Reduction of Endogenous Kynurenic Acid Formation Enhances Extracellular Glutamate, Hippocampal Plasticity, and Cognitive Behavior

Potter, Michelle C.; Elmer, Gregory I.; Bergeron, Richard; Albuquerque, Edson X.; Guidetti, Paolo; Wu, Hui‐Qiu; Schwarcz, Robert

doi:10.1038/npp.2010.39

Cited by 192 publications

(172 citation statements)

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“…Our findings confirm and extend reports of similar glutamate changes following KYNA manipulations in other forebrain regions (Carpenedo et al, 2001;Konradsson-Geuken et al, 2009;Wu et al, 2010), and are also in line with experiments showing cognitive impairments following systemic administration of kynurenine, the immediate bioprecursor of KYNA (Chess and Bucci, 2006;Chess et al, 2007;Erhardt et al, 2004;Shepard et al, 2003). Most importantly, the present data provide the first demonstration that the cognitive improvement seen in animals with genetic, that is, chronic, elimination of KAT-II (Potter et al, 2010) can be duplicated by acute, specific KAT-II inhibition.…”

Section: Discussionsupporting

confidence: 80%

“…These KAT-II-knockout mice also showed enhanced cognitive abilities and showed increased hippocampal long-term potentiation, providing the first proof-of-concept that a reduction in endogenous KYNA boosts cognition and synaptic plasticity (Potter et al, 2010). In turn, our present results are the first to reveal a similar effect after an acute decrease in endogenous KYNA levels.…”

Section: Discussionsupporting

confidence: 69%

“…Indeed, acute systemic administration of kynurenine or peripheral KMO inhibition not only leads to increases in brain KYNA (Carpenedo et al, 1994;Russi et al, 1992;Swartz et al, 1990) but also causes distinct cognitive impairments in experimental animals (Chess and Bucci, 2006;Chess et al, 2007;Erhardt et al, 2004;Shepard et al, 2003). By contrast, we showed recently that chronic reduction of brain KYNA in KAT-II-knockout mice improves cognitive performance (Potter et al, 2010). Notably, the latter study also included microdialysis in the hippocampus, a brain area critically implicated in several important aspects of cognitive processing and abundantly endowed with both a7nAChRs and NMDARs (Fabian-Fine et al, 2001;Monaghan et al, 1989;Morris, 2006).…”

Section: Introductionmentioning

confidence: 92%

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Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

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Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 92%

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Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

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137

157

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“…Whereas QA is a neurotoxin that in elevated concentrations can act as an agonist of the NMDA receptor, and 3HK is a potent free radical donor that promotes oxidative stress, and KA acts as an antagonist of both the glycine co-agonist site of the NMDA receptor and the a7 nicotinic receptor situated on glutamatergic neuronal terminals in the hippocampus and other brain regions, reducing glutamate release (Hilmas et al, 2001;Kessler et al, 1989;Perkins and Stone, 1982;Potter et al, 2010;Schwarcz et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Savitz

Drevets

Smith

et al. 2014

Neuropsychopharmacol

200

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Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/ QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.

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“…9 Decreasing central KYNA levels in afflicted individuals may therefore provide therapeutic benefit for treating these and other psychiatric and neurological disorders. 10,11 Among the four homologous members of the KAT family, KAT II is largely responsible for centrally produced KYNA, thereby emerging as an attractive target for medicinal chemists. 12 As such, recent articles have reported both reversible and irreversible KAT II inhibitors.…”

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confidence: 99%

Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions

Tuttle

Anderson

Bechle

et al. 2012

ACS Med. Chem. Lett.

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A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure−activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact /K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles. KEYWORDS: kynurenine amino transferase, kynurenic acid, aryl hydrocarbon receptor, irreversible inhibition, hydroxamic acid, dose response modeling, in vivo microdialysis, schizophrenia T he kynurenine amino transferase (KAT) class of pyridoxal phosphate (PLP)-dependent transaminases catalyzes the cyclization of L-kynurenine to kynurenic acid (KYNA) in the Ltryptophan metabolic pathway. 1,2 Recently, KYNA has been shown to agonize the arylhydrocarbon receptor (AHR), a nuclear protein involved in gene transcription and other cellular regulatory functions. 3 Additionally, a burgeoning body of research implicates KYNA in a range of neurological disorders due to its antagonism of the α7 nicotinic acetylcholine receptor and the N-methyl-D-aspartate (NMDA) receptor. 4,5 Elevated levels of KYNA have been found in the cerebral spinal fluid (CSF) and postmortem brain tissue of schizophrenics. 6−8 Furthermore, individuals with bipolar disorder have also been found to have increased levels of KYNA in the CSF. 9 Decreasing central KYNA levels in afflicted individuals may therefore provide therapeutic benefit for treating these and other psychiatric and neurological disorders. 10,11 Among the four homologous members of the KAT family, KAT II is largely responsible for centrally produced KYNA, thereby emerging as an attractive target for medicinal chemists. 12 As such, recent articles have reported both reversible and irreversible KAT II inhibitors. 13−16 One useful scaffold is hydroxamate 1, a centrally active and irreversible inhibitor of KAT II. 14,17 Preliminary structure−activity relationship (SAR) indicated that substituents were better tolerated on C6 and C7, whereas potency losses were observed with substitution on C5 and C8 (Figure 1). This SAR was supported by the crystal structure, which showed that positions 6 and 7 are oriented toward a solvent-exposed region in the enzyme. 14 In contrast, positions 5 and 8 are directed toward the walls of the binding pocket. As a consequence of these findings, a broad range of analogues were designed to assess the SAR of this series. 14,15 This communication focuses on key analogues that led to the discovery of substantial potency-enhancing interactions with human KAT II.

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Reduction of Endogenous Kynurenic Acid Formation Enhances Extracellular Glutamate, Hippocampal Plasticity, and Cognitive Behavior

Cited by 192 publications

References 59 publications

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions

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