title: The absence of indoleamine 2,3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain.
abstract: We previously showed that the expression and activity of indoleamine 2,3-dioxygenase (Ido1) are chronically elevated in the striatum of YAC128 mouse model of HD. This was followed by increased production of neurotoxic metabolite hydroxykynurenine (3-HK) in the striatum of symptomatic mice. We therefore hypothesized that the chronic Ido1 induction in the striatum of YAC128 mice leads to increased neurotoxicity in this mouse model; based on this hypothesis, we predicted that the absence of Ido1 expression would result in decreased sensitivity to neurotoxicity in mice. The work described in this brief communication will include the characterization of Ido(-/-) striatum in terms of enzymatic expression and activity in the first step of the pathway. Additionally, we assessed the sensitivity of the striatum to excitotoxic insult in the absence of Ido1 expression in the striatum of constitutive Ido1 null mice (Ido(-/-)) and demonstrated that Ido(-/-) mice are less sensitive to QA-induced striatal neurotoxicity. Finally, through measurement of kynurenine pathway (KP) metabolites in Ido(-/-) mice, we showed decreased levels of 3-HK in the striatum of these mice. This study suggests that the inhibition of the first step in the KP may be neuroprotective and should be considered as a potential therapeutic target in HD and other neurodegenerative diseases.
authors.affiliation: Centre for Molecular Medicine and Therapeutics and Department of Medical Genetics, University of British Columbia, 980 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Mazarei
authors.forename: D P
authors.initials: DP
authors.lastname: Budac
authors.forename: G
authors.initials: G
authors.lastname: Lu
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Möller
authors.forename: B R
authors.initials: BR
authors.lastname: Leavitt
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006816:Huntington Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D017378:Quinolinic Acid
keywords: 3-Hydroxykynurenine; BBB; HD; Huntingtin; Huntington disease; Huntington's disease; Ido1; Ido2; Indoleamine 2,3-dioxygenase; KA; KP; Kyn; Kynurenine pathway; LC-MS/MS; MSN; N-methyl-d-aspartate; NMDA; NMDA receptor-mediated excitotoxicity; QA; SP; Striatum; Tdo2; Trp; blood brain barrier; indoleamine 2,3-dioxygenase (gene); indoleamine 2,3-dioxygenase 2 (gene); kynurenic acid; kynurenine; kynurenine pathway; liquid chromatography tandem mass spectrometry; medium spiny neurons; quinolinic acid; serotonin pathway; tryptophan; tryptophan 2,3-dioxygenase (gene)