title: Absence of aryl hydrocarbon receptors increases endogenous kynurenic acid levels and protects mouse brain against excitotoxic insult and oxidative stress.
abstract: 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.
authors.affiliation: Departamento de Fisiología, Biofísica, y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México, D.F., México.
authors.forename: Lucia
authors.initials: L
authors.lastname: García-Lara
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, D.F., México.
authors.forename: Francisca
authors.initials: F
authors.lastname: Pérez-Severiano
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, D.F., México.
authors.forename: Dinora
authors.initials: D
authors.lastname: González-Esquivel
authors.affiliation: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México, D.F., México.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Elizondo
authors.affiliation: Departamento de Fisiología, Biofísica, y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México, D.F., México.
authors.forename: José
authors.initials: J
authors.lastname: Segovia
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D017378:Quinolinic Acid / Q000378:metabolism / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency* / Q000235:genetics; D014364:Tryptophan / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000123:Acetyltransferases; D051792:Basic Helix-Loop-Helix Proteins; D005968:Glutamate Decarboxylase; D007736:Kynurenic Acid; D017378:Quinolinic Acid; D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan; D005680:gamma-Aminobutyric Acid; C484722:Ahr protein, mouse; C402565:glutamate decarboxylase 1
keywords: aryl hydrocarbon receptor; excitotoxicity; neuroprotection; kynurenic acid; kynurenine