A systemically-available kynurenine aminotransferase II (KAT II) inhibitor restores nicotine-evoked glutamatergic activity in the cortex of rats

Cherian, Ajeesh Koshy; Gritton, Howard J.; Johnson, David E.; Young, Damon; Kozak, Rouba; Sarter, Martin

doi:10.1016/j.neuropharm.2014.03.004

Cited by 46 publications

(31 citation statements)

References 36 publications

(52 reference statements)

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“…Kynurenic acid, in turn, acts as an antagonist of NMDA receptors, creating a hypoglutamatergic state with decreased brain-derived neurotrophic factor (BDNF) and ultimately potentiating the dopaminergic hyperfunction in the limbic system that is responsible for the development of positive symptoms characteristic of SZ. 15,[58][59][60] In our study, we found that positive symptoms appear to be most robustly linked to inflammation, with more severe symptomatology correlated to higher levels of CRP. Thus, a pro-inflammatory state with activation of the kynurenine pathway may be one possible explanation for the association of CRP with SZ.…”

Section: Discussionsupporting

confidence: 52%

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

et al. 2015

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The inflammatory hypothesis of schizophrenia (SZ) posits that inflammatory processes and neural-immune interactions are involved in its pathogenesis, and may underpin some of its neurobiological correlates. SZ is the psychiatric disorder causing the most severe burden of illness, not just owing to its psychiatric impairment, but also owing to its significant medical comorbidity. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation worldwide. There are some conflicting results regarding the behaviour of CRP in SZ. The aims of this study were to verify whether peripheral CRP levels are indeed increased in SZ, whether different classes of antipsychotics divergently modulate CRP levels and whether its levels are correlated with positive and negative symptomatology. With that in mind, we performed a meta-analysis of all cross-sectional studies of serum and plasma CRP levels in SZ compared to healthy subjects. In addition, we evaluated longitudinal studies on CRP levels before and after antipsychotic use. Our meta-analyses of CRP in SZ included a total of 26 cross-sectional or longitudinal studies comprising 85 000 participants. CRP levels were moderately increased in persons with SZ regardless of the use of antipsychotics and did not change between the first episode of psychosis and with progression of SZ (g=0.66, 95% confidence interval (95% CI) 0.43 to 0.88, P<0.001, 24 between-group comparisons, n=82 962). The extent of the increase in peripheral CRP levels paralleled the increase in severity of positive symptoms, but was unrelated to the severity of negative symptoms. CRP levels were also aligned with an increased body mass index. Conversely, higher age correlated with a smaller difference in CRP levels between persons with SZ and controls. Furthermore, CRP levels did not increase after initiation of antipsychotic medication notwithstanding whether these were typical or atypical antipsychotics (g=0.01, 95% CI -0.20 to 0.22, P=0.803, 8 within-group comparisons, n=713). In summary, our study provides further evidence of the inflammatory hypothesis of SZ. Whether there is a causal relationship between higher CRP levels and the development of SZ and aggravation of psychotic symptoms, or whether they are solely a marker of systemic low-grade inflammation in SZ, remains to be clarified.

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Section: Discussionsupporting

confidence: 52%

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

et al. 2015

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“…Recently the genetic , Potter et al, 2010 and pharmacological (Zmarowski et al, 2009, Koshy Cherian et al, 2014 inhibition of KATII has been studied primarily for the treatment of psychiatric and cognitive disorders (Jayawickrama et al, 2015). Kozak et al showed that lowering KYNA level with selective KATII inhibitor improves cognitive function under conditions considered relevant for schizophrenia in rats (2014).…”

Section: Therapeutical Manipulation Of Katii Expression and Kyna Syntmentioning

confidence: 99%

Astrocytic and neuronal localization of kynurenine aminotransferase-2 in the adult mouse brain

et al. 2016

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During catabolism of tryptophan through the kynurenine (KYN) pathway, several endogenous metabolites with neuromodulatory properties are produced, of which kynurenic acid (KYNA) is one of the highest significance. The causal role of altered KYNA production has been described in several neurodegenerative and neuropsychiatric disorders (e.g., Parkinson's disease, Huntington's disease, schizophrenia) and therefore kynurenergic manipulation with the aim of therapy has recently been proposed. Conventionally, KYNA is produced from its precursor L-KYN with the aid of the astrocytic kynurenine aminotransferase-2 (KAT-2) in the murine brain. Although the mouse is a standard therapeutic research organism, the presence of KAT-2 in mice has not been described in detail. This study demonstrates the presence of kat-2 mRNA and protein throughout the adult C57Bl6 mouse brain. In addition to the former expression data from the rat, we found prominent KAT-2 expression not only in the astrocyte, but also in neurons in several brain regions (e.g., hippocampus, substantia nigra, striatum, and prefrontal cortex). A significant number of the KAT-2 positive neurons were positive for GAD67; the presence of the KAT-2 enzyme we could also demonstrate in mice brain homogenate and in cells overexpressing recombinant mouse KAT-2 protein. This new finding attributes a new role to interneuron-derived KYNA in neuronal network operation. Furthermore, our results suggest that the thorough investigation of the spatio-temporal expression pattern of the relevant enzymes of the KYN pathway is a prerequisite for developing and understanding the pharmacological and transgenic murine models of kynurenergic manipulation.

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“…We therefore conclude that endogenous KYNA does not regulate stimulated glutamate release unless KYNA levels are elevated. This notion is supported by another study where a systemically-administered KAT II inhibitor, PF-04859989, was shown to restore nicotine-induced glutamate transients in PFC after kynurenine injections, but had no effect in the absence of exogenous kynurenine (Koshy Cherian et al, 2014). …”

Section: 0 Discussionmentioning

confidence: 75%

“…Additionally, the first-generation KAT II inhibitor S -ESBA demonstrates pro-cognitive effects following intracerebral infusion in intact rats (Pocivavsek et al, 2012). Second-generation KAT II inhibitors were recently developed that are active in brain following systemic administration (Tuttle et al, 2013; Dounay et al, 2013; Koshy Cherian et al, 2014; Kozak et al, 2014). One of these compounds, the orally available BFF816, was not only found to reduce extracellular KYNA and increase extracellular glutamate levels in the rat hippocampus, but also to improve the performance of intact rats in the Morris water maze (Wu et al, 2014).…”

Section: 0 Introductionmentioning

confidence: 99%

Oral administration of a specific kynurenic acid synthesis (KAT II) inhibitor attenuates evoked glutamate release in rat prefrontal cortex

Bortz

Schwarcz

et al. 2017

Neuropharmacology

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Cognitive deficits represent core symptoms in schizophrenia (SZ) and predict patient outcome; however, they remain poorly treated by current antipsychotic drugs. Elevated levels of the endogenous alpha7 nicotinic receptor negative allosteric modulator and NMDA receptor antagonist, kynurenic acid (KYNA), are commonly seen in post-mortem tissue and cerebrospinal fluid of patients with SZ. When acutely or chronically elevated in rodents, KYNA produces cognitive deficits similar to those seen in the disease, making down-regulation of KYNA, via inhibition of kynurenine aminotransferase II (KAT II), a potential treatment strategy. We determined, in adult Wistar rats, if the orally available KAT II inhibitor BFF816 a) prevents KYNA elevations in prefrontal cortex (PFC) after a systemic kynurenine injection and b) reverses the kynurenine-induced attenuation of evoked prefrontal glutamate release caused by stimulation of the nucleus accumbens shell (NAcSh). Systemic injection of kynurenine (25 or 100 mg/kg, i.p.) increased KYNA levels in PFC (532% and 1104% of baseline, respectively). NMDA infusions (0.15 μg/0.5 μL) into NAcSh raised prefrontal glutamate levels more than 30-fold above baseline. The two doses of kynurenine reduced evoked glutamate release in PFC (by 43% and 94%, respectively, compared to NMDA alone). Co-administration of BFF816 (30 or 100 mg/kg, p.o.) with kynurenine (25 mg/kg, i.p.) attenuated the neosynthesis of KYNA and dose-dependently restored NMDA-stimulated glutamate release in the PFC (16% and 69%, respectively). The ability to prevent KYNA neosynthesis and to normalize evoked glutamate release in PFC justifies further development of KAT II inhibitors for the treatment of cognitive deficits in SZ.

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A systemically-available kynurenine aminotransferase II (KAT II) inhibitor restores nicotine-evoked glutamatergic activity in the cortex of rats

Cited by 46 publications

References 36 publications

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications

Astrocytic and neuronal localization of kynurenine aminotransferase-2 in the adult mouse brain

Oral administration of a specific kynurenic acid synthesis (KAT II) inhibitor attenuates evoked glutamate release in rat prefrontal cortex

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