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1.
Int J Neuropsychopharmacol ; 20(6): 445-454, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339618

RESUMO

Background: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls. Methods: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-α, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Results: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers. Conclusions: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.


Assuntos
Transtorno Bipolar/metabolismo , Senescência Celular/fisiologia , Inflamação/sangue , Estresse Oxidativo/fisiologia , Irmãos , Telômero/metabolismo , Biomarcadores/sangue , Transtorno Bipolar/tratamento farmacológico , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Entrevista Psicológica , Masculino , Pessoa de Meia-Idade
2.
Int J Neuropsychopharmacol ; 18(1)2014 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-25522387

RESUMO

BACKGROUND: Impaired stress resilience and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients. METHODS: Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR). RESULTS: Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels. CONCLUSIONS: Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness.


Assuntos
Transtorno Bipolar/metabolismo , Hidrocortisona/metabolismo , Receptores de Glucocorticoides/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Hormônio Adrenocorticotrópico/sangue , Adulto , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Dexametasona/farmacologia , Progressão da Doença , Epigênese Genética , Feminino , Glucocorticoides/farmacologia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Metilação , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , RNA Mensageiro/metabolismo , Saliva/metabolismo , Irmãos , Proteínas de Ligação a Tacrolimo/genética
3.
Neurosci Lett ; 694: 143-147, 2019 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-30521946

RESUMO

Although the etiology of Bipolar Disorder (BD) remains unknown, a strong genetic component to the pathogenesis and risk for this disorder has been widely hypothesized. Several risk genes for BD have been identified; of these, the purinergic P2 × 7 receptor (P2 × 7R) constitutes a pro-inflammatory receptor and a potential risk gene candidate. The purpose of the present study was to assess the frequency of the 1513 A > C P2RX7 polymorphism (rs3751143; Glu496Ala), which leads to receptor loss-of-function, in 154 BD patients versus 184 control subjects. The existence of a differential modulation of P2 × 7R was also analyzed in 22 euthymic BD patients, in comparison to 18 healthy controls. Our data show a decrease in 1513C allele frequency (p = 0.045) and a potential increase in 1513 A A/AC (p = 0.055) genotype frequency in BD patients, compared to controls, indicating an enhanced function of the pro-inflammatory P2 × 7 receptor in BD subjects. Interestingly, no differences in P2RX7 gene and protein expression were found between euthymic BD patients and matched healthy controls. In conclusion, our results suggest that P2 × 7R might play a role in the pathophysiology of BD and add new information regarding this receptor as a potential biomarker for the prediction and diagnosis of the disorder.


Assuntos
Transtorno Bipolar/genética , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2X7/genética , Adulto , Transtorno Bipolar/sangue , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Purinérgicos P2X7/sangue , Fatores de Risco
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