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1.
Cells ; 10(2)2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525562

RESUMO

Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Compostos de Lítio/uso terapêutico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Animais , Antimaníacos/farmacologia , Transtorno Bipolar/metabolismo , Coronavirus/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Compostos de Lítio/farmacologia , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Medicine (Baltimore) ; 99(28): e21122, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664138

RESUMO

RATIONALE: Lithium is the first-line medication for bipolar disorder, given a narrow therapeutic window of 0.8 to 1.2 mEq/L. Change of lithium pharmacokinetics following bariatric surgery may lead to lithium toxicity, which is particularly concerned. PATIENT CONCERNS: We presented a 39-year-old man with morbid obesity and bipolar affective disorder for 20 years, who was treated with lithium. He developed serious lithium toxicity following sleeve gastrectomy and prolonged neurologic sequelae. DIAGNOSES: He suffered from persistent watery diarrhea, general weakness, and then drowsy consciousness. Lithium level was checked immediately to be 3.42 mEq/L and lithium toxicity was diagnosed. INTERVENTIONS: After 3 courses of hemodialysis, his serum lithium level subsequently declined to 0.63 mEq/L, while his consciousness returned normal. Lithium was replaced by lamotrigine. OUTCOMES: The patient was discharged thirty-five days after admission, while his serum lithium declined to 0.06 mEq/L. Neurologic sequelae were noted by muscle weakness and pain sensation in both feet. The nerve conduction test revealed sensorimotor polyneuropathy with conduction block. He was advised to keep a passive range of motion exercise. LESSONS: Although the consensus guideline remains lacking, our report reviewed cases of relevance in the literature and highlighted the awareness of the potential risk of lithium toxicity following bariatric surgery. We suggest close monitoring of the lithium levels and perhaps a dosage adjustment for the postoperative period.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Gastrectomia/efeitos adversos , Carbonato de Lítio/efeitos adversos , Obesidade Mórbida/cirurgia , Polineuropatias/induzido quimicamente , Complicações Pós-Operatórias , Adulto , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Transtorno Bipolar/complicações , Transtorno Bipolar/metabolismo , Humanos , Laparoscopia/efeitos adversos , Lítio , Carbonato de Lítio/farmacocinética , Masculino , Obesidade Mórbida/complicações
3.
Psychiatry Res Neuroimaging ; 301: 111086, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32464340

RESUMO

Electroconvulsive therapy (ECT) is an effective treatment for major depression. Previous studies suggested that dopaminergic neurotransmission plays a crucial role in the mechanism of the action of ECT. Since dopamine transporters (DAT) regulate extracellular dopamine concentration, DAT represents an interesting target for the study of the mechanism of action of ECT. Eight inpatients (7 patients with major depressive disorder and 1 patient with bipolar disorder with a DSM-IV diagnosis) received a series of 7-15(11.3±5.2) bilateral ECT sessions.The severity of symptoms was assessed using the 21-item Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression-Severity (CGI-S). All patients were examined with [18F]FE-PE2I positron emission tomography (PET) at pre-ECT, after the 10th ECT, and at post-ECT. Striatal DAT-binding potential (BPND) of all patients was reduced, with an average change ratio of DAT-BPND of -13.1±5.6%. In the 2 cases with 15 ECT sessions, the ratio change of DAT-BPND after the 15th ECT was larger than that after the 10th ECT. Also, HDRS and CGI-S were reduced. These results indicate that the dopamine nervous system is part of themechanism of action of ECT.


Assuntos
Transtorno Bipolar/metabolismo , Corpo Estriado/metabolismo , Transtorno Depressivo Maior/terapia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Eletroconvulsoterapia/métodos , Adulto , Idoso , Transtorno Bipolar/terapia , Corpo Estriado/diagnóstico por imagem , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Resultado do Tratamento , Adulto Jovem
5.
BMC Psychiatry ; 20(1): 145, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245436

RESUMO

BACKGROUND: Major depressive disorder and bipolar disorder are prevalent and debilitating psychiatric disorders that are difficult to distinguish, as their diagnosis is based on behavioural observations and subjective symptoms. Quantitative protein profile analysis might help to objectively distinguish between these disorders and increase our understanding of their pathophysiology. Thus, this study was conducted to compare the peripheral protein profiles between the two disorders. METHODS: Serum samples were collected from 18 subjects with major depressive disorder and 15 subjects with bipolar disorder. After depleting abundant proteins, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and label-free quantification were performed. Data-dependent acquisition data were statistically analysed from the samples of 15 subjects with major depressive disorder and 10 subjects with bipolar disorder who were psychotropic drug-free. Two-sided t-tests were performed for pairwise comparisons of proteomes to detect differentially-expressed proteins (DEPs). Ingenuity Pathway Analysis of canonical pathways, disease and functions, and protein networks based on these DEPs was further conducted. RESULTS: Fourteen DEPs were significant between subjects with major depressive disorder and those with bipolar disorder. Ras-related protein Rab-7a (t = 5.975, p = 4.3 × 10- 6) and Rho-associated protein kinase 2 (t = 4.782, p = 8.0 × 10- 5) were significantly overexpressed in subjects with major depressive disorder and Exportin-7 (t = -4.520, p = 1.5 × 10- 4) was significantly overexpressed in subjects with bipolar disorder after considering multiple comparisons. Bioinformatics analysis showed that cellular functions and inflammation/immune pathways were significantly different. CONCLUSIONS: Ras-related protein Rab-7a, Rho-associated protein kinase 2, and Exportin-7 were identified as potential peripheral protein candidates to distinguish major depressive disorder and bipolar disorder. Further large sample studies with longitudinal designs and validation processes are warranted.


Assuntos
Transtorno Bipolar/sangue , Proteínas Sanguíneas/metabolismo , Transtorno Depressivo Maior/sangue , Adulto , Biomarcadores/sangue , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/metabolismo , Cromatografia Líquida , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Masculino , Espectrometria de Massas em Tandem
6.
Nat Neurosci ; 23(4): 510-519, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203495

RESUMO

Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C. These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain.


Assuntos
Giro Denteado/metabolismo , Predisposição Genética para Doença , Neurônios/metabolismo , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Esquizofrenia/metabolismo , Transcriptoma , Adulto Jovem
8.
Proc Natl Acad Sci U S A ; 117(8): 4392-4399, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32041882

RESUMO

The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.


Assuntos
Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Sinaptotagminas/metabolismo , Adulto , Animais , Comportamento , Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Sinaptotagminas/genética , Adulto Jovem
9.
J Neuroinflammation ; 17(1): 42, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000805

RESUMO

BACKGROUND: Previous individual studies have shown the differences in inflammatory cytokines and gray matter volumes between bipolar disorder (BD) and unipolar depression (UD). However, few studies have investigated the association between pro-inflammatory cytokines and differences in brain gray matter volumes between BD and UD. METHODS: In this study, 72 BD patients and 64 UD patients were enrolled, with comparable gender and age distributions (33.8% males and an average age of 39.3 ± 13.7 years). Each participant underwent metabolic profiling (including body mass index (BMI), glucose, triglyceride, high-density lipoprotein (HDL), leptin, insulin, adiponectin), pro-inflammatory cytokine (including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1) examinations, and structural magnetic resonance imaging exams. Voxel-based morphometry was performed to investigate the gray matter volume differences between BD and UD patients. Correlations between pro-inflammatory cytokines and the gray matter volume difference were analyzed. RESULTS: Compared to UD patients, the BD group had significantly higher BMI, and higher levels of sIL-6R and sTNF-R1 than the UD patients. The BMI significantly correlated with the level of pro-inflammatory cytokines. Adjusted for age, sex, BMI, duration of illness and total intracranial volume, the BD individuals had significantly more reduced gray matter volumes over 12 areas: R. cerebellar lobule VIII, R. putamen, L. putamen, R. superior frontal gyrus, L. lingual gyrus, L. precentral gyrus, R. fusiform gyrus, L. calcarine, R. precuneus, L. inferior temporal gyrus, L. hippocampus, and L. superior frontal gyrus. These 12 gray matter volume differences between BP and UD patients negatively correlated with sIL-6R and sTNF-R1 levels. CONCLUSIONS: Our results suggested that BD patients had higher BMI and pro-inflammatory cytokine levels in comparison to UD patients, especially IL-6 and sTNF-R1, which may contribute to greater gray matter reductions in BD patients in comparison to UD patients. The results support the neuro-inflammation pathophysiology mechanism in mood disorder. It is clinically important to monitor BMI, which, in this investigation, positively correlated with levels of inflammatory cytokines.


Assuntos
Transtorno Bipolar/imunologia , Transtorno Bipolar/metabolismo , Transtorno Depressivo/imunologia , Transtorno Depressivo/metabolismo , Substância Cinzenta/patologia , Adulto , Idoso , Transtorno Bipolar/patologia , Índice de Massa Corporal , Citocinas/metabolismo , Transtorno Depressivo/patologia , Encefalite/imunologia , Encefalite/metabolismo , Encefalite/patologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Saudi Med J ; 41(1): 38-45, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31915793

RESUMO

OBJECTIVES: To examine the changes in nitric oxide (NO), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-arginine levels in schizophrenia during acute psychotic exacerbation and in bipolar disorder during mania and to compare those changes to healthy controls. METHODS: Thirty schizophrenia patients with acute psychotic exacerbation and 30 bipolar disorder patients with mania, who attended the Psychiatry Department,  Erenköy Hospital for Mental and Nervous Diseases, Istanbul, Turkey, in 2010. Thirty healthy controls were included. The diagnosis was made using the Structured Clinical Interview for Axis I Disorders (SCID-I) interviews. Patients' demographic data were recorded, and NO, SDMA, L-arginine, and ADMA levels were studied. RESULTS: Nitric oxide levels in schizophrenia patients were significantly lower than the control group. Nitric oxide levels in the bipolar group were lower than the control group but the difference was not statistically significant. The levels of SDMA, ADMA, and L-arginine were found to be significantly higher in schizophrenia and bipolar disorder patients than the control group. The disease duration was slightly negatively correlated with NO levels in bipolar patients. In schizophrenia patients, the disease severity was slightly positively correlated with NO levels. CONCLUSION: Significant changes in NO, SDMA, ADMA, and L-arginine levels in schizophrenia and bipolar disorder patients suggest that NO and inhibitors of NO might be implicated in the neurobiology of schizophrenia and bipolar disorder.


Assuntos
Arginina/análogos & derivados , Arginina/metabolismo , Transtorno Bipolar/metabolismo , Óxido Nítrico/metabolismo , Esquizofrenia/metabolismo , Progressão da Doença , Humanos
11.
PLoS One ; 15(1): e0225353, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31986152

RESUMO

The Alda score is commonly used to quantify lithium responsiveness in bipolar disorder. Most often, this score is dichotomized into "responder" and "non-responder" categories, respectively. This practice is often criticized as inappropriate, since continuous variables are thought to invariably be "more informative" than their dichotomizations. We therefore investigated the degree of informativeness across raw and dichotomized versions of the Alda score, using data from a published study of the scale's inter-rater reliability (n = 59 raters of 12 standardized vignettes each). After learning a generative model for the relationship between observed and ground truth scores (the latter defined by a consensus rating of the 12 vignettes), we show that the dichotomized scale is more robust to inter-rater disagreement than the raw 0-10 scale. Further theoretical analysis shows that when a measure's reliability is stronger at one extreme of the continuum-a scenario which has received little-to-no statistical attention, but which likely occurs for the Alda score ≥ 7-dichotomization of a continuous variable may be more informative concerning its ground truth value, particularly in the presence of noise. Our study suggests that research employing the Alda score of lithium responsiveness should continue using the dichotomous definition, particularly when data are sampled across multiple raters.


Assuntos
Intervalos de Confiança , Compostos de Lítio/efeitos adversos , Probabilidade , Animais , Transtorno Bipolar/metabolismo , Transtorno Bipolar/patologia , Humanos , Linguagens de Programação
12.
Bipolar Disord ; 22(1): 59-69, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31398273

RESUMO

OBJECTIVES: Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause neurotoxicity. We measured inflammatory markers in patients with bipolar disorder (BD) and studied their relation to kynurenine metabolites and mood. METHODS: Patients with BD suffering from an acute mood episode were assigned to the depressive (n = 35) or (hypo)manic (n = 32) subgroup. Plasma levels of inflammatory markers [cytokines, C-reactive protein] and kynurenine metabolites [tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KYNA)] were measured on 6 time points during 8 months follow-up. Biological marker levels in patients were compared to controls (n = 35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis. RESULTS: Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor-α and KYN, KYN/TRP, 3-HK and QA (ρ > 0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3-HK, P = .0004) and a strong association between interferon-y and kynurenine pathway activation (P < .0001). KYNA was low in both patient groups versus controls throughout the whole follow-up (P = .0008). CONCLUSIONS: Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism.


Assuntos
Afeto/fisiologia , Transtorno Bipolar , Inflamação/sangue , Cinurenina/metabolismo , Triptofano/metabolismo , Adulto , Biomarcadores/sangue , Transtorno Bipolar/imunologia , Transtorno Bipolar/metabolismo , Proteína C-Reativa/metabolismo , Depressão/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Sintomas
13.
Mol Psychiatry ; 25(1): 94-113, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31249382

RESUMO

Bipolar disorder (BD) is a chronic affective disorder with extreme mood swings that include mania or hypomania and depression. Though the exact mechanism of BD is unknown, neuroinflammation is one of the numerous investigated etiopathophysiological causes of BD. This article presents a systematic review of the data regarding brain inflammation evaluating microglia, astrocytes, cytokines, chemokines, adhesion molecules, and other inflammatory markers in postmortem BD brain samples. This systematic review was performed according to PRISMA recommendations, and relevant studies were identified by searching the PubMed/MEDLINE, PsycINFO, EMBASE, LILACS, IBECS, and Web of Science databases for peer-reviewed journal articles published by March 2019. Quality of included studies appraised using the QUADAS-2 tool. Among the 1814 articles included in the primary screening, 51 articles measured inflammatory markers in postmortem BD brain samples. A number of studies have shown evidence of inflammation in BD postmortem brain samples. However, an absolute statement cannot be concluded whether neuroinflammation is present in BD due to the large number of studies did not evaluate the presence of infiltrating peripheral immune cells in the central nervous system (CNS) parenchyma, cytokines levels, and microglia activation in the same postmortem brain sample. For example, out of 15 studies that evaluated microglia cells markers, 8 studies found no effect of BD on these cells. Similarly, 17 out of 51 studies evaluating astrocytes markers, 9 studies did not find any effect of BD on astrocyte cells, whereas 8 studies found a decrease and 2 studies presented both increase and decrease in different brain regions. In addition, multiple factors account for the variability across the studies, including postmortem interval, brain area studied, age at diagnosis, undergoing treatment, and others. Future analyses should rectify these potential sources of heterogeneity and reach a consensus regarding the inflammatory markers in postmortem BD brain samples.


Assuntos
Transtorno Bipolar/imunologia , Transtorno Bipolar/metabolismo , Neuroimunomodulação/fisiologia , Astrócitos/metabolismo , Autopsia , Biomarcadores , Transtorno Bipolar/diagnóstico , Encéfalo/metabolismo , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Microglia/metabolismo , Transtornos do Humor/metabolismo , Transtornos do Humor/fisiopatologia
14.
Bipolar Disord ; 22(1): 46-58, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31025493

RESUMO

OBJECTIVES: Bipolar disorder (BD) is a debilitating psychiatric illness affecting 2%-5% of the population. Although mania is the cardinal feature of BD, inattention and related cognitive dysfunction are observed across all stages. Since cognitive dysfunction confers poor functional outcome in patients, understanding the relevant neural mechanisms remains key to developing novel-targeted therapeutics. METHODS: The 5-choice continuous performance test (5C-CPT) is a mouse and fMRI-compatible human attentional task, requiring responding to target stimuli while inhibiting responding to nontarget stimuli, as in clinical CPTs. This task was used to delineate systems-level neural deficits in BD contributing to inattentive performance in human subjects with BD as well as mouse models with either parietal cortex (PC) lesions or reduced dopamine transporter (DAT) expression. RESULTS: Mania BD participants exhibited severe 5C-CPT impairment. Euthymic BD patients exhibited modestly impaired 5C-CPT. High impulsivity BD subjects exhibited reduced PC activation during target and nontarget responding compared with healthy participants. In mice, bilateral PC lesions impaired both target and nontarget responding. In the DAT knockdown mouse model of BD mania, knockdown mice exhibited severely impaired 5C-CPT performance versus wildtype littermates. CONCLUSIONS: These data support the role of the PC in inattention in BD-specifically regarding identifying the appropriate response to target vs nontarget stimuli. Moreover, the findings indicate that severely reduced DAT function/hyperdopaminergia recreates the attentional deficits observed in BD mania patients. Determining the contribution of DAT in the PC to attention may provide a future target for treatment development.


Assuntos
Atenção/fisiologia , Transtorno Bipolar , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transmissão Sináptica/fisiologia , Adulto , Animais , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Cognição/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Análise e Desempenho de Tarefas
15.
Food Chem Toxicol ; 136: 110986, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31760073

RESUMO

It is recognized that d-amphetamine (AMPH)-induced hyperactivity is thought to be a valid animal model of mania. In the present study, we investigated whether a proinflammatory oxidative gene indoleamine-2,3-dioxygenase (IDO) is involved in AMPH-induced mitochondrial burden, and whether mood stabilizers (i.e., lithium and valproate) modulate IDO to protect against AMPH-induced mania-like behaviors. AMPH-induced IDO-1 expression was significantly greater than IDO-2 expression in the prefrontal cortex of wild type mice. IDO-1 expression was more pronounced in the mitochondria than in the cytosol. AMPH treatment activated intra-mitochondrial Ca2+ accumulation and mitochondrial oxidative burden, while inhibited mitochondrial membrane potential and activity of the mitochondrial complex (I > II), mitochondrial glutathione peroxidase, and superoxide dismutase, indicating that mitochondrial burden might be contributable to mania-like behaviors induced by AMPH. The behaviors were significantly attenuated by lithium, valproate, or IDO-1 knockout, but not in IDO-2 knockout mice. Lithium, valproate administration, or IDO-1 knockout significantly attenuated mitochondrial burden. Neither lithium nor valproate produced additive effects above the protective effects observed in IDO-1 KO in mice. Collectively, our results suggest that mood stabilizers attenuate AMPH-induced mania-like behaviors via attenuation of IDO-1-dependent mitochondrial stress, highlighting IDO-1 as a novel molecular target for the protective potential of mood stabilizers.


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Lítio/uso terapêutico , Ácido Valproico/uso terapêutico , Animais , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Cálcio/metabolismo , Dextroanfetamina , Glutationa Peroxidase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Locomoção/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Córtex Pré-Frontal/patologia , Superóxido Dismutase/metabolismo
16.
Mol Brain ; 12(1): 107, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822292

RESUMO

Bipolar disorder is a major mental illness characterized by severe swings in mood and activity levels which occur with variable amplitude and frequency. Attempts have been made to identify mood states and biological features associated with mood changes to compensate for current clinical diagnosis, which is mainly based on patients' subjective reports. Here, we used infradian (a cycle > 24 h) cyclic locomotor activity in a mouse model useful for the study of bipolar disorder as a proxy for mood changes. We show that metabolome patterns in peripheral blood could retrospectively predict the locomotor activity levels. We longitudinally monitored locomotor activity in the home cage, and subsequently collected peripheral blood and performed metabolomic analyses. We then constructed cross-validated linear regression models based on blood metabolome patterns to predict locomotor activity levels of individual mice. Our analysis revealed a significant correlation between actual and predicted activity levels, indicative of successful predictions. Pathway analysis of metabolites used for successful predictions showed enrichment in mitochondria metabolism-related terms, such as "Warburg effect" and "citric acid cycle." In addition, we found that peripheral blood metabolome patterns predicted expression levels of genes implicated in bipolar disorder in the hippocampus, a brain region responsible for mood regulation, suggesting that the brain-periphery axis is related to mood-change-associated behaviors. Our results may serve as a basis for predicting individual mood states through blood metabolomics in bipolar disorder and other mood disorders and may provide potential insight into systemic metabolic activity in relation to mood changes.


Assuntos
Afeto , Transtorno Bipolar/sangue , Transtorno Bipolar/metabolismo , Metaboloma , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/metabolismo , Ritmo Infradiano/genética , Masculino , Camundongos , Mitocôndrias/metabolismo , Atividade Motora/genética
17.
Transl Psychiatry ; 9(1): 331, 2019 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819046

RESUMO

In bipolar disorder (BPD), long-term psychotropic drug treatment is often necessary to prevent relapse or recurrence. Nevertheless, adverse drug effects including disturbances in hepatic metabolism are observed and still poorly understood. Here, the association between hepatic gene expression and histopathological changes of the liver was investigated. By the use of microarrays (Affymetrix U133 plus2.0), a genome-wide expression study was performed on BPD patients with psychotropic drug treatment (n = 29) compared to unaffected controls (n = 20) and validated by quantitative real-time PCR. WebGestalt was used to identify over-represented functional pathways of the Reactome database. Association analyses between histopathological changes and differentially expressed genes comprised in the over-represented functional pathways were performed using regression analyses, from which feature-expression heatmaps were drawn. The majority of identified genes were underexpressed and involved in energy supply, metabolism of lipids and proteins, and the innate immune system. Positive associations were found for genes involved in all pathways and degenerative changes. The strongest negative association was observed between genes involved in energy supply and hepatic activity, as well as inflammation. In summary, we found a possible association between gene expression involved in various biological pathways and histopathological changes of the liver in BPD. Further, we found support for the probable primary toxic effect of psychotropic drugs on hepatic injury in BPD. Even if the safety of psychotropic drugs improves, adverse effects especially on hepatic function should not be underestimated.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Expressão Gênica , Fígado , Psicotrópicos/efeitos adversos , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Análise em Microsséries , Pessoa de Meia-Idade
18.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801218

RESUMO

Lithium is the mainstay in the maintenance of bipolar disorder (BD) and the most efficacious pharmacological treatment in suicide prevention. Nevertheless, its use is hampered by a high interindividual variability and important side effects. Genetic and epigenetic factors have been suggested to modulate lithium response, but findings so far have not allowed identifying molecular targets with predictive value. In this study we used next generation sequencing to measure genome-wide miRNA expression in lymphoblastoid cell lines from BD patients excellent responders (ER, n = 12) and non-responders (NR, n = 12) to lithium. These data were integrated with microarray genome-wide expression data to identify pairs of miRNA/mRNA inversely and significantly correlated. Significant pairs were prioritized based on strength of association and in-silico miRNA target prediction analyses to select candidates for validation with qRT-PCR. Thirty-one miRNAs were differentially expressed in ER vs. NR and inversely correlated with 418 genes differentially expressed between the two groups. A total of 331 of these correlations were also predicted by in-silico algorithms. miR-320a and miR-155-3p, as well as three of their targeted genes (CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regulator of G Protein Signaling 16) for miR-320, SP4 (Sp4 Transcription Factor) for miR-155-3p) were validated. These miRNAs and mRNAs were previously implicated in psychiatric disorders (miR-320a and SP4), key processes of the central nervous system (CAPNS1, RGS16, SP4) or pathways involved in mental illnesses (miR-155-3p). Using an integrated approach, we identified miRNAs and their targeted genes potentially involved in lithium response in BD.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Lítio/uso terapêutico , MicroRNAs/genética , Psicotrópicos/uso terapêutico , RNA Mensageiro/genética , Adulto , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Calpaína/genética , Calpaína/metabolismo , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma Humano , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , MicroRNAs/classificação , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Cultura Primária de Células , Proteínas RGS/genética , Proteínas RGS/metabolismo , RNA Mensageiro/classificação , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Fator de Transcrição Sp4/genética , Fator de Transcrição Sp4/metabolismo , Resultado do Tratamento
19.
Sci Rep ; 9(1): 15627, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666560

RESUMO

Intracerebroventricular (ICV) administration of ouabain, an inhibitor of the Na, K-ATPase, is an approach used to study the physiological functions of the Na, K-ATPase and cardiotonic steroids in the central nervous system, known to cause mania-like hyperactivity in rats. We describe a mouse model of ouabain-induced mania-like behavior. ICV administration of 0.5 µl of 50 µM (25 pmol, 14.6 ng) ouabain into each lateral brain ventricle results in increased locomotor activity, stereotypical behavior, and decreased anxiety level an hour at minimum. Fast-scan cyclic voltammetry showed that administration of 50 µM ouabain causes a drastic drop in dopamine uptake rate, confirmed by elevated concentrations of dopamine metabolites detected in the striatum 1 h after administration. Ouabain administration also caused activation of Akt, deactivation of GSK3ß and activation of ERK1/2 in the striatum of ouabain-treated mice. All of the abovementioned effects are attenuated by haloperidol (70 µg/kg intraperitoneally). Observed effects were not associated with neurotoxicity, since no dystrophic neuron changes in brain structures were demonstrated by histological analysis. This newly developed mouse model of ouabain-induced mania-like behavior could provide a perspective tool for studying the interactions between the Na,K-ATPase and the dopaminergic system.


Assuntos
Transtorno Bipolar/induzido quimicamente , Ouabaína/efeitos adversos , Receptores de Dopamina D2/metabolismo , Animais , Comportamento Animal , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Camundongos , Ouabaína/administração & dosagem , Receptores de Dopamina D2/genética , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo
20.
Genome Biol ; 20(1): 233, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694669

RESUMO

The driver tissues or cell types in which susceptibility genes initiate diseases remain elusive. We develop a unified framework to detect the causal tissues of complex diseases or traits according to selective expression of disease-associated genes in genome-wide association studies (GWASs). This framework consists of three components which run iteratively to produce a converged prioritization list of driver tissues. Additionally, this framework also outputs a list of prioritized genes as a byproduct. We apply the framework to six representative complex diseases or traits with GWAS summary statistics, which leads to the estimation of the lung as an associated tissue of rheumatoid arthritis.


Assuntos
Doença/etiologia , Expressão Gênica , Predisposição Genética para Doença , Genômica/métodos , Algoritmos , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Estatura/genética , Encéfalo/metabolismo , Colesterol/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Esquizofrenia/genética , Esquizofrenia/metabolismo
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