Programa Atitude, Movimento e Escolhas para uma vida saudável em adolescentes: relação entre comportamento sedentário e desempenho cognitivo / Attitude, Movement and Choices Program for a healthy life in adolescents: relationship between sedentary behavior and cognitive performance

A adolescência é um período marcado por alterações neuroendócrinas que influenciam o desenvolvimento do cérebro e o comportamento. Adolescentes apresentam chances aumentadas de adotar comportamentos de risco em seu estilo de vida, dentre eles o comportamento sedentário. Nesse sentido, estudos de intervenção têm buscado desenvolver estratégias eficientes para estimular adolescentes a adotarem um estilo de vida saudável. No entanto, embora ações promissoras possam ser identificadas na literatura, o real mecanismo que atua na regulação do comportamento em adolescentes parece estar associado a uma neurotrofina chamada de Fator Neurotrófico Derivado do Cérebro (BDNF), e estudar como os comportamentos de risco influenciam na sua secreção são de grande relevância para desenvolver intervenções mais efetivas. Sendo assim, o objetivo da presente tese é descrever a fundamentação teórica para o planejamento de uma intervenção multicomponente baseada na escola com ações combinadas para a promoção da atividade física, redução do comportamento sedentário e educação alimentar e nutricional, e as possíveis consequências para o desempenho cognitivo e saúde de adolescentes. A metodologia está descrita em formato de coletânea de artigos e foi dividida em quatro etapas. A primeira etapa descreve uma revisão sistemática que foi desenvolvida durante os estudos de fundamentação teórica para o planejamento da intervenção do Programa Atitude, Movimento e Escolhas para uma vida saudável (Programa AME), em que foi possível identificar a necessidade de implementar uma etapa específica de formação dos professores de educação física. Na segunda etapa foi detalhada a metodologia de uma revisão sistemática que tem como objetivo de investigar a associação entre comportamento sedentário e BDNF em adolescentes. O protocolo metodológico da revisão foi registrado no Registro Internacional Prospectivo de Revisões Sistemáticas (PROSPERO) sob o identificador CRD42023392246 e segue as diretrizes dos Principais Itens para relatar Revisões Sistemáticas e Meta-análises (PRISMA). A etapa três apresenta essa revisão sistemática concluída, com todos os resultados das buscas e análise das informações extraídas dos artigos incluídos. A quarta etapa trata-se de um estudo de justificativa e fundamentação teórica para os métodos abordados no eixo de comportamento sedentário da intervenção do Programa AME, a qual foi registrada na plataforma do Registro Brasileiro de Ensaios Clínicos sob o número RBR-86xv46. Pode-se dizer que o Programa AME é uma proposta integrada, sustentável e de baixo custo, com grande potencial para produzir benefícios no estilo de vida, desempenho cognitivo e saúde de adolescentes. Por fim, os resultados desses estudos fortalecerão a prática baseada em evidências no âmbito de pesquisas voltadas para a promoção da saúde no contexto escolar (AU).

Adolescence is a period marked by several neuroendocrine changes that influence brain development and behavior. Adolescents are more likely to adopt risky behaviors in their lifestyle, including sedentary behavior. In this sense, intervention studies have sought to develop efficient strategies to encourage adolescents to adopt a healthy lifestyle. However, although promising actions can be identified in the literature, the real mechanism that acts in the regulation of behavior in adolescents seems to be associated with the neurotrophin Brain-Derived Neurotrophic Factor (BDNF), and studying how risk behaviors influence its secretion are of great relevance to develop more effective interventions. Therefore, the objective of this thesis is to describe the theoretical foundation to the planning of a school-based multicomponent intervention with combined actions to promote physical activity, reduction of sedentary behavior and food and nutrition education, and the possible consequences for cognitive performance and adolescent health. The methodology of this thesis is described in the format of a collection of articles and was divided into four stages. The first stage describes a systematic review that was developed during the theoretical foundation studies for planning the intervention of the Attitude, Movement and Choices for a Healthy Life Program (AME Program), and it was possible to identify the need to implement a specific training stage for physical education teachers. In the second stage, was detailed the methodology of a systematic review that will be developed with the objective of investigating the association between sedentary behavior and BDNF in adolescents. The methodological protocol for the review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the identifier CRD42023392246 and follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The third stage presents this completed systematic review, with all search results and analysis of information extracted from the included articles. The fourth step is a study of rationale and theoretical foundation for the methods addressed in the sedentary behavior axis of the AME Program intervention, which was registered on the Brazilian Registry of Clinical Trials platform under the number RBR-86xv46. It can be said that the AME Program is an integrated, sustainable and low-cost proposal, with great potential to produce benefits in lifestyle, cognitive performance and health of adolescents. Finally, the results of these studies will strengthen evidence-based practice in research aimed at promoting health in the school context (AU).

Validation of the Brazilian version of the child pain catastrophizing scale and its relationship with a marker of central sensitization

Abstract Objectives The Pain Catastrophizing Scale-Child version (PCS-C) allows to identify children who are prone to catastrophic thinking. We aimed to adapt the Brazilian version of PCS-C (BPCS-C) to examine scale psychometric properties and factorial structure in children with and without chronic pain. Also, we assessed its correlation with salivary levels of Brain-Derived Neurotrophic factor (BDNF). Methods The Brazilian version of PCS-C was modified to adjust it for 7-12 years old children. To assess psychometric properties, 100 children (44 with chronic pain from a tertiary hospital and 56 healthy children from a public school) answered the BPCS-C, the visual analogue pain scale, and questions about pain interference in daily activities. We also collected a salivary sample to measure BDNF. Results We observed good internal consistency (Cronbach's value = 0.81). Parallel analysis retained 2 factors. Confirmatory factor analysis of our 2-factor model revealed consistent goodness-of-fit (IFI = 0.946) when compared to other models. There was no correlation between visual analogue pain scale and the total BPCS-C score; however, there was an association between pain catastrophizing and difficulty in doing physical activities in school (p= 0.01). BPCS-C total scores were not different between groups. We found a marginal association with BPCS-C (r= 0.27, p= 0.01) and salivary BDNF levels. Discussion BPCS-C is a valid instrument with consistent psychometric properties. The revised 2-dimension proposed can be used for this population. Children catastrophism is well correlated with physical limitation, but the absence of BPCS-C score differences between groups highlights the necessity of a better understanding about catastrophic thinking in children.

Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway

Purpose: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. Methods: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). Results: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. Conclusions: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.

ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling / 南方医科大学学报

OBJECTIVE@#To investigate the inhibitory effect of ANA-12 that blocks brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrkB) signaling on inflammatory pain in rats and explore the underlying mechanism.@*METHODS@#Forty-two adult SD rats were randomized into BDNF-induced acute pain group (n=24) and CFA-induced chronic pain group. The former group were randomly divided into 4 subgroups, including a control group, ANA-12 treatment group, BDNF treatment group, and BDNF+ANA-12 treatment group; the latter group were subgrouped into control group, CFA treatment group (CFA) and CFA + ANA-12 treatment group. The effects of ANA-12 treatment on pain behaviors of the rats with BDNF-induced acute pain and CFA-induced chronic inflammatory pain were observed. Western blotting was used to examine TrkB signaling and expressions of microglia marker protein Iba1 and TNF-α in the spinal cord of the rats.@*RESULTS@#BDNF injection into the subarachnoid space significantly increased the number of spontaneous paw withdrawal of the rats (P < 0.05), which was obviously reduced by ANA-12 treatment (P < 0.05). The rats with intraplantar injection of CFA, showed significantly increased ipsilateral mechanical stimulation sensitivity (P < 0.05), and ANA-12 treatment obviously increased the ipsilateral foot withdrawal threshold (P < 0.05). Treatment with either BDNF or CFA significantly increased the phosphorylation level of TrkB (Y705) in the spinal cord of the rats (P < 0.05), which was significantly lowered by ANA-12 treatment (P < 0.05). Treatment with BDNF and CFA both significantly up-regulated the expressions of Iba1 and TNF-α in the spinal cord (P < 0.05), but ANA-12 significantly reduced their expression levels (P < 0.05).@*CONCLUSION@#ANA-12 can reduce spinal cord inflammation and relieve acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling.

The influencing factors of cognitive impairment in patients with silicosis / 中华劳动卫生职业病杂志

Objective: To explore the influencing factors of cognitive impairment in patients with silicosis, and to analyze the effect of brain-derived neurotrophic factor (BDNF) on cognitive function. Methods: In March 2021, 484 silicosis patients from April 2018 to April 2020 were included in the study. The Montreal Cognitive Assessment Scale of Chinese version was used to evaluate their cognitive function, and they were divided into the cognitive impairment group (n=282) and the non cognitive impairment group (n=202) , another 30 healthy persons from body check were served as control group. The concentrations of BDNF were compared between the three groups. And the receiver operating characteristic (ROC) curve was drawed to analyze the value of BDNF in predicting cognitive impairment in silicosis patients. And the logistic regression analysis was used to explore the risk factors of cognitive impairment. Results: The incidence of cognitive impairment in silicosis patients was 58.26% (282/484) . The level of BDNF in the cognitive impairment group[ (10.32±2.11) mg/L] was significantly lower than that in the non cognitive impairment group[ (13.43±3.45) mg/L] (t=-12.27, P<0.001) . The results of ROC curve analysis showed that the area unde the curve of BDNF in predicting cognitive impairment of silicosis patients was 0.763 (95%CI: 0.613-0.874, P=0.024) , the cut off value was 10 mg/L, the sensitivity was 0.88, and the specificity was 0.84. Logistic regression analysis showed that the level of BDNF (≤10 mg/L) , age (≥65 years old) , course of disease (≥5 years) and diabetes mellitus were the risk factors of cognitive impairment in silicosis patients (OR=2.346, 95%CI: 1.654-3.103; OR=1.757, 95%CI: 1.214-1.998; OR=1.346, 95%CI: 1.112-1.564; OR=1.165, 95%CI: 1.102-1.542, P=0.001, 0.012, 0.027, 0.036) . Conclusion: BDNF may be one of the indicator to predict the risk of cognitive impairment in patients with silicosis.

Effect of BDNF-AS/miR-145-5p axis on renal tubular epithelial cell injury induced by high glucose / 中华医学遗传学杂志

OBJECTIVE@#To investigate the effect and possible mechanism of BDNF-AS on renal tubular epithelial cell injury induced by high glucose.@*METHODS@#Human renal tubular epithelial cells HK-2 were cultured in vitro and transfected with BDNF-AS small interfering RNA or miR-145-5p mimic, or co-transfected with BDNF-AS small interfering RNA and miR-145-5p inhibitor, respectively. The cells were then intervened with 30 mmol/L glucose for 24 hours. The expression of BDNF-AS and miR-145-5p were detected by RT-qPCR. Cell proliferation was detected by CCK-8, and apoptosis was detected by flow cytometry. The expression of Bcl-2 and Bax proteins were detected by Western blotting, and the levels of IL-1β and IL-6 in cell culture supernatant were detected by enzyme-linked immunosorbent assay. Dual luciferase reporter gene experiment was used to verify the regulatory relationship of BDNF-AS with miR-145-5p.@*RESULTS@#High glucose promoted the expression of BDNF-AS in HK-2 cells (P<0.05), but inhibited that of miR-145-5p (P<0.05). Interfering with BDNF-AS or overexpression of miR-145-5p decreased the inhibition rate, apoptosis rate and expression of Bax protein, IL-1β and IL-6 of HK-2 cells induced by high glucose (P<0.05), but promoted the expression of Bcl-2 protein (P<0.05). Interfering with miR-145-5p reversed the effect of interfering with BDNF-AS on the proliferation, apoptosis rate and the expression of IL-1β and IL-6 of HK-2 cells induced by high glucose. BDNF-AS could target and down-regulate miR-145-5p.@*CONCLUSION@#Interfering with BDNF-AS may promote the proliferation of renal tubular epithelial cells induced by high glucose and inhibit cell apoptosis and the expression of inflammatory factor by down-regulating miR-145-5p.

Dysfunctional eating behavior in fibromyalgia and its association with serum biomarkers of brain plasticity (BDNF and S100B): an exploratory study

ABSTRACT Objectives: To assess disordered eating, hunger and satiety perceptions in women with fibromyalgia (FM) compared to healthy controls (HC) and their association with biomarkers of brain plasticity (brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B)). Subjects and methods: Cross-sectional exploratory study. The sample included FM (n = 20) and HC (n = 19), matched to age and waist perimeter. Dysfunctional eating was assessed through the Three Factor Eating Questionnaire and Eating Disorders Examination with a questionnaire. Hunger and satiety levels were rated by a Numerical Scale. Serum leptin, S100B and BDNF were analyzed. Results: The MANCOVA analysis showed that the mean of Emotional Eating rates was 30.65% higher in FM compared to HC ( p = 0.015). Eating, shape and weight concerns were 77.77%, 57.14% and 52.22% higher in FM ( p = <0.001) compared to HC, respectively. Moreover, the FM group reported higher scores for feeling of hunger "[5.2 (±2.9) vs. 4.8 (±2.0); p = 0.042] and lower scores for satiety [7.0 (±1.7) vs . 8.3 (±1.0); p = 0.038]. In the FM group, serum BDNF was negatively associated with hunger (r = - 0.52; p = 0.02), while S100B was positively associated with hunger scores (r = 0.463; p = 0.004). Conclusion: The present findings support the hypothesis that the association between FM and obesity can be mediated by a hedonistic pathway. Further research is needed.

BDNF Val66Met polymorphism and resilience in major depressive disorder: the impact of cognitive psychotherapy

Objective: Clinical and biological correlates of resilience in major depressive disorder are scarce. We aimed to investigate the effect of the Val66Met polymorphism in the BDNF gene on resilience scores in major depressive disorder patients and evaluate the polymorphism's moderation effect on resilience scores in response to cognitive therapy. Method: A total of 106 major depressive disorder patients were enrolled in this clinical randomized study. The Resilience Scale and the Hamilton Rating Scale for Depression were applied at baseline, post-treatment, and at six months of follow-up. Blood samples were obtained at baseline for molecular analysis. Results: The baseline resilience scores were higher in patients with the Met allele (114.6±17.6) than in those with the Val/Val genotype (104.04±21.05; p = 0.037). Cognitive therapy treatment increased resilience scores (p ≤ 0.001) and decreased depressive symptoms (p ≤ 0.001). In the mixed-effect model, the Val/Val genotype represented a decrease in resilience scores (t218 = -1.98; p = 0.048), and the Val66Met polymorphism interacted with sex to predict an increase in total resilience scores during cognitive treatment (t218 = 2.69; p = 0.008). Conclusion: Our results indicate that cognitive therapy intervention could improve resilience in follow-up, considering that gender and genetic susceptibility are predicted by the Val66Met polymorphism.

Effects of scorpion venom heat-resistant peptide on the hippocampal neurons of kainic acid-induced epileptic rats

Scorpion venom is a Chinese medicine for epilepsy treatment, but the underlying mechanism is not clear. Scorpion venom heat-resistant peptide (SVHRP), a peptide isolated from the venom of Buthus martensii Karsch, has an anti-epileptic effect by reducing seizure behavior according to a modified Racine scale. The present study aimed to investigate the molecular mechanism of SVHRP on temporal lobe epilepsy. The hippocampus and hippocampal neurons from kainic acid-induced epileptic rats were treated with SVHRP at different doses and duration. Quantitative RT-PCR and immunoblotting were used to detect the expression level of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), cAMP-response element binding protein (CREB), stromal interaction molecule (STIM), and calcium release-activated calcium channel protein 1 (ORAI1). In the hippocampal tissues and primary hippocampal neuron cultures, SVHRP treatment resulted in increased mRNA and protein levels of BDNF and NPY under the epileptic condition. The upregulation of BDNF and NPY expression was positively correlated with the dose level and treatment duration of SVHRP in hippocampal tissues from kainic acid-induced epileptic rats. On the other hand, no significant changes in the levels of CREB, STIM, or ORAI1 were observed. SVHRP may exhibit an anti-epileptic effect by upregulating the expression of BDNF and NPY in the epileptic hippocampus.

Rapid and long-lasting antidepressant-like effects of ketamine and their relationship with the expression of brain enzymes, BDNF, and astrocytes

Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug's sustained antidepressant-like effects.

Estado nutricional de indivíduos com Comprometimento Cognitivo Leve e Doença de Alzheimer em relação ao Selênio e sua associação com parâmetros que predispõem ao declínio cognitivo / Nutritional status of subjects with mild cognitive impairment and Alzheimer's disease in relation to selenium and its association with paramenters that predispose to cognitive decline

A Doença de Alzheimer (DA) é a principal forma de demência e um dos grandes desafios no sistema de saúde do século 21. O Comprometimento Cognitvo Leve (CCL) é um estágio que antecede a DA e que compartilha algumas vias metabólicas em comum. A fisiopatologia da DA é caracterizada pela ampla morte neuronal e pela presença de placas neuríticas e emaranhados neurofibrilares, respectivamente relacionadas ao acúmulo de peptídeo beta amiloide (Aß) em tecidos cerebrais e alterações no citoesqueleto que se originam da hiperfosforilação da proteína tau nos neurônios. Algumas linhas de evidência sustentam a hipótese de que o estresse oxidativo, nitrosativo e a inflamação tenham um papel importante na patogênese tanto do DA como do CCL. O selênio, mineral essencial ao ser humano, encontra-se incorporado ao sítio ativo de 25 selenoproteínas, das quais pelo menos um terço apresenta papel antioxidante, além de potencialmente modularem o sistema inflamatório. Deste modo, o estado nutricional adequado dos indivíduos relativo ao selênio, parece exercer efeito neuroprotetor, reduzindo o risco para o CCL e DA e retardando a progressão destas doenças. A entrega de selênio para o cérebro se dá pela interação da selenoproteína P (SELENOP) com o receptor de apolipoproteína E2 (ApoER2). A apolipoproteína E (ApoE) também interage com o ApoER2 no metabolismo de lipídeos. Assim, pode-se pensar que indivíduos portadores do polimorfismo do gene da apolipoproteína E ε4 (APOE ε4), o principal polimorfismo genético para o aumento no risco de desenvolvimento de DA, possam ter essa entrega de selênio prejudicada para o cérebro uma vez que os receptores ApoER2 dos portadores do polimorfismo de APOE ε4 são sequestrados para compartimentos intracelulares, sendo menos expressos na membrana plasmática e portanto diminuindo a interação com a SELENOP. Este trabalho teve por objetivo avaliar se a distribuição do selênio no plasma e líquor de indivíduos portadores de CCL e DA é afetada pelo alelo APOE ε4, avaliar se o estado nutricional do indivíduo em relação ao selênio afeta marcadores de assinatura biológica para DA (peptídeo beta amilóide, proteína tau e proteína tau fosforilada) e concentrações de citocinas inflamatórias. Para tanto, foram selecionadas amostras de plasma e líquor do banco de material biológico do Instituto de Psiquiatria da FMUSP, sendo 14 indivíduos do grupo CCL, 28 indivíduos do grupo DA e 28 indivíduos controles, de ambos os gêneros, com idade acima de 60 anos e residentes na cidade de São Paulo. Foram avaliados os seguintes marcadores: concentrações de selênio no plasma e líquor, concentrações SELENOP no plasma e líquor, citocinas inflamatórias, fator neurotrófico derivado do cérebro (BDNF) e marcadores de assinatura biológica para DA. Não foi evidenciada diferença entre os três diferentes grupos em relação ao selênio e a SELENOP da mesma forma que não houve influência do genótipo APOE ε4 nas concentrações de selênio e SELENOP, porém houve uma tendência de menores concentrações de selênio plasmático nos carreadores do alelo APOE ε4. Também houve uma tendência a uma menor pontuação nos testes MMSE e CAMCOG em indivíduos com menores concentrações plasmáticas de selênio. Não se evidenciou que o estado nutricional dos indivíduos em relação ao selênio influencie as concentrações de marcadores para assinatura biológica para DA e de citocinas inflamatórias, com exceção da IL-10 que apresentou correlação positiva com SELENOP plasmática. A partir desses resultados, conclui-se que o estado nutricional dos indivíduos relativo ao selênio parece não ter influencia significativa em aspectos do CCL e DA e que sua distribuição não é alterada pelo genótipo APOE ε4

Alzheimer's disease (AD) is the main form of dementia and one of the major challenges in the healthcare system of the 21st century. Mild Cognitive Impairment (MCI) is a stage that precedes AD and shares common metabolic pathways. The pathophysiology of AD is characterized by extensive neuronal death, presence of neuritic plaques and neurofibrillary tangles, respectively related to the accumulation of amyloid beta peptide (Aß) in brain tissues and changes in the cytoskeleton that originate from hyperphosphorylation of the Tau protein in neurons. Some lines of evidence support the hypothesis that oxidative, nitrosative stress and inflammation play an important role in the pathogenesis of both AD and MCI. Selenium, an essential mineral to humans, is incorporated into the active site of 25 selenoproteins, of which at least one third has an antioxidant role, in addition to its potential in modulating the inflammatory system. Therefore, the appropriate nutritional status related to selenium seems to exert a neuroprotective effect, reducing the risk for MCI and AD and decreasing the progression of these diseases. Selenium is delivered to the brain by the interaction of selenoprotein P (SELENOP) with the ApoE2 receptor (ApoER2). Apolipoprotein E (ApoE) also interacts with ApoER2 in lipid metabolism. Thus, it can be speculated that individuals that carry apolipoprotein E ε4 gene (APOE ε4), the main genetic polymorphism that increases the risk of AD, may have impaired selenium delivery to the brain since ApoER2 receptors of the APOE ε4 carriers are sequestered to intracellular compartments, being less expressed in the plasma membrane decreasing its interaction with SELENOP. This study aimed to assess whether the distribution of selenium in the plasma and CSF of subjects with MCI and AD is affected by the APOE ε4 allele, evaluate whether the nutritional status of selenium affects biological signature markers for AD (amyloid beta peptide, tau protein and phosphorylated tau protein) and to asses the concentrations of inflammatory cytokines. For this purpose, plasma and cerebrospinal fluid (CSF) samples were selected from the biological material bank of the Institute of Psychiatry of FMUSP, with 14 subjects from the MCI group, 28 from the DA group and 28 from control subjects, both genders, aged over 60 years and São Paulo residents. The following markers were evaluated: selenium concentrations in plasma and CSF, SELENOP concentrations in plasma and CSF, inflammatory cytokines, brain-derived neurotrophic factor (BDNF) and biological signature for AD. There was no difference between the three different groups in relation to selenium and SELENOP; in addition, there was no influence of the APOE ε4 genotype on selenium and SELENOP concentrations, but there was a tendency towards lower plasma selenium concentrations in the APOE ε4 carriers. There was also a tendency for lower scores on the MMSE and CAMCOG tests in subjects with lower plasma selenium concentrations. It was not shown that selenium nutritional status influences the concentrations of biological signature for AD and inflammatory cytokines, with the exception of IL-10 which showed a positive correlation with plasma SELENOP. From these results, we concluded that selenium nutritional status does not seem to have a significant influence in aspects of MCI and DA and that its distribution is not altered by the APOE genotype ε4

GluN2B-BDNF pathway in the cerebrospinal fluid-contacting nucleus mediates nerve injury-induced neuropathic pain in rats / 生理学报

The present study was aimed to investigate the role of GluN2B-BDNF pathway in the cerebrospinal fluid-contacting nucleus (CSF-CN) in neuropathic pain. Intra-lateral ventricle injection of cholera toxin subunit B conjugated with horseradish peroxidase (CBHRP) was used to label the CSF-CN. Double-labeled immunofluorescent staining and Western blot were used to observe the expression of GluN2B and BDNF in the CSF-CN. Chronic constriction injury of sciatic nerve (CCI) rat model was used to duplicate the neuropathic pain. Pain behavior was scored to determine the analgesic effects of GluN2B antagonist Ro 25-6981 and BDNF neutralizing antibody on CCI rats. GluN2B and BDNF were expressed in the CSF-CN and their expression was up-regulated in CCI rats. Intra-lateral ventricle injection of GluN2B antagonist Ro 25-6981 or BDNF neutralizing antibody notably alleviated thermal hyperalgesia and mechanical allodynia in CCI rats. Moreover, the increased expression of BDNF protein in CCI rats was reversed by intra-lateral ventricle injection of Ro 25-6981. These results suggest that GluN2B and BDNF are expressed in the CSF-CN and alteration of GluN2B-BDNF pathway in the CSF-CN is involved in the modulation of the peripheral neuropathic pain.

Beneficial effects of octreotide in alcohol-induced neuropathic pain. Role of H 2S, BDNF, TNF-α and Nrf2

ABSTRACT Purpose To explore the role and molecular mechanisms of neuroprotective effects of octreotide in alcohol-induced neuropathic pain. Methods Male Wistar rats were employed and were administered a chronic ethanol diet containing 5% v/v alcohol for 28 days. The development of neuropathic pain was assessed using von Frey hair (mechanical allodynia), pinprick (mechanical hyperalgesia) and cold acetone drop tests (cold allodynia). The antinociceptive effects of octreotide (20 and 40 µg·kg-1) were assessed by its administration for 28 days in ethanol-treated rats. ANA-12 (0.25 and 0.50 mg·kg-1), brain-derived neurotrophic factor (BDNF) receptor blocker, was coadministered with octreotide. The sciatic nerve was isolated to assess the biochemical changes including hydrogen sulfide (H2S), cystathionine β synthase (CBS), cystathionine γ lyase (CSE), tumor necrosis factor-α (TNF-α), BDNF and nuclear factor erythroid 2-related factor 2 (Nrf2). Results Octreotide significantly attenuated chronic ethanol-induced neuropathic pain and it also restored the levels of H2S, CBS, CSE, BDNF, Nrf2 and decreased TNF-α levels. ANA-12 abolished the effects of octreotide on pain, TNF-α, BDNF, Nrf2 without any significant effects on H2S, CBS, CSE. Conclusions Octreotide may attenuate the behavioral manifestations of alcoholic neuropathic pain, which may be due to an increase in H2S, CBS, CSE, BDNF, Nrf2 and a decrease in neuroinflammation.

Níveis Séricos do BDNF na Proteção Cardiovascular e em Resposta ao Exercício / Serum Levels of BDNF in Cardiovascular Protection and in Response to Exercise

Resumo As doenças cardiovasculares (DCV) são atualmente a maior causa de morte no Brasil e no mundo. Em 2016 as DCV foram responsáveis por mais de 17 milhões de mortes, representando 31% de todas as mortes em nível global. Mecanismos moleculares e genéticos podem estar envolvidos na proteção cardiovascular e devem ser considerados nas novas abordagens terapêuticas. Nesse sentido, recentes estudos têm relatado que o Fator Neurotrófico Derivado do Encéfalo (Brain-Derived Neurotrophic Factor, BDNF) está reduzido em indivíduos predispostos a desenvolverem DCV, e que o treinamento físico aeróbio aumenta as quantidades de BDNF circulante. O BDNF é uma neurotrofina encontrada em altas concentrações no hipocampo e córtex cerebral, sendo considerada molécula-chave na manutenção da plasticidade sináptica e na sobrevivência das células neuronais. Além da plasticidade neuronal, BDNF também é importante na função vascular, promovendo angiogênese por meio da regulação por espécies reativas de oxigênio (ROS). Entretanto, uma variante do gene do BDNF em humanos, o polimorfismo Val66Met (substituição do aminoácido valina por uma metionina na posição 66 do códon), que ocorre em 20-30% da população caucasiana, pode afetar as concentrações de BDNF no plasma e sua atividade em todos os tecidos periféricos contendo receptores tirosina quinase B (TrkB), como o endotélio. De fato, recentemente observamos que o polimorfismo Val66Met prejudica a reatividade vascular e o BDNF circulante em resposta ao treinamento físico. Dessa forma, apresentaremos a seguir uma discussão sobre os níveis séricos de BDNF na proteção cardiovascular, a variante genética Val66Met na reatividade vascular e o efeito do exercício físico.

Abstract Cardiovascular disease (CVD) is currently the leading cause of death in Brazil and worldwide. In 2016, CVD accounted for more than 17 million deaths, representing 31% of all deaths globally. Molecular and genetic mechanisms may be involved in vascular protection and should be considered in new therapeutic approaches. In this sense, recent studies have reported that brain-derived neurotrophic factor (BDNF) is reduced in individuals predisposed to develop CVD, and that aerobic physical training increases the amounts of circulating BDNF. BDNF is a neurotrophin found at high concentrations in the hippocampus and cerebral cortex and is considered a key molecule for the maintenance of synaptic plasticity and survival of neuronal cells. In addition to neuronal plasticity, BDNF is also important in vascular function, promoting angiogenesis through the regulation of reactive oxygen species (ROS). However, a variant of the BDNF gene in humans, the Val66Met polymorphism (substitution of the amino acid valine for a methionine at position 66 of the codon), occurring in 20-30% of the Caucasian population, may affect plasma BDNF concentrations and its activity in all peripheral tissues containing tyrosine kinase B receptors (TrkB), such as the endothelium. Thus, we will present a discussion about the role of serum BDNF levels in cardiovascular protection, Val66Met genetic variant in vascular reactivity and the effect of physical exercise.

Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial

Objective: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. Methods: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. Results: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. Conclusion: Larger, combined datasets are necessary to identify candidate genes for tDCS response.

Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal

Objective: To evaluate the association between childhood trauma (CT) and serum levels of brain-derived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crack-cocaine withdrawal. Method: Thirty-three male crack-cocaine users were recruited at admission to a public addiction treatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Information about drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reported throughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on a latent analysis model that divided the sample into low-, medium-, and high-level trauma groups. Results: There was a significant increase in BDNF levels from admission to discharge, which did not differ across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction (F2,28 = 6.357, p = 0.005,ηp 2 = 0.312). In participants with low trauma level, TBARS decreased, while in those with a high trauma level, TBARS increased during early withdrawal. Conclusion: TBARS levels showed opposite patterns of change in crack-cocaine withdrawal according to baseline CT. These results suggest that CT could be associated with more severe neurological impairment during withdrawal.

Relationship of brain-derived neurotrophic factor, malondialdehyde, and 8-Hydroxy 2-Deoxyguanosine with post-ischemic stroke depression / A relação do fator neurotrófico derivado do cérebro, malondialdeído e 8-hidroxi 2-desoxiganosina com a depressão pós-avc isquêmica

ABSTRACT A few studies have shown that serum brain-derived neurotrophic factor (BDNF) level in post-stroke depression is highly correlated with memory and neuropsychiatric disturbances. Objective: This study aimed to elucidate the relationship of serum BDNF, malondialdehyde (MDA), and 8-Hydroxy 2-Deoxyguanosine (8-OhdG) levels in acute stroke cases with one-month post-stroke depression. Methods: An observational study was conducted of 72 post-ischemic stroke patients in the Neurology ward of the Dr. M. Djamil Hospital, Padang, West Sumatra, Indonesia. Acute stroke (< 48 hours) serum BDNF, MDA, and 8-OhdG levels were measured using ELISA. Based on observations using the Hamilton Depression Rating Scale conducted one month after stroke, respondents were divided into two groups: with and without depression. The mean serum level was analyzed using the t-test and Mann-Whitney test, while differences in basic characteristics were analyzed using the Chi-square test. Multivariate analysis was conducted to determine the most significant factor associated with post-stroke depression. The error rate was set at 5%. Results: BDNF levels in acute stroke were significantly lower in the depression group than in the non-depression group (p < 0.05). MDA and 8-OhdG levels in acute stroke were higher in the depression group (p < 0.05). BDNF level during acute stroke was negatively correlated with post-stroke depression, while, conversely, acute stroke MDA and 8-OhdG levels were positively correlated with depression. Conclusion: BDNF had a negative correlation, while MDA and 8-OhdG had a positive correlation, with depression one-month post-stroke. 8-OhdG was the most influential factor in post-stroke depression.

RESUMO Alguns estudos mostraram que o nível sérico de fator neurotrófico derivado do cérebro (BDNF) na depressão pós-AVC está altamente correlacionado com a memória e com os distúrbios neuropsiquiátricos. Objetivo: Este estudo teve como objetivo elucidar a relação entre os níveis séricos de BDNF, malondialdeído (MDA) e 8-hidroxi 2-desoxiganosanos (8 OhdG) em casos de AVC agudo com depressão pós-AVC de um mês. Métodos: Um estudo observacional foi realizado em 72 pacientes com AVC pós-isquêmico na enfermaria de Neurologia do Hospital Dr. M. Djamil, Padang, Sumatra Ocidental, Indonésia. Os níveis séricos de BDNF, MDA e 8-OhdG no AVC agudo (< 48 horas) foram medidos usando ELISA. Com base nas observações da Hamilton Depression Rating Scale realizada um mês após o AVC, os entrevistados foram divididos em dois grupos: com e sem depressão. O nível sérico médio foi analisado pelo teste T e Mann-Whitney, enquanto as diferenças nas características básicas foram analisadas pelo teste do qui-quadrado. A análise multivariada foi realizada para determinar o fator mais significativo associado à depressão pós-AVC. A taxa de erro foi fixada em 5%. Resultados: O nível de BDNF no AVC agudo foi significativamente menor na depressão do que no grupo sem depressão (p < 0,05). Os níveis de MDA e 8-OhdG no AVC agudo foram maiores no grupo de depressão (p < 0,05). O nível de BDNF durante o AVC agudo foi negativamente correlacionado com os casos de depressão pós-AVC, enquanto, inversamente, os níveis de MDA e 8-OhdG do AVC agudo foram positivamente correlacionados com os casos de depressão. Conclusão: O BDNF tem uma correlação negativa, enquanto o MDA e o 8-OhdG tiveram uma correlação positiva com a depressão um mês após o AVC. 8-OhdG foi o fator mais influente na depressão pós-AVC.

Enriched environment improves sevoflurane-induced cognitive impairment during late-pregnancy via hippocampal histone acetylation

Fetal exposure to sevoflurane induces long-term cognitive impairment. Histone acetylation regulates the transcription of genes involved in memory formation. We investigated whether sevoflurane exposure during late-pregnancy induces neurocognitive impairment in offspring, and if this is related to histone acetylation dysfunction. We determined whether the effects could be reversed by an enriched environment (EE). Pregnant rats were exposed to 2.5% sevoflurane or control for 1, 3, or 6 h on gestational day 18 (G18). Sevoflurane reduced brain-derived neurotrophic factor (BDNF), acetyl histone H3 (Ac-H3), and Ac-H4 levels and increased histone deacetylases-2 (HDAC2) and HDAC3 levels in the hippocampus of the offspring on postnatal day 1 (P1) and P35. Long-term potentiation was inhibited, and spatial learning and memory were impaired in the 6-h sevoflurane group at P35. EE alleviated sevoflurane-induced cognitive dysfunction and increased hippocampal BDNF, Ac-H3, and Ac-H4. Exposure to 2.5% sevoflurane for 3 h during late-pregnancy decreased hippocampal BDNF, Ac-H3, and Ac-H4 in the offspring but had no effect on cognitive function. However, when the exposure time was 6 h, impaired spatial learning and memory were linked to reduced BDNF, Ac-H3, and Ac-H4, which could be reversed by EE.

Association of BDNF gene polymorphism with endophenotypes in posttraumatic stress disorder

SUMMARY OBJECTIVE To explore the association of brain-derived neurotrophic factor gene (BDNF) polymorphism with the latent cognitive endophenotype of posttraumatic stress disorder (PTSD) after major natural disasters in Hainan Province, China. METHODS A total of 300 patients with PTSD and 150 healthy controls (HC) were surveyed by psychoanalysis scale to assess their cognitive functions. Polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE) were used to detect the BDNF gene polymorphism. RESULTS In terms of the cognitive function, the scores in the PTSD group were worse than those of the HC group (P < 0.05 or P < 0.01). There was a significant difference in the distribution of BDNF genotype and allele frequency between the two groups (P < 0.05). PTSD endophenotypes were significantly different among the BDNF genotypes in the PTSD group (P ≤ 0.01). CONCLUSION There is a statistically significant difference in the polymorphism of BDNF gene between PTSD and HC groups, and the alleles are associated with the incidence of PTSD. Thus, it may be a risk factor for PTSD.

RESUMO OBJETIVO Explorar a associação do polimorfismo do gene fator neurotrófico derivado do cérebro (BDNF) com o endofenótipo cognitivo latente de transtorno de estresse pós-traumático (TEPT) após grandes desastres naturais na província de Hainan, China. MÉTODOS Um total de 300 doentes com TEPT e 150 controles saudáveis (HC) foi investigado pela escala de psicanálise para avaliar as suas funções cognitivas. A reação em cadeia polimerase (PCR) e a eletroforese em gel de poliacrilamida (Page) foram usadas para detectar o polimorfismo do gene BDNF. RESULTADOS Em termos de função cognitiva, as pontuações no grupo TEPT foram piores do que as do grupo HC (P<0,05 ou P<0,01). Houve uma diferença significativa na distribuição do genótipo de BDNF e frequência do alelo entre os dois grupos (P<0,05). Os endofenótipos de TEPT foram significativamente diferentes entre os genótipos de BDNF do grupo TEPT (P≤0,01). CONCLUSÃO Existe uma diferença estatisticamente significativa no polimorfismo do gene BDNF entre o TEPT e os grupos HC, e os alelos estão associados à incidência do TEPT. Assim, pode ser um fator de risco para TEPT.