Brain KAT II is predominantly expressed in astrocytes in comparison to other neural cell kinds (Kiss et al., 2003; Guidetti et al., 2007b). Indeed, protein expression of TDO2 is selectively upregulated in white matter astrocytes of post-mortem frontal cortex of schizophrenic patients in comparison with that from handle subjects, coincident using a considerable elevation of TDO2 but not IDO mRNA levels (Miller et al., 2004). Similar results had been obtained for post-mortem anterior cingulate cortex of subjects with schizophrenia and bipolar disorder, accompanied by an increaseFrontiers in Neuroscience | Neuroendocrine ScienceFebruary 2014 | Volume 8 | Post 12 |Campbell et al.Kynurenines in CNS diseasein tissue levels of L-KYN in comparison with controls (Miller et al., 2006). Hence, selective upregulation of astrocytic TDO2-mediated L-KYN synthesis may partially account for the overproduction of KYNA in brain regions implicated in cognitive impairment related with schizophrenia. Regulatory mechanisms governing astrocytic TDO2 expression are not well-understood, even though it really is worth noting that the regulatory area with the gene encoding both human and rat TDO2 contain a minimum of two glucocorticoid response elements (GREs), and TDO2 mRNA is induced by dexamethasone in rat liver (Danesch et al., 1983, 1987; Comings et al., 1995). Given this, it truly is tempting to speculate that, unlike the microglial branch in the KP, activity from the KYNA-producing astrocytic branch may possibly be positively regulated by anti-inflammatory, as opposed to by proinflammatory signaling. That is consistent together with the enhancement of brain KYNA production following administration with the COX-2 inhibitor parecoxib in rat (Schwieler et al., 2006), although the mechanism underlying this impact is unknown. An additional mechanism by which L-KYN availability for KAT II-mediated TMS site metabolism could be enhanced is by means of suppression of KMO expression andor enzyme activity. KMO exhibits a somewhat high affinity for L-KYN compared to that of KAT II, and thus exerts preferential handle over the fate of LKYN. As a result, reduction in KMO activity is anticipated to increase the availability of L-KYN for KAT II-mediated metabolism, an impact which has been demonstrated experimentally making use of the KMO inhibitor JM-6 (Zwilling et al., 2011). Lately it has been reported that a coding SNP inside the human KMO gene is connected with lowered KMO mRNA expression and elevated CSF KYNA in bipolar patients with psychotic attributes in the course of mania (Lavebratt et al., 2013). Moreover, an intronic SNP within the human KMO gene is related with decreased KMO mRNA expression and impaired schizophrenia-related endophenotypes (Wonodi et al., 2011). Hence, disease-relevant genetic impairment of KMO expressionactivity could play a contributing function in the overproduction of KYNA in schizophrenia and related psychiatric disorders. It remains to become noticed, even so, irrespective of whether KMO expressionactivity may possibly be similarly influenced by dysregulated inflammatory signaling connected with these issues. As discussed earlier, expression of each IDO and KMO is induced by proinflammatory cytokines including IFN-. Conversely, IFN-mediated IDO expression is inhibited by IL-4 and IL-13 (Musso et al., 1994; Chaves et al., 2001), even though opposing results have been reported (Yadav et al., 2007). Due to the fact IDO and KMO expression seem to be positively regulated by equivalent mechanisms, it would be 2-Methoxy-4-vinylphenol Technical Information intriguing to determine regardless of whether KMO expression is similarly inhibited by IL-4 andor I.