Pharmacology of the kynurenine pathway

Stone, T.W.; Darlington, L. Gail

doi:10.1016/j.ics.2007.07.013

Cited by 4 publications

(4 citation statements)

References 48 publications

(52 reference statements)

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“…L-Kynurenine (L-KYN) is the central intermediate in this complex metabolic cascade, which ends with nicotinamide adenine dinucleotide, kynurenic acid (KYNA) and xanthurenic acid (Beadle et al, 1947 ; Heidelberg et al, 1949 ; Fujigaki et al, 1998 ). Certain kynurenines (e.g., KYNA) have been demonstrated to have neuroactive properties (Lapin, 1978 ; Perkins and Stone, 1982 ; Stone and Darlington, 2007 ; Vécsei et al, 2013 ). The de novo formation of KYNA from its precursor L-KYN is associated with the action of the kynurenine aminotransferases (KATs), and especially KAT II, which is located predominantly in the glial cells, but can also be found in the neurons (Guidetti et al, 1997 ; Rzeski et al, 2005 ; Lim et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

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Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Varga

Herédi

Kánvási

et al. 2015

Front. Behav. Neurosci.

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L-Kynurenine (L-KYN) is a central metabolite of tryptophan degradation through the kynurenine pathway (KP). The systemic administration of L-KYN sulfate (L-KYNs) leads to a rapid elevation of the neuroactive KP metabolite kynurenic acid (KYNA). An elevated level of KYNA may have multiple effects on the synaptic transmission, resulting in complex behavioral changes, such as hypoactivity or spatial working memory deficits. These results emerged from studies that focused on rats, after low-dose L-KYNs treatment. However, in several studies neuroprotection was achieved through the administration of high-dose L-KYNs. In the present study, our aim was to investigate whether the systemic administration of a high dose of L-KYNs (300 mg/bwkg; i.p.) would produce alterations in behavioral tasks (open field or object recognition) in C57Bl/6j mice. To evaluate the changes in neuronal activity after L-KYNs treatment, in a separate group of animals we estimated c-Fos expression levels in the corresponding subcortical brain areas. The L-KYNs treatment did not affect the general ambulatory activity of C57Bl/6j mice, whereas it altered their moving patterns, elevating the movement velocity and resting time. Additionally, it seemed to increase anxiety-like behavior, as peripheral zone preference of the open field arena emerged and the rearing activity was attenuated. The treatment also completely abolished the formation of object recognition memory and resulted in decreases in the number of c-Fos-immunopositive-cells in the dorsal part of the striatum and in the CA1 pyramidal cell layer of the hippocampus. We conclude that a single exposure to L-KYNs leads to behavioral disturbances, which might be related to the altered basal c-Fos protein expression in C57Bl/6j mice.

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Section: Introductionmentioning

confidence: 99%

“…The therapeutic application of kynurenergic manipulation was therefore proposed recently (Németh et al, 2004 ; Gigler et al, 2007 ; Stone and Darlington, 2007 ; Wonodi and Schwarcz, 2010 ; Gellért et al, 2011 ; Schwarcz et al, 2012 ; Tan et al, 2012 ; Stone et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Varga

Herédi

Kánvási

et al. 2015

Front. Behav. Neurosci.

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“…However, just about 30% of the dietary pool of tryptophan is incorporated into proteins, while the remaining amount is metabolized via various pathways to different, bioactive end products. The principal metabolic pathway for tryptophan is the kynurenic pathway, which performs regulatory functions in the nervous and immune systems [1]. One of the metabolites of this pathway is kynurenic acid (KYNA), an organic hydroxy acid, an antagonist of ionotropic glutamate receptors (NDMA) and α-7 nicotinic acetylcholine receptors (nACh) in the nervous tissue, known mainly as an endogenous neuroprotectant.…”

Section: Introductionmentioning

confidence: 99%

Effect of dietary administration of kynurenic acid on the activity of splenocytes of the rainbow trout (Oncorhynchus mykiss)

Małaczewska¹,

Siwicki²,

Wójcik³

et al. 2013

cejoi

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“…One candidate mechanism is the disruption by chronic immune activation of the kynurenine pathway of tryptophan oxidative metabolism, which can induce cell damage through dysregulation of NMDA receptor function or generation of reactive oxygen species. 35 Higher neopterin level is associated with lower serum tryptophan, brain atrophy, and dementia in HIV infection, 11 and neurotoxic glutamate is known to be elevated in the CSF and plasma of patients with HIV. 36 CA1 hippocampal cells have a high expression of NMDA receptors (which are critical for learning and memory) and are thus vulnerable to glutamate-mediated excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Neopterin is associated with hippocampal subfield volumes and cognition in HIV

Fleischman

Arfanakis

Leurgans

et al. 2018

Neurol Neuroimmunol Neuroinflamm

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ObjectiveHIV infection sets off an immediate immune response and inflammatory cascade that can lead to neuronal injury and cognitive impairment, but the relationship between immune markers, regional brain volumes, and cognition remains understudied in HIV-infected adults.MethodsCross-sectional associations were examined between serum immune markers of activation (neopterin) and inflammation (interleukin [IL]-1β, IL-6, tumor necrosis factor alpha, and C-reactive protein) with regional brain volumes (cortical, subcortical, total gray matter, hippocampus, and subfields) and cognition in 66 HIV-infected, virally suppressed, adults who underwent 3.0-T MRI as part of the Research Core of the Rush Center of Excellence on Disparities in HIV and Aging. Immune markers were assayed from frozen plasma, values were entered into linear regression models as predictors of regional brain volumes, and interactive effects of immune response and regional brain volumes on cognition were examined.ResultsNo inflammatory marker was associated with any regional brain volume. Higher neopterin level was associated with lower total hippocampal, presubiculum, and cornu ammonis (CA) subfield volumes. Higher neopterin level and lower total hippocampal volume were independently associated with lower episodic memory, and neopterin level fully mediated the effect of hippocampal atrophy on episodic memory. Higher neopterin levels were associated with lower presubiculum, CA1, and CA4/dentate volumes and lower semantic memory, working memory, and global cognition.ConclusionImmune activation in response to HIV infection, measured by neopterin, has a deleterious and targeted effect on regional brain structure, which can be visualized with clinically available MRI measures of hippocampus and its subfields, and this effect is associated with lower cognitive function.

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Pharmacology of the kynurenine pathway

Cited by 4 publications

References 48 publications

Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Systemic L-Kynurenine sulfate administration disrupts object recognition memory, alters open field behavior and decreases c-Fos immunopositivity in C57Bl/6 mice

Effect of dietary administration of kynurenic acid on the activity of splenocytes of the rainbow trout (Oncorhynchus mykiss)

Neopterin is associated with hippocampal subfield volumes and cognition in HIV

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