Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals With Schizophrenia
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...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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"Impaired Kynurenine Pathway Metabol..." refers background in this paper
...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 glutamate(14,15,20) by initially targeting and thus reducing the activity of a7nAChRs....
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...We reported previously that KYNA levels in the PFC are significantly elevated in individuals with SZ.(22) The present study constitutes a first effort to explore the cause(s) of these high KYNA levels....
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...Postmortem analysis reveals that kynurenine levels are elevated in the PFC of patients, and this increase is correlated with KYNA levels in the same tissue.(22) The explanation for this nexus seems unambiguous because the high Km of KAT II and all other cerebral kynurenine aminotransferases allows for a proportional increase in KYNA formation when kynurenine levels rise....
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...The question then arises whether and how specific impairments in KP enzymes might account for the significant increases in prefrontal KYNA levels in SZ, which were originally described in 2001.(22) The most parsimonious explanation would be that a reduction in KMO activity eventually triggers a shift in cerebral KP metabolism Fig....
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"Impaired Kynurenine Pathway Metabol..." refers background in this paper
...In the brain, kynurenine gives rise to two physically segregated branches of the pathway, producing 3-hydroxykynurenine and its downstream metabolites 3-hydroxyanthranilic acid and quinolinic acid in microglial cells and KYNA in astrocytes (cf Introduction).(23) Excessive formation of the three microglial compounds, which are neurotoxins and generators of highly reactive free radicals, may play significant roles in brain pathology....
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...In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ....
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...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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