RESUMO
Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.
Assuntos
Transtorno Bipolar/genética , Adulto , Proteínas de Ciclo Celular/genética , Citocinas/genética , Dessaturase de Ácido Graxo Delta-5 , Ácidos Graxos Dessaturases/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Japão/epidemiologia , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fatores de Transcrição NFI/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Extracts of Asparagus cochinchinensis (AC) have antitumor, anti-inflammatory, and immunostimulant effects. The neurobiological mechanisms underlying the effects of AC have not been sufficiently explored. Thus we performed in vivo and in vitro experiments to further characterize potential therapeutic effects and to clarify the underlying mechanisms. In the tail suspension test immobility time was significantly reduced after administration of AC which suggests antidepressant-like activity without effect on body core temperature. Moreover, in animals pretreated with AC infarct size after occlusion of the middle cerebral artery was reduced. In vitro experiments confirmed neuroprotective effects. Total saponin obtained from AC significantly inhibited H2O2-induced cell death in cultured cortical neurons. The survival-promoting effect by AC saponins was partially blocked by inhibitors for extracellular signal-regulated kinase (ErK) and phosphoinositide 3-kinase Akt (PI3K/Akt) cascades, both of which are known as survival-promoting signaling molecules. Furthermore, phosphorylation of Scr homology-2 (SH2) domain-containing phosphatase 2 (Shp-2) was induced by AC, and the protective effect of AC was abolished by NSC87877, an inhibitor for Shp-2, suggesting an involvement of Shp-2 mediated intracellular signaling in AC saponins. Moreover, AC-induced activation of pShp-2 and ErK1/2 were blocked by NSC87877 indicating that activation of these signaling pathways was mediated by the Shp-2 signaling pathway. These effects appear to be associated with activation of the Shp-2, ErK1/2 and Akt signaling pathways. Our results suggest that AC has antidepressant-like and neuroprotective (reducing infarct size) effects and that activation of pShp-2 and pErK1/2 pathways may be involved in the effects.
Assuntos
Antidepressivos/farmacologia , Asparagus , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Animais , Antidepressivos/química , Asparagus/química , Encéfalo/patologia , Encéfalo/fisiopatologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/patologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Infarto da Artéria Cerebral Média , Masculino , Metanol/química , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Extratos Vegetais/química , Distribuição Aleatória , Ratos Wistar , Saponinas/químicaRESUMO
Synthetic glucocorticoids such as dexamethasone are widely used to treat a variety of inflammatory and autoimmune conditions, but they may induce adverse events including hyperglycemia. To shed light on the effect and action mechanism of dexamethasone, we examined the alterations of gene expression levels caused by dexamethasone.Microarray analysis was performed on whole blood collected from 24 physically healthy subjects at baseline and after dexamethasone administration. The expression levels of resistin mRNA were found to be significantly increased after the dexamethasone administration. In a separate sample of 12 subjects, we examined plasma resistin protein levels and found that they were increased after dexamethasone administration. Furthermore, the plasma mRNA and protein levels of resistin were significantly higher in individuals who carried the A allele of RETN single nucleotide polymorphism rs3219175 than in those who did not carry the allele. There was no significant interaction between the genotype and dexamethasone administration. No significant correlation was found between plasma levels of cortisol and resistin. Consistent with previous studies, the genotype of RETN rs3219175 was a strong determinant of resistin levels. The present study showed that oral administration of dexamethasone increases the protein and mRNA levels of resistin irrespective of the rs3219175 genotype.
Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Resistina/metabolismo , Adulto , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resistina/genéticaRESUMO
INTRODUCTION: Weight gain and metabolic abnormalities are common side effects of antipsychotic treatment. Retinoids have been suggested as promising substances to suppress obesity. This study has investigated the effects of a retinoid agonist AM-80 on olanzapine-induced weight gain and metabolic changes in rats. METHODS: Female Sprague-Dawley rats (7 weeks) were treated with AM-80 (1 mg/kg/day, subcutaneously) and/or olanzapine (4 mg/kg/day, intraperitoneally) for 21 days. Body weight and food/water intake were measured daily. The open field (OFT) and prepulse inhibition (PPI) tests were done on days 18 and 21, respectively. Animals were sacrificed on day 22 to measure weight of adipose tissues and serum levels of adiponectin and leptin levels. RESULTS: Olanzapine significantly increased body weight, food/water intake and the mass of inguinal adipose tissue (IAT) compared to vehicle-treated rats. AM-80 demonstrated significant inhibition of weight gain. No significant effect of olanzapine or AM-80 was found on behaviors or serum adiponectin/leptin levels. CONCLUSION: These findings suggests that AM-80 is a potential therapeutic agent to attenuate weight gain and metabolic side effects associated with olanzapine.
Assuntos
Antipsicóticos/efeitos adversos , Benzoatos/farmacologia , Benzodiazepinas/antagonistas & inibidores , Retinoides/farmacologia , Tetra-Hidronaftalenos/farmacologia , Aumento de Peso/efeitos dos fármacos , Adiponectina/sangue , Adiposidade/efeitos dos fármacos , Animais , Benzodiazepinas/efeitos adversos , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Leptina/sangue , Atividade Motora/efeitos dos fármacos , Olanzapina , Ratos , Filtro Sensorial/efeitos dos fármacosRESUMO
PURPOSE: Smoking rates in schizotypic individuals are shown to be elevated, as in patients with schizophrenia, although findings on the association of smoking with different symptomatology of schizotypy have been mixed. Moreover, possible moderating effects of schizotypy on the relationship between smoking and cognition have not been well documented. SUBJECTS AND METHODS: The Schizotypal Personality Questionnaire (SPQ) and the full version of the Wechsler Memory Scale-Revised (WMS-R) were administered to 501 healthy adults. Subjects were divided into smokers (n=85) and non-smokers (n=416) based on the presence/absence of current smoking. RESULTS: The analysis of covariance (ANCOVA) on the three factor scores as well as the total score of the SPQ, controlling for age and gender, revealed that cognitive-perceptual factor was significantly associated with an increased rate of smoking (P=0.048). The ANCOVA on the WMS-R indices, with smoking group as a fixed factor and age, gender and total SPQ score as covariates, revealed that the schizotypy-by-smoking interaction was significant for attention/working memory (P=0.029). DISCUSSION AND CONCLUSION: Positive schizotypy may be associated with more smoking. Schizotypy and smoking could interact with each other to negatively affect attention/working memory.
Assuntos
Atenção , Cognição , Memória de Curto Prazo , Transtorno da Personalidade Esquizotípica/psicologia , Fumar/psicologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Inquéritos e QuestionáriosRESUMO
Association between response to antidepressant treatment and genetic polymorphisms was examined in two independent Japanese samples of patients with major depressive disorder (MDD). Genome-wide approach using the Illumina Human CNV370-quad Bead Chip was utilized in the analysis of the 92 MDD patients in the first sample. In all, 11 non-intergenic single-nucleotide polymorphisms with uncorrected allelic P-value <0.0001 were selected for the subsequent association analyses in the second sample of 136 MDD patients. Difference in allele distribution between responders and nonresponders were found in the second-stage sample for rs365836 and rs201522 of the CUX1 gene (P=0.005 and 0.004, respectively). The allelic P-values for rs365836 and rs201522 in both samples combined were 0.0000023 and 0.0000040, respectively. Our results provide the first evidence that polymorphisms of the CUX1 gene may be associated with response to antidepressant treatment in Japanese patients with MDD.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adulto , Idoso , Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/patologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de TranscriçãoRESUMO
Brain-derived neurotrophic factor (BDNF) has multiple roles in the central nervous system (CNS), including maintaining cell survival and regulation of synaptic function. In CNS neurons, BDNF triggers activation of phospholipase Cγ (PLCγ), mitogen-activated protein/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide 3-kinase (PI3K)/Akt pathways, influencing neuronal cells beneficially through these intracellular signaling cascades. There is evidence to suggest that decreased BDNF expression or function is related to the pathophysiology of brain diseases including psychiatric disorders. Additionally, glucocorticoids, which are critical stress hormones, also influence neuronal function in the CNS, and are putatively involved in the onset of depression when levels are abnormally high. In animal models of depression, changes in glucocorticoid levels, expression of glucocorticoid receptor (GR), and alterations in BDNF signaling are observed. Interestingly, several studies using in vivo and in vitro systems suggest that glucocorticoids interact with BDNF to ultimately affect CNS function. In the present review, we provide an overview of recent evidence concerning the interaction between BDNF and glucocorticoids.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Glucocorticoides/metabolismo , Animais , Depressão/metabolismo , Humanos , Neurônios/metabolismoRESUMO
Phenylalanine is an essential amino acid required for the synthesis of catecholamines including dopamine. Altered levels of phenylalanine and its metabolites in blood and cerebrospinal fluid have been reported in schizophrenia patients. This study attempted to examine for the first time whether phenylalanine kinetics is altered in schizophrenia using L-[1-(13)C]phenylalanine breath test ((13)C-PBT). The subjects were 20 chronically medicated schizophrenia patients (DSM-IV) and the same number of age- and sex-matched controls. (13)C-phenylalanine (99 atom% (13)C; 100 mg) was administered orally and the breath (13)CO(2) /(12)CO(2) ratio was monitored for 120 min. The possible effect of antipsychotic medication (risperidone (RPD) or haloperidol (HPD) treatment for 21 days) on (13)C-PBT was examined in rats. Body weight (BW), age and diagnostic status were significant predictors of the area under the curve of the time course of Δ(13)CO(2) () and the cumulative recovery rate (CRR) at 120 min. A repeated measures analysis of covariance controlled for age and BW revealed that the patterns of CRR change over time differed between the patients and controls and that Δ(13)CO(2) was lower in the patients than in the controls at all sampling time points during the 120 min test, with an overall significant difference between the two groups. Chronic administration of RPD or HPD had no significant effect on (13)C-PBT indices in rats. Our results suggest that (13)C-PBT is a novel laboratory test that can detect altered phenylalanine kinetics in chronic schizophrenia patients. Animal experiments suggest that the observed changes are unlikely to be attributable to antipsychotic medication.
Assuntos
Isótopos de Carbono , Fenilalanina/farmacocinética , Esquizofrenia/diagnóstico , Adulto , Animais , Antipsicóticos/uso terapêutico , Testes Respiratórios , Doença Crônica , Dopamina/fisiologia , Haloperidol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Espectrofotometria InfravermelhoRESUMO
An increased incidence of sudden death has been observed among patients treated with antidepressants. A prolonged QTc interval is a known prognostic factor for fatal arrhythmia, and several studies have shown that the use of antidepressants can cause a prolonged QTc interval. However, few studies, especially in Japan, have compared the effects of multiple drugs on QTc interval or examined dose relationships in a clinical setting.We compared the effects of antidepressants on QT interval, corrected to QTc by Bazett's formula, in 729 Japanese patients who were diagnosed with mood disorder.Using stepwise multiple linear regression analysis, we found that the use of tricyclic antidepressants (P<0.01) and concomitant use of antipsychotics (P<0.05), as well as advanced age and being female (known factors for prolonged QTc interval; both P<0.01), significantly prolonged the QTc interval. Analysis of individual antidepressants also revealed that the use of clomipramine (P<0.01) and amitriptyline (P<0.05) significantly prolonged the QTc interval.Our results reveal that tricyclic antidepressants, especially clomipramine and amitriptyline, confer a risk of prolonged QTc interval in a dose-dependent manner. The selective serotonin reuptake inhibitors investigated (fluvoxamine, paroxetine, sertraline) were not indicated as risk factors for QTc prolongation.
Assuntos
Antidepressivos Tricíclicos/efeitos adversos , Antipsicóticos/efeitos adversos , Povo Asiático/psicologia , Síndrome do QT Longo/induzido quimicamente , Transtornos do Humor/fisiopatologia , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Fatores Etários , Antidepressivos Tricíclicos/administração & dosagem , Antipsicóticos/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada/efeitos adversos , Eletrocardiografia/psicologia , Eletrocardiografia/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/tratamento farmacológico , Análise de Regressão , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Caracteres SexuaisRESUMO
OBJECTIVE: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. This study was aimed to examine several brain chemical mediators, including Glx (glutamate + glutamine), using (1)H magnetic resonance spectroscopy (MRS) in medicated patients with schizophrenia, with and without psychotic exacerbation. METHOD: (1)H MRS was acquired in 24 patients with schizophrenia, with psychotic exacerbation; 22 patients without exacerbation; and 27 age- and sex-matched healthy volunteers. The levels of metabolites were measured in the left frontal and inferior parietal white matter and compared across the three groups. RESULTS: The Glx level was significantly elevated in the left inferior parietal white matter in the patients with psychotic exacerbation in comparison with that in the healthy volunteers and the patients without exacerbation (P < 0.05). We also detected that there was a significant correlation between Positive and Negative Syndrome Scale-positive scale and Glx level in the left parietal white matter (r = 0.51, P < 0.001). CONCLUSION: Higher than normal Glx levels indicate glutamatergic overactivity in the left inferior parietal white matter with schizophrenic exacerbation, a finding that is in accordance with the glutamatergic hypothesis in schizophrenia. The Glx level measured by (1)H MRS could be a biomarker for exacerbation in schizophrenia.
Assuntos
Química Encefálica/fisiologia , Ácido Glutâmico/fisiologia , Glutamina/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Progressão da Doença , Aminoácidos Excitatórios/metabolismo , Aminoácidos Excitatórios/fisiologia , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Lobo Parietal/metabolismo , Lobo Parietal/fisiopatologia , Esquizofrenia/metabolismo , Esquizofrenia/patologiaRESUMO
Interleukin-1 (IL-1) plays a crucial role in stress responses and its mRNA is induced in the brain by stress load; however, the precise role of IL-1 in higher brain functions and their abnormalities is largely unknown. Here, we report that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lack IL-1Ra molecules that antagonize the IL-1 receptor, displayed anti-depression-like phenotypes in the tail suspension test (TST) and forced-swim test (FST) only at a young stage (8 weeks), whereas the phenotypes disappeared at later stages (20 and 32 weeks). These anti-depression-like phenotypes were reversed by administration of adrenergic receptor (AR) antagonists against the ARα(1), ARα(2), and ARß subtypes. Although the contents of 5-HT, norepinephrine (NE), and dopamine (DA), which are known to be associated with major symptoms of psychiatric disorders, were not significantly different in the hippocampus or cerebral cortex between IL-1Ra KO and their wild-type (WT) littermate mice, the mRNA expression level of the ARα(1A) subtype was significantly changed in the cerebral cortex. Interestingly, the change in expression of the ARα(1A) subtype was correlated with an age-dependent alteration in the TST and FST in IL-1Ra KO mice. Furthermore, mild immobilization stress loaded on C57BL/6J male mice caused similar anti-depression-like phenotypes in the TST and FST to those observed in mutant mice. These results suggest that sustained activation of IL-1 signaling induced by gene manipulation in mutant mice affects the expression of the ARα(1A) subtype and that modification of adrenergic signaling by the IL-1 system may ultimately cause significant psychiatric abnormalities such as depression, and this mutant mouse could be regarded as a model animal of depression that specifically appears in children and adolescents.
Assuntos
Depressão/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Transdução de Sinais/fisiologia , Animais , Cromatografia Líquida de Alta Pressão , Depressão/genética , Modelos Animais de Doenças , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptores Adrenérgicos alfa 1/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Several lines of evidence suggest that alterations in circadian rhythms might be associated with the pathophysiology of psychiatric disorders such as schizophrenia and bipolar disorder (BP). A recent study reported that SIRT1 is a molecule that plays an important role in the circadian clock system. Therefore, to evaluate the association among the SIRT1 gene, schizophrenia and BP, we conducted a case-control study of Japanese population samples (1158 schizophrenia patients, 1008 BP patients and 2127 controls) with four tagging SNPs (rs12778366, rs2273773, rs4746720 and rs10997875) in the SIRT1 gene. Marker-trait association analysis was used to evaluate the allele and the genotype association with the χ(2) test, and haplotype association analysis was evaluated with a likelihood ratio test. We showed an association between rs4746720 in the SIRT1 gene and schizophrenia in the allele and the genotype analysis. However, the significance of these associations did not survive after Bonferroni's correction for multiple testing. On the other hand, the SIRT1 gene was associated with Japanese schizophrenia in a haplotype-wise analysis (global P(all markers) = 4.89 × 10(-15)). Also, four tagging SNPs in the SIRT1 gene were not associated with BP. In conclusion, the SIRT1 gene may play an important role in the pathophysiology of schizophrenia in the Japanese population.
Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Sirtuína 1/genética , Adulto , Povo Asiático/etnologia , Povo Asiático/genética , Transtorno Bipolar/fisiopatologia , Estudos de Casos e Controles , Transtornos Cronobiológicos/epidemiologia , Transtornos Cronobiológicos/genética , Transtornos Cronobiológicos/fisiopatologia , Comorbidade/tendências , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Japão/epidemiologia , Japão/etnologia , Masculino , Pessoa de Meia-Idade , Esquizofrenia/etnologia , Esquizofrenia/fisiopatologiaRESUMO
We investigated the plasma levels of VEGF and FGF-2, important factors for regulation of neuroplasticity such as neurogenesis, in patients in remission from major depressive disorders (MDD). The plasma VEGF levels were significantly higher in the MDD patients than in the matched control subjects, while no significant difference in plasma FGF-2 levels was found. In particular, the MDD patients with family history of psychiatric disorders, but not patients without such a family history, showed significantly higher values of plasma VEGF than the controls. Although this is a preliminary study, altered VEGF levels might be involved in the pathophysiology of MDD.
Assuntos
Transtorno Depressivo Maior/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Análise de Variância , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Brain-specific microRNAs (miRs) may be involved in synaptic plasticity through the control of target mRNA translation. Brain-derived neurotrophic factor (BDNF) also contributes to the regulation of synaptic function. However, the possible involvement of miRs in BDNF-regulated synaptic function is poorly understood. Importantly, an increase in glucocorticoid levels and the downregulation of BDNF are supposed to be involved in the pathophysiology of depressive disorders. Previously, we reported that glucocorticoid exposure inhibited BDNF-regulated synaptic function via weakening mitogen-activated protein kinase/extracellular signal-regulated kinase1/2 (MAPK/ERK) and/or phospholipase C-gamma (PLC-gamma) intracellular signaling in cultured neurons [Kumamaru et al (2008) Mol Endocrinol 22:546-558; Numakawa et al (2009) Proc Natl Acad Sci U S A 106:647-652]. Therefore, in this study, we investigate the possible influence of glucocorticoid on BDNF/miRs-stimulated biological responses in cultured cortical neurons. Significant upregulation of miR-132 was caused by BDNF, although miR-9, -124, -128a, -128b, -134, -138, and -16 were intact. Transfection of exogenous ds-miR-132 induced marked upregulation of glutamate receptors (NR2A, NR2B, and GluR1), suggesting that miR-132 has a positive effect on the increase in postsynaptic proteins levels. Consistently, transfection of antisense RNA to inhibit miR-132 function decreased the BDNF-dependent increase in the expression of postsynaptic proteins. U0126, an inhibitor of the MAPK/ERK pathway, suppressed the BDNF-increased miR-132, suggesting that BDNF upregulates miR-132 via the MAPK/ERK1/2 pathway. Interestingly, pretreatment with glucocorticoid (dexamethasone, DEX) reduced BDNF-increased ERK1/2 activation, miR-132 expression, and postsynaptic proteins. We demonstrate that the exposure of neurons to an excess glucocorticoid results in a decrease in the BDNF-dependent neuronal function via suppressing miR-132 expression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dexametasona/farmacologia , Glucocorticoides/farmacologia , MicroRNAs/metabolismo , Neurônios/efeitos dos fármacos , Receptores de Glutamato/metabolismo , Animais , Butadienos/farmacologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Inibidores Enzimáticos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/metabolismo , Nitrilas/farmacologia , RNA Antissenso/metabolismo , Ratos , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Genetic factors, such as apolipoprotein E (ApoE) polymorphisms, are thought to play an important role in the etiology of Alzheimer's disease (AD). Recent association studies have suggested that the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene could play a role in the development of AD. To identify genotypic effects of the BDNF and the ApoE genes on disease progression in preclinical AD, we assessed morphological changes using serial magnetic resonance imaging during the preclinical period of AD in 35 individuals. When all subjects were analyzed as one group, progressive atrophy was noted in the limbic, paralimbic and neocortical areas. Individuals of the BDNF Val/Val genotype showed progressive atrophy in the left medial temporal areas, whereas the BDNF Met allele carriers showed additional changes in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and the precuneus. An interaction between the BDNF genotype and progressive morphological changes was found in the PCC. The noncarriers for the ApoE epsilon4 allele showed progressive atrophy in the bilateral medial temporal areas. In addition to changes in the medial temporal areas, epsilon4 carriers showed progressive atrophy in the PCC, ACC and precuneus. An interaction between the ApoE genotype and progressive morphological change was noted in the right medial temporal area. The present preliminary study indicates that polymorphisms of the ApoE and the BDNF genes could affect disease progression in preclinical AD and implies that the Met-BDNF polymorphism could be an additional risk factor for rapid disease progression in preclinical AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Idoso , Doença de Alzheimer/patologia , Atrofia , Encéfalo/patologia , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polimorfismo Genético/genéticaRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.
Assuntos
Predisposição Genética para Doença , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Alelos , Animais , Antipsicóticos/administração & dosagem , Comportamento Animal , Distribuição de Qui-Quadrado , Modelos Animais de Doenças , Feminino , Frequência do Gene , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Inibição Neural/efeitos dos fármacos , Inibição Neural/genética , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/deficiência , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Risperidona/administração & dosagem , Esquizofrenia/patologia , Esquizofrenia/fisiopatologiaRESUMO
Epigenetic genome modifications such as DNA methylation appear to be involved in various diseases. Here, we suggest that the levels of DNA methylation at the BssHII methylation-sensitive restriction enzyme sites in the human REELIN (RELN) gene in the forebrain vary among individuals. Interestingly, although a statistically significant correlation between the levels of DNA methylation in RELN and age was detected in healthy individuals, no such correlations were seen in either schizophrenic or bipolar patients. In addition, reverse correlations between DNA methylation levels and RELN expression were also detected in postmortem brain RNA and on in vitro assay. These data suggest the possibility that epigenetic aberration from the normal DNA methylation status of RELN may confer susceptibility to psychiatric disorders.
Assuntos
Transtorno Bipolar/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Metilação de DNA , DNA/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/metabolismo , Serina Endopeptidases/metabolismo , Adolescente , Adulto , Fatores Etários , Transtorno Bipolar/genética , Moléculas de Adesão Celular Neuronais/genética , Criança , DNA/análise , Epigênese Genética , Proteínas da Matriz Extracelular/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Prosencéfalo/metabolismo , RNA/análise , Proteína Reelina , Valores de Referência , Esquizofrenia/genética , Serina Endopeptidases/genética , Método Simples-CegoRESUMO
We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.
Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Quinases/genética , Esquizofrenia/genética , Alelos , Quinase do Linfoma Anaplásico , Feminino , Frequência do Gene , Genótipo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Receptores Proteína Tirosina QuinasesRESUMO
Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles ('A1' allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5-5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.
Assuntos
Transtorno Bipolar/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Repetições de Dinucleotídeos , Polimorfismo Genético , Transcrição Gênica/genética , Adulto , Alelos , Substituição de Aminoácidos , Animais , Sequência de Bases , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Estudos de Casos e Controles , Células Cultivadas/metabolismo , Feminino , Frequência do Gene , Genes Reporter , Predisposição Genética para Doença , Humanos , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Neurônios/metabolismo , Mutação Puntual , Ratos , Proteínas Recombinantes de Fusão/biossínteseRESUMO
Altered expression of Disrupted-In-Schizophrenia-1 (DISC1) and dysbindin (DTNBP1), susceptibility genes for schizophrenia, in schizophrenic brain has been reported; however, the possible effect of antipsychotics on the expression levels of these genes has not yet been studied. We measured the mRNA expression levels of these genes in frontal cortex and hippocampus of mice chronically treated with typical and atypical antipsychotics by a real-time quantitative RT-PCR method. We found that atypical antipsychotics, olanzapine and risperidone, in a clinically relevant dose increased DISC1 expression levels in frontal cortex, while a typical antipsychotic, haloperidol, did not. No significant effect on dysbindin expression levels was observed in either brain region. These data suggest that prior evidence of decreased expression of dysbindin in postmortem brain of schizophrenics is not likely to be a simple artifact of antemortem drug treatment. Our results also suggest a potential role of DISC1 in the therapeutic mechanisms of certain atypical antipsychotics.