Efeitos do ácido propiônico sobre o conteúdo de lipídios e proteínas em cerebelo de ratos wistar jovens

57

Níveis séricos de proteína C-reativa e o papel da inflamação crônica no transtorno bipolar

Evidências sugerem o envolvimento de um estado de inflamação crônica de baixo grau na fisiopatologia do transtorno bipolar (TB). Os estudos apresentados nesta tese tiveram como objetivo explorar o papel da inflamação crônica nos mecanismos fisiopatológicos do TB através da avaliação dos níveis séricos de proteína C-reativa (PCR). A PCR é um marcador de inflamação sistêmica comumente utilizado na prática clínica, sendo considerado fator de risco para várias patologias, incluindo câncer e doença cardiovascular. O primeiro artigo, através de um estudo de meta-análise, teve como objetivo avaliar o tamanho de efeito da associação entre níveis de PCR em pacientes bipolares nas diferentes fases de humor (n=730) comparado a indivíduos controles (n=888). Pacientes bipolares apresentaram níveis de PCR significativamente elevados em comparação ao grupo controle, com moderado tamanho de efeito (effect size, ES = 0.39; 95% IC, 0.24 – 0.55; P < 0.0001). Níveis de PCR foram significativamente maiores em pacientes maníacos (ES = 0.73; 95% IC, 0.44 – 1.02; P < 0.001) e em eutímicos (ES = 0.26; 95% IC, 0.01 – 0.51; P = 0.04). O segundo artigo se propôs a revisar dados da literatura relacionados a biomarcadores periféricos potencialmente implicados na progressão do TB. Pacientes em diferentes estágios do TB apresentaram níveis alterados de marcadores de estresse oxidativo, neurotrofinas e de inflamação, incluindo a PCR, o que reforça a hipótese da inflamação crônica exercer um papel importante na fisiopatologia do TB. Em seguida, considerando a abordagem multidimensional no TB, o terceiro artigo avaliou a reatividade emocional como uma dimensão relevante para caracterizar pacientes bipolares apresentando sintomas subclínicos de humor durante a fase de remissão (N=613). Apesar de todos pacientes estarem em remissão, a maioria deles (68%) apresentou reatividade emocional anormal (hipo ou hiper-reatividade emocional). Esse estudo avaliou, também, o funcionamento psicossocial nesses pacientes e os níveis de PCR ultra-sensível como um possível marcador objetivo de hiper-reatividade emocional no TB. Os pacientes com hiper-reatividade emocional, em comparação aos pacientes com hipo- ou normal reatividade emocional, apresentaram prejuízo cognitivo e níveis de PCR significativamente mais elevados (P < 0.001). Esses resultados provêm de um estudo transversal e, portanto, conclusões sobre causalidade dessas associações não podem ser inferidas, já que outros fatores, além dos níveis de PCR, podem também contribuir para o estado inflamatório crônico observado nesses pacientes. Em suma, os resultados desta tese sugerem que a inflamação crônica de baixo grau, evidenciada pelas alterações nos níveis de PCR, parece estar implicada na fisiopatologia e na progressão do TB. Novas intervenções terapêuticas com alvo em mecanismos inflamatórios e na modulação dos níveis de PCR devem ser priorizados em estudos futuros.Evidence suggests that chronic low-grade inflammation appears to be involved in the pathophysiology of bipolar disorder (BD). The studies presented in this thesis aimed at exploring the role of chronic inflammation in the BD pathophysiological mechanisms by assessing serum levels of C-reactive protein (CRP). CRP is a marker of low-grade inflammation widely used in clinical practice, and a risk factor for cardiovascular and malignant diseases. The first article, a meta-analysis, aimed at evaluating the effect size of the association between CRP levels in bipolar patients (n=730) compared to healthy subjects (n=888). Overall, CRP levels were significantly elevated in patients with BD versus controls (effect size, ES = 0.39; 95% CI, 0.24 to 0.55; P < .0001). CRP levels were significantly higher in manic (ES = 0.73; 95% CI, 0.44 to 1.02; P < 0.001) and euthymic (ES = 0.26; 95% CI, 0.01 to 0.51; P = 0.04). The second paper aimed at reviewing the scientific literature regarding peripheral biomarkers potentially implicated in the progression of BD. Bipolar patients within different disease’s stages presented altered levels of oxidative stress, neurotrophins and inflammatory markers, including PCR. These findings reinforce the hypothesis of the potential role of the chronic inflammation in BD pathophysiology. Regarding the multidimensional approach in BD, the third article assessed emotional reactivity as a major dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms (N=613). Although all patients were in remission, most of them (68%) showed abnormal emotional reactivity (hipo- or hyper-reactivity). In addition, this study assessed the psychosocial functioning in these patients as well as the levels of high-sensitivty PCR (hsCRP) as an objective marker of emotional hyper-reactivity in BD. Patients with emotional hyper-reactivity had higher levels of PCR and cognitive impairment compared to patients with emotional hypo or normal emotional reactivity (P < 0.001). This was a crosssectional study of emotional reactivity, hsCRP levels and functional status in remitted bipolar patients, and no conclusions regarding the causality of these associations can be substantiated. Others factors could also be contributing to the chronic inflammatory state in these patients. In conclusion, the results of this thesis suggest that low-grade chronic inflammation, as evidenced by alteration in CRP levels, may be implicated in the pathophysiology as well as in the BD progression. Novel therapeutic interventions targeting inflammatory mechanisms and the modulation of CRP levels should be prioritized in future studies

Can olfactory dysfunction be a marker of trait or states of bipolar disorders? A comprehensive review

International audienceBackground: Olfactory deficits (OD) are reported as markers for a large spectrum of neuro-psychiatric disorders. Alterations can concern perception, identification, discrimination and assignment of odour's valence of olfaction process. We propose a comprehensive review to summarize which kind of OD were reported in bipolar disorders (BD) and in which phase of the disease, to know if they could be a marker of state or trait.Methods: A Systematic Literature Review was conducted using PRISMA guidelines to include all studies assessing olfaction with objective measures in BD.Results: 9 studies were identified. All of them have assessed odour identification and 3 reported deficits mainly in patients with psychotic features or elements of illness severity in comparison to healthy subjects. There is no difference in threshold of perception between BD patients and controls and it is no possible to conclude for discrimination because only one study has assessed this dimension in comparison to control. We cannot conclude for hedonic value of odours regarding these studies.Limitations: These studies are very incomplete because only one has evaluated all the processes involved in olfaction process.Conclusions: In light of this review, evidence is still missing to unveil potential disturbances of olfactory process as a marker of BD. These new avenues of research could help to clarify the links between OD and BD and provide information on the pathophysiology of the disorder according to the impaired dimension

An emotional-response model of bipolar disorders integrating recent findings on amygdala circuits

International audienceBecause of our classification system limitations for defining psychiatric disorders and understanding their physiopathology, a new research area based on dimensions has emerged. It consists of exploring domains derived from fundamental behavioral components linked to neurobiological systems. Emotional processing is among the most affected dimensions in bipolar disorders (BD), but is excluded from the definition criteria. The purpose of this review is to synthesize the emotional responses disruption during the different phases of BD, using intensity and valence as the two key characteristics of emotions. We integrate those emotional disruptions into an original, emotion-based model contrasting with the current diagnostic frame built on mood. Emotional processing is underpinned by cortico-limbic circuits involving the amygdala. Recent publications showed the crucial role of the amygdala in emotional processes triggered by stimuli of negative, but also positive valence. We show how these neuroscience data can provide physiological basis for emotional disturbances observed in BD. We conclude with translational perspectives to improve the current knowledge about neural substrates underlying altered emotional responses characterizing BD

Efeitos do ácido propiônico sobre o conteúdo de lipídios e proteínas em cerebelo de ratos wistar jovens

57

Atividade da proteína quinase C (PKC) e ornitina decarboxilase (ODC) em linhagens de glioblastoma humano

11