Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals With Schizophrenia
Citations
1,097 citations
664 citations
342 citations
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)....
[...]
280 citations
References
176 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....
[...]
...This further supports the notion that distinct, rather than generalized, KP impairments exist in the brain of patients with SZ....
[...]
...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....
[...]
...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....
[...]
...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....
[...]
167 citations
166 citations
"Impaired Kynurenine Pathway Metabol..." refers background in this paper
...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)...
[...]
166 citations
159 citations