Inhibition of kynurenine aminotransferase II attenuates hippocampus‐dependent memory deficit in adult rats treated prenatally with kynurenine

Pocivavsek, Ana; Elmer, Gregory I.; Schwarcz, Robert

doi:10.1002/hipo.23040

Cited by 47 publications

(59 citation statements)

References 38 publications

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“…These changes resulted in significant molecular, structural, immunocytochemical and functional (electrophysiological) changes in neonates produced by the treated dams and changes in all these parameters persisted into adulthood (161)(162)(163)(164). Similar results were obtained by the administration of kynurenine itself to pregnant animals (196)(197)(198)(199), and in animals lacking KMO by genetic manipulation (165,166).…”

Section: Embryonic Developmentsupporting

confidence: 52%

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

et al. 2020

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The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.

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Section: Embryonic Developmentsupporting

confidence: 52%

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

et al. 2020

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“…Some of the negative effects of prenatal THC treatment on cognitive functions in the offspring resemble those observed in adult rats that had been prenatally exposed to Lkynurenine ("kynurenine"), a pivotal metabolite of the kynurenine pathway (KP) of tryptophan degradation (Pocivavsek et al, 2014(Pocivavsek et al, , 2019 during the final week of gestation. Circulating kynurenine readily crosses the blood-brain barrier, as well as the placental barrier, and is then readily converted to kynurenic acid (KYNA), which has remarkable neuroactive properties ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…In humans, particular attention has been paid to the cognitive deficits of persons with SZ in this regard since KYNA levels are elevated in cerebrospinal fluid and in the PFC (assessed post mortem) in the disease (Erhardt et al, 2001;Schwarcz et al, 2001;Wonodi and Schwarcz, 2010;Sathyasaikumar et al, 2011;Linderholm et al, 2012). Of considerable interest in this context, the cognitive abnormalities seen in adult offspring of rats which were administered kynurenine prenatally (see above) are associated with increased cerebral KYNA levels (Pocivavsek et al, 2014(Pocivavsek et al, , 2019).…”

Section: Introductionmentioning

confidence: 99%

Prenatal THC exposure raises kynurenic acid levels in the prefrontal cortex of adult rats

Beggiato

Ieraci

Tomasini

et al. 2020

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Cannabis remains one of the most widely used illicit drugs during pregnancy. The main psychoactive component of marijuana (Δ 9-tetrahydrocannabinol, THC) is correlated with untoward physiological effects in the offspring. Neurobehavioral and cognitive impairments have been reported in longitudinal studies on children and adolescents prenatally exposed to marijuana, and a link to psychiatric disorders has been proposed. Interestingly, the deleterious effects of prenatal cannabis use are similar to those observed in adult rats prenatally exposed to (L)kynurenine, the direct bioprecursor of the neuroactive metabolite kynurenic acid (KYNA). We therefore investigated whether alterations in KYNA levels in the rat brain might play a role in the long-term consequences of prenatal cannabinoid exposure. Pregnant Wistar rats were treated daily with THC [5 mg/kg, p.o.] from gestational day (GD)5 through GD20. Using in vivo microdialysis in the medial prefrontal cortex, adult animals were then used to determine the extracellular levels of KYNA and glutamate. Compared to controls, extracellular basal KYNA levels were higher, and basal glutamate levels were lower, in prenatally THC-exposed rats. These rats also showed abnormal short-term memory. Following an additional acute challenge with a low dose of *

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“…BFF816 indeed improves performance in the Morris water maze after acute administration in intact rats (Wu et al, 2014). Moreover, preliminary results indicate that BFF816 is able to reverse cognitive deficits in a well-validated neurodevelopmental animal preparation that duplicates several cognitive impairments seen in SZ (Pocivavsek et al, SFN abstract 2014). …”

Section: 0 Discussionmentioning

confidence: 88%

“…the MEA; Bortz et al, 2014; Bortz et al, 2016). The glutamate signal measured by this method has been referred to as phasic based on its high temporal resolution and faster kinetics (Burmeister & Gerhardt, 2001; Bortz et al, 2014; Parikh et al, 2008; Pocivavsek et al, SFN abstract 2014). It is not known, however, if this signal is caused by a single release event or by several signals that are captured under a single symmetrical wave form due to limited temporal resolution.…”

Section: 0 Discussionmentioning

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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Inhibition of kynurenine aminotransferase II attenuates hippocampus‐dependent memory deficit in adult rats treated prenatally with kynurenine

Cited by 47 publications

References 38 publications

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

Prenatal THC exposure raises kynurenic acid levels in the prefrontal cortex of adult rats

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

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