kynurenine aminotransferase II (KAT II) and kynurenine 3-monooxygenase (KMO), key enzymes of the kynurenine pathway (KP) of tryptophan degradation, form the neuroactive metabolites kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), respectively. Although physically segregated, both enzymes use the pivotal KP metabolite l-kynurenine as a substrate. We studied the functional consequences of this cellular compartmentalization in vivo using two specific tools, the KAT II inhibitor BFF 122 and the KMO inhibitor UPF 648. The acute effects of selective KAT II or KMO inhibition were studied using a radiotracing method in which the de novo synthesis of KYNA, and of 3-HK and its downstream metabolite quinolinic acid (QUIN), is monitored following an intrastriatal injection of (3)H-kynurenine. In naive rats, intrastriatal BFF 122 decreased newly formed KYNA by 66%, without influencing 3-HK or QUIN production. Conversely, UPF 648 reduced 3-HK synthesis (by 64%) without affecting KYNA formation. Similar, selective effects of KAT II and KMO inhibition were observed when the inhibitors were applied acutely together with the excitotoxin QUIN, which impairs local KP metabolism. Somewhat different effects of KMO (but not KAT II) inhibition were obtained in rats that had received an intrastriatal QUIN injection 7 days earlier. In these neuron-depleted striata, UPF 648 not only decreased both 3-HK and QUIN production (by 77% and 66%, respectively) but also moderately raised KYNA synthesis (by 27%). These results indicate a remarkable functional segregation of the two pathway branches in the brain, boding well for the development of selective KAT II or KMO inhibitors for cognitive enhancement and neuroprotection, respectively.
135 citations
"Impaired Kynurenine Pathway Metabol..." refers background in this paper
...As demonstrated in a recent in vivo study in rats, such a redirection of KP metabolism toward increased KYNA synthesis does not occur in the normal brain when KMO activity is acutely reduced by pharmacological means.(54) However, KYNA production is indeed enhanced under these conditions when the experiment is performed in injured brain tissue where glial functions are abnormal....
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...However, KYNA production is indeed enhanced under these conditions when the experiment is performed in injured brain tissue where glial functions are abnormal.(54) This mechanism may therefore also operate in SZ, where microglial and astrocytic anomalies in the PFC have been repeatedly described (see above)....
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TL;DR: Measurements of brain 3HA0 indicate that measurements of brain may yield significant information concerning a possible role of quinolinic acid in brain function and/or dysfunction.
Abstract: In mammalian peripheral organs, 3-hydroxyanthranilic acid oxygenase (3HAO), catalyzing the conversion of 3-hydroxyanthranilic acid to quinolinic acid, constitutes a link in the catabolic pathway of tryptophan to NAD Because of the possible involvement of quinolinic acid in the initiation of neurodegenerative phenomena, we examined the presence and characteristics of 3HAO in rat brain tissue A simple and sensitive assay method, based on the use of [carboxy-14C]3-hydroxyanthranilic acid as a substrate, was developed and the enzymatic product, [14C]quinolinic acid, identified by chromatographic and biochemical means Kinetic analysis of rat forebrain 3HAO revealed a Km of 36 +/- 05 microM for 3-hydroxyanthranilic acid and a Vmax of 737 +/- 95 pmol quinolinic acid/h/mg tissue The enzyme showed pronounced selectivity for its substrate, since several substances structurally and metabolically related to 3-hydroxyanthranilic acid caused less than 25% inhibition of activity at 500 microM Both the Fe2+ dependency and the distinct subcellular distribution (soluble fraction) of brain 3HAO indicated a close resemblance to 3HAO from peripheral tissues Examination of the regional distribution in the brain demonstrated a 10-fold variation between the region of highest (olfactory bulb) and lowest (retina) 3HAO activity The brain enzyme was present at the earliest age tested (7 days postnatum) and increased to 167% at 15 days before reaching adult levels Enzyme activity was stable over extended periods of storage at -80 degrees C Taken together, these data indicate that measurements of brain 3HAO may yield significant information concerning a possible role of quinolinic acid in brain function and/or dysfunction
135 citations
"Impaired Kynurenine Pathway Metabol..." refers methods in this paper
...The supernatant, containing newly formed (14)Cquinolinic acid, was applied to a Dowex 50W (Hþ-form) cation exchange column, and radioactivity in the eluate was quantitated by liquid scintillation spectrometry.(28)...
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TL;DR: It is shown that nanomolar concentrations of KYNA, infused directly or produced in situ from its bioprecursor kynurenine, significantly decrease extracellular glutamate levels in the prefrontal cortex, and fluctuations in endogenous KYNA formation bidirectionally influence cortical glutamate concentrations.
Abstract: The cognitive deficits seen in schizophrenia patients are likely related to abnormal glutamatergic and cholinergic neurotransmission in the prefrontal cortex. We hypothesized that these impairments may be secondary to increased levels of the astrocyte-derived metabolite kynurenic acid (KYNA), which inhibits α7 nicotinic acetylcholine receptors (α7AChR) and may thereby reduce glutamate release. Using in vivo microdialysis in unanesthetized rats, we show here that nanomolar concentrations of KYNA, infused directly or produced in situ from its bioprecursor kynurenine, significantly decrease extracellular glutamate levels in the prefrontal cortex. This effect was prevented by the systemic administration of galantamine (3 mg/kg) but not by donepezil (2 mg/kg), indicating that KYNA blocks the allosteric potentiating site of the α7AChR, which recognizes galantamine but not donepezil as an agonist. In separate rats, reduction of prefrontal KYNA formation by (S)-4-ethylsulfonyl benzoylalanine, a specific inhibitor of KYNA synthesis, caused a significant elevation in extracellular glutamate levels. Jointly, our results demonstrate that fluctuations in endogenous KYNA formation bidirectionally influence cortical glutamate concentrations. These findings suggest that selective attenuation of cerebral KYNA production, by increasing glutamatergic tone, might improve cognitive function in individuals with schizophrenia.
133 citations