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Absence of aryl hydrocarbon receptors increases endogenous kynurenic acid levels and protects mouse brain against excitotoxic insult and oxidative stress
Author(s) -
GarcíaLara Lucia,
PérezSeveriano Francisca,
GonzálezEsquivel Dinora,
Elizondo Guillermo,
Segovia José
Publication year - 2015
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23595
Subject(s) - kynurenic acid , quinolinic acid , kynurenine , aryl hydrocarbon receptor , neuroprotection , kynurenine pathway , nmda receptor , oxidative stress , excitotoxicity , pharmacology , endogeny , chemistry , glutamate receptor , receptor , medicine , endocrinology , biology , biochemistry , tryptophan , transcription factor , amino acid , gene
L‐kynurenine (Kyn) is a key element of tryptophan metabolism; it is enzymatically converted by kynurenine aminotransferase II (KAT II) to kynurenic acid (KYNA), which acts as an antagonist to the NMDA receptor–glycine site. Kyn is also an endogenous ligand of the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of a diverse set of genes. KYNA levels are reduced in several regions of the brain of Huntington's disease (HD) patients. The present work uses an AhR‐null mouse and age‐matched wild‐type mice to determine the effect of the absence of AhR on KYNA availability. We found that, in AhR‐null mice, there is an increase of KYNA levels in specific brain areas associated with higher expression of KAT II. Moreover, we induced an excitotoxic insult by intrastriatal administration of quinolinic acid, a biochemical model of HD, in both AhR‐null and wild‐type mice to evaluate the neurological damage as well as the oxidative stress caused by the lesion. The present work demonstrates that, in specific brain regions of AhR‐null mice, the levels of KYNA are increased and that this induces a neuroprotective effect against neurotoxic insults. Moreover, AhR‐null mice also show improved motor performance in the rotarod test, indicating a constitutive protection of striatal tissue. © 2015 Wiley Periodicals, Inc.