Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Brain Res Bull ; 150: 317-327, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31251961

RESUMO

Mitochondrial dysfunction can result from the interplay between elevated inflammatory markers and alterations in hypothalamic-pituitary-adrenal (HPA) axis, and can contribute to pathogenesis of major depression. Therefore, in this study we investigated whether the effects of lipopolysaccharide (LPS) on glucocorticoid receptor (GR) could be associated with alterations in mitochondrial apoptotic signaling in the prefrontal cortex of male and female Wistar rats with depressive-like behavior. To that end, we measured LPS-induced alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of PFC of female and male rats, as well as the levels of cleaved cytosolic PARP-1. We also measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246, as well as the mRNA levels of two GR-regulated mitochondrial genes, COX-1 and COX-3. We discovered that although seven-day LPS treatment evoked depressive-like behavior and induced apoptosis in the PFC of both sexes, it affected apoptotic cascades in both sexes differently. In females the treatment initiated both intrinsic and extrinsic apoptotic cascade, while in males only intrinsic cascade was engaged. Alterations in intrinsic apoptotic pathway were more associated with GR alterations in males, where LPS treatment decreased levels of mitochondrial GR and increased pGR232/pGR246 ratio. Alterations in mitochondrial GR could be associated with changes in expression of genes involved in oxidative metabolism in the PFC of this sex, and could, in combination with elevated levels of BCL-2 and decreased levels of BAX detected in this cell fraction, mitigate the detrimental effect of LPS on mitochondria in male PFC.


Assuntos
Depressão/metabolismo , Mitocôndrias/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Corticosterona/metabolismo , Transtorno Depressivo Maior/metabolismo , Feminino , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Fosforilação , Sistema Hipófise-Suprarrenal/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-30580022

RESUMO

Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα, their interactions and FKBP5 explained 22%-35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα, and emphasized its role in fear extinction and neural plasticity.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Afeto/fisiologia , Receptores de Glucocorticoides/sangue , Adulto , Animais , Núcleo Celular/metabolismo , Estudos de Coortes , Condicionamento Psicológico , Modelos Animais de Doenças , Extinção Psicológica/fisiologia , Medo/fisiologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Projetos Piloto , Biossíntese de Proteínas , Isoformas de Proteínas , Distribuição Aleatória
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...