title: Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aβ)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (400pmol/mice; 3μl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aβ1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aβ1-42 induced memory impairment in the object recognition test. Aβ1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aβ1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aβ-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aβ-induced neuroinflammation.
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Leandro Cattelan
authors.initials: LC
authors.lastname: Souza
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil. Electronic address: cristianoricardojesse@yahoo.com.br.
authors.forename: Cristiano R
authors.initials: CR
authors.lastname: Jesse
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Antunes
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Jossana Rodrigues
authors.initials: JR
authors.lastname: Ruff
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Dieniffer
authors.initials: D
authors.lastname: de Oliveira Espinosa
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Nathalie Savedra
authors.initials: NS
authors.lastname: Gomes
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Franciele
authors.initials: F
authors.lastname: Donato
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Giacomeli
authors.affiliation: Laboratório de Avaliações Farmacológicas e Toxicológicas Aplicadas às Moléculas Bioativas, LaftamBio Pampa, Universidade Federal do Pampa, Itaqui, RS, Brazil.
authors.forename: Silvana Peterini
authors.initials: SP
authors.lastname: Boeira
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000139:chemically induced*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced*; D007276:Injections, Intraventricular; D007737:Kynurenine / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced*; D051379:Mice; D009414:Nerve Growth Factors / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects; D014364:Tryptophan / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009414:Nerve Growth Factors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D007737:Kynurenine; D014364:Tryptophan
keywords: Alzheimer’s disease; Anxiety; Depression; Indoleamine-2,3-dyoxigenase; Kynurerine; Memory; Neuroinflammation; Neurotrophic factor; Tryptophan