Avaliação dos efeitos neuroprotetores da tianeptina e seu derivado NANT 03 em uma linhagem de células SH-SY5Y diferenciadas

Introdução: O Transtorno Bipolar (TB) é uma doença crônica e recorrente, e sua fisiopatologia ainda não esta completamente elucidada. Recentes estudos têm encontrado significativas alterações em vias neurotróficas em pacientes com TB, principalmente na neurotrofina BDNF. O BDNF está envolvido em muitas funções cerebrais, como sobrevivência, diferenciação neuronal e plasticidade sináptica. Fármacos que atuem aumentando os níveis de BDNF podem se tornar promissores tratamentos para o TB. Objetivos: O objetivo desse trabalho foi avaliar os efeitos neuroprotetores da tianeptina, um antidepressivo atípico, e de uma nova molécula sintetizada a partir da tianeptina em um modelo in vitro. Métodos: Para o estudo, foi utilizada uma linhagem de células de neuroblastoma humano SH-SY5Y, diferenciada em neurônios dopaminérgicos tratadas com tianeptina e NANT 03 nas concentrações de 30, 50 e 100μM por 48 horas. Após, foi quantificado os níveis de mRNA do BDNF, BDNF intracelular e secretado e níveis intracelulares de Bcl-2. Resultado: NANT 03 aumentou os níveis de mRNA do BDNF no tratamento com 50 e 100μM, aumentou BDNF intracelular e secretado e Bcl-2 na dose de 100μM. A tianeptina na dose de 100μM aumentou os níveis de BDNF intracelular e secretado. Conclusão: O novo composto apresentou um caráter neuroprotetor maior que a tianeptina o que demonstra que essa nova molécula pode contribuir para melhorar a plasticidade sináptica e cognição dos pacientes com TB.Background: Bipolar disorder (BD) is a chronic and recurrent illness and its pathophysiology is not yet completely understood. Recent studies have found significant changes in neurotrophic pathways in patients with BD, especially in the neurotrophin BDNF. BDNF is involved in several brain functions, such as neuronal survival and differentiation and synaptic plasticity. Drugs that act by increasing levels of BDNF may become promising treatments for BD. Objectives: The aim of this study was to evaluate the neuroprotective effects of tianeptine, an atypical antidepressant, and of new molecule synthesized from tianeptine in an in vitro model. Methods: For study, a cell line of human neuroblastoma SH-SY5Y differentiated into dopaminergic neurons was treated with concentrations of 30, 50 and 100μM of tianeptine and NANT 03 for 48 hours. Afterwards, it was measured the levels of BDNF mRNA, intracellular and secreted BDNF and intracellular levels of Bcl-2. Results: NANT 03 increased BDNF mRNA levels in treatment with 50 and 100μM, and increased intracellular and secreted BDNF and Bcl-2 levels in a dose of 100μM. The tianeptine in the dose of 100μM increased levels of intracellular and secreted BDNF. Conclusion: The new compound showed a neuroprotective character greater than tianeptine. This suggests this new molecule can improve cognition and neuronal plasticity of bipolar patients

Promises and pitfalls of immune-based strategies for Huntington's disease

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by the selective loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD. The objective of this review is to discuss the data obtained so far on the immune-based therapeutic strategies for HD

Gene Expression Profiling in Huntington’s Disease: Does Comorbidity with Depressive Symptoms Matter?

Huntington’s disease (HD) is an inherited neurodegenerative disease. Besides the well-characterized motor symptoms, HD is marked by cognitive impairment and behavioral changes. In this study, we analyzed the blood of HD gene carries using RNA-sequencing techniques. We evaluated samples from HD gene carriers with (n = 8) and without clinically meaningful depressive symptoms (n = 8) compared with healthy controls (n = 8). Groups were age- and sex-matched. Preprocessing of data and between-group comparisons were calculated using DESeq2. The Wald test was used to generate p-values and log2 fold changes. We found 60 genes differently expressed in HD and healthy controls, of which 21 were upregulated and 39 downregulated. Within HD group, nineteen genes were differently expressed between patients with and without depression, being 6 upregulated and 13 downregulated. Several of the top differentially expressed genes are involved in nervous system development. Although preliminary, our findings corroborate the emerging view that in addition to neurodegenerative mechanisms, HD has a neurodevelopmental component. Importantly, the emergence of depression in HD might be related to these mechanisms

Peripheral oxidative damage in early-stage mood disorders : a nested population-based case-control study

Systemic toxicity is a relevant dimension of pathophysiology in bipolar disorder, and oxidative damage is one potential link between central and peripheral pathology. Although there is mounting evidence that chronic bipolar disorder is associated with oxidative stress, studies in the early stages of bipolar disorder are scarce, and heavily reliant on clinical in lieu of population studies. The objective of this study was to confirm leading hypotheses about the role of oxidative damage in bipolar disorder. To that end, we nested a case-control study in a population-based study of young adults aged 18–24 yr. After an initial psychopathology screen, all people with a lifetime history of (hypo)mania and matched controls underwent a structured diagnostic interview. This yielded a sample of 231 participants, in whom we measured serum protein carbonyl content (PCC) and thiobarbituric acid reactive substances (TBARS). People with bipolar disorder had higher PCC levels than healthy subjects. Those with major depression were not different from control subjects in either PCC or TBARS levels. Both bipolar disorder and major depression were associated with higher PCC levels in the a priori regression model controlling for possible confounders. These findings indicate that protein oxidative damage is present from early stages and can be seen as a sign of early illness activity in mood disorders