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Alzheimer's disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aβ) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aβ accumulation and neuronal loss are not completely clear. Importantly, the blood-brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD. Yes

Both conditions, major depressive disorder (MDD) and diabetes mellitus (DM) are chronic and disabling diseases that affect a very significant percentage of the world’s population. Studies have been shown that patients with DM are more susceptible to develop depression, when compared to the general population. The opposite also happens; MDD could be a risk factor for DM development. Some mechanisms have been proposed to explain the pathophysiological mechanisms involved with these conditions, such as excess of glucocorticoids, hyperglycemia, insulin resistance, and inflammation. These processes can lead to an increase in damage to biomolecules and a decrease in antioxidant defense capacity, leading to oxidative stress.

Early-life challenges, particularly infections and stress, are related to neuropsychiatric disorders such as autism and schizophrenia. Here, we conducted a wide range of behavioral tests in periadolescent (postnatal day (PN) 35) and adult (PN70) Swiss mice neonatally challenged with LPS on PN5 and -7, to unveil behavioral alterations triggered by LPS exposure. Immune and neurotrophic (brain-derived neurotrophic factor—BDNF) alterations were determined in the prefrontal cortex (PFC), hippocampus (HC), and hypothalamus (HT). Since the incidence and clinical manifestations of neurodevelopmental disorders present significant sex-related differences, we sought to distinctly evaluate male and female mice. While on PN35, LPS-challenged male mice presented depressive, anxiety-like, repetitive behavior, and working memory deficits; on PN70, only depressive- and anxiety-like behaviors were observed. Conversely, females presented

Background: The assessment of a ff ective temperaments has provided useful insights for the psychopatholo- gical understanding of a ff ective disorders and for the conceptualization of bipolar spectrum disorders. The Temperament in Memphis Pisa and San Diego (TEMPS) instrument has been widely used in research, yet its psychometric properties and optimal factor structure are unclear. Methods: The PubMed/MEDLINE, PsycINFO, and EMBASE electronic databases were searched from inception until March 15th, 2016. Validation peer-reviewed studies of di ff erent versions of the TEMPS performed in adult samples were considered for inclusion. Results: Twenty-seven studies ( N =20,787) met inclusion criteria. Several versions of the TEMPS have been validated in 14 languages across 15 countries. The 110-item self-reported version of the TEMPS has been the most studied version. Most studies (50%) supported a fi ve factor solution although few studies performed con fi rmatory factor analyses. A fi ve-factor solution has consistently been reported for the 39-item version of the TEMPS-A. Overall, evidence indicates that di ff erent versions of the TEMPS have adequate internal consistency reliability, while the TEMPS-A-110 version has acceptable test-retest reliability. The methodological quality of included studies varied. Limitations: A meta-analysis could not be performed due to the heterogeneity of settings and versions of the TEMPS utilized

Objectives: The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). Methods: Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. Results: The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. Conclusions: Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system − alterations presented in the animal models of mania – is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers.

Objectives The first drug repurposed for the treatment of depression was the tuberculostatic iproniazid. At present, drugs belonging to new classes of antidepressants still have antimicrobial effects. Dysbiosis of gut microbiota was implicated in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). Based on the current interest in the gut-brain axis, the focus of this narrative review is to compile the available studies regarding the influences of gut microbiota in behavior and depression and to show the antimicrobial effect of antidepressant drugs. A discussion regarding the possible contribution of the antimicrobial effect of antidepressant drugs to its effectiveness/resistance is included. Methods The search included relevant articles from PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge. Results MDD is associated with changes in gut permeability and microbiota composition. In this respect, antidepressant drugs present antimicrobial effects that could also be related to the effectiveness of these drugs for MDD treatment. Conversely, some antimicrobials present antidepressant effects. Conclusion Both antidepressants and antimicrobials present neuroprotective/antidepressant and antimicrobial effects. Further studies are needed to evaluate the participation of antimicrobial mechanisms of antidepressants in MDD treatment as well as to determine the contribution of this effect to antidepressant resistance.

© The Royal Australian and New Zealand College of Psychiatrists 2017, Objective: It is unclear whether blockade of the angiotensin system has effects on mental health. Our objective was to determine the impact of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor (AT1R) blockers on mental health domain of quality of life. Study design: Meta-analysis of published literature. Data sources: PubMed and clinicaltrials.gov databases. The last search was conducted in January 2017. Study selection: Randomized controlled trials comparing any angiotensin converting enzyme inhibitor or AT1R blocker versus placebo or non-angiotensin converting enzyme inhibitor or non-AT1R blocker were selected. Study participants were adults without any major physical symptoms. We adhered to meta-analysis reporting methods as per PRISMA and the Cochrane Collaboration. Data synthesis: Eleven studies were included in the analysis. When compared with placebo or other antihypertensive medications, AT1R blockers and angiotensin converting enzyme inhibitors were associated with improved overall quality of life (standard mean difference = 0.11, 95% confidence interval = [0.08, 0.14], p < 0.0001), positive wellbeing (standard mean difference = 0.11, 95% confidence interval = [0.05, 0.17], p < 0.0001), mental (standard mean difference = 0.15, 95% confidence interval = [0.06, 0.25], p < 0.0001), and anxiety (standard mean difference = 0.08, 95% confidence interval = [0.01, 0.16], p < 0.0001) domains of QoL. No significant difference was found for the depression domain (standard mean difference = 0.05, 95% confidence interval = [0.02, 0.12], p = 0.15). Conclusions: Use of angiotensin blockers and inhibitors for the treatment of hypertension in otherwise healthy adults is associated with improved mental health domains of quality of life. Mental health quality of life was a secondary outcome in the included studies. Research specifically designed to analyse the usefulness of drugs that block the angiotensin system is necessary to properly evaluate this novel psychiatric target., B.S.F. is supported by a postdoctoral fellowship from Deakin University, Australia. C.A.K. is supported by a postdoctoral scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; Brazil). A.F.C. is supported by a research fellowship award from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil). J.Q. is a 1A CNPq Research Fellow. M.B. is supported by a NHMRC Senior Principal Research Fellowship 1059660.

New studies suggest that polyunsaturated fatty acids, such as omega-3, may reduce the symptoms of schizophrenia. The present study evaluated the preventive effect of omega-3 on interleukines (IL) and neurotrophin brain-derived neurotrophic factor (BDNF) levels in the brains of young rats subjected to a model of schizophrenia. Treatment was performed over 21 days, starting on the 30th day of rat’s life. After 14 days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25 mg/kg) was started and maintained until the last day of the experiment. BDNF levels in the rat’s prefrontal cortex were decreased at 1 h and 24 h after the last administration of ketamine, whereas the group administered with ketamine and omega-3 showed a decrease in BDNF levels only after 24 h. In contrast, both interventions induced similar responses in levels of IL-1β and IL6. These findings suggest that the similarity of IL-1β and IL6 levels in our experimental groups is due to the mechanism of action of ketamine on the immune system. More studies have to be carried out to explain this pathology. In conclusion, according to previous studies and considering the current study, we could suggest a prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate into all lineages of mesodermal origin, e.g., cartilage, bone, and adipocytes. MSCs have been identified at different stages of development, including adulthood, and in different tissues, such as bone marrow, adipose tissue and umbilical cord. Recent studies have shown that MSCs have the ability to migrate to injured sites. In this regard, an important characteristic of MSCs is their immunomodulatory and antiinflammatory effects. For instance, there is evidence that MSCs can regulate the immune system by inhibiting proliferation of T and B cells. Clinical interest in the use of MSCs has increased considerably over the past few years, especially because of the ideal characteristics of these cells for regenerative medicine. Therapies with MSCs have shown promising results neurodegenerative diseases, in addition to regulating inflammation, they can promote other beneficial effects, such as neuronal growth, decrease free radicals, and reduce apoptosis. Notwithstanding, despite the vast amount of research into MSCs in neurodegenerative diseases, the mechanism of action of MSCs are still not completely clarified, hindering the development of effective treatments. Conversely, studies in models of psychiatric disorders are scarce, despite the promising results of MSCs therapies in this field as well.

Table S1. Studies excluded in secondary screening (with reasons). Table S2. Characteristics of studies included in between-group meta-analyses of peripheral BDNF levels in bipolar disorder, across different mood states. Table S3. Characteristics of studies included in within-group meta-analyses of peripheral BDNF levels in bipolar disorder across different mood states. Table S4. Characteristics of meta-analyses of peripheral BDNF in bipolar disorder. Table S5. Assessment of bias across meta-analyses of peripheral BDNF in bipolar disorder. (PDF 690 kb)

Figure S1. PRISMA flowchart of the meta-analytic review. Figure S2. Forest plot for random effects between-group meta-analysis of peripheral BDNF levels in participants with bipolar disorder on a mixed episode. Figure S3. Sensitivity analysis of included studies in between-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in mania. Figure S4. Sensitivity analysis of included studies in between-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in depression. Figure S5. Sensitivity analysis of included studies in between-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in euthymia. Figure S6. Sensitivity analysis of included studies in within-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in mania. Figure S7. Sensitivity analysis of included studies in within-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in depression. Figure S8. Cumulative Meta-Analysis of included studies in between-group meta-analyses of peripheral BDNF levels in participants with mania. Figure S9. Cumulative Meta-Analysis of included studies in between-group meta-analyses of peripheral BDNF levels in participants with depression. Figure S10. Cumulative Meta-Analysis of included studies in between-group meta-analyses of peripheral BDNF levels in participants with euthymia. Figure S11. Cumulative Meta-Analysis of included studies in within-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in mania. Figure S12. Cumulative Meta-Analysis of included studies in within-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in depression. Figure S13. Funnel plot of included studies in between-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in mania compared to healthy controls. The white diamond shows the observed summary effect size. The black diamond shows the adjusted effect size after the trim and fill procedure. Figure S14. Funnel plot of included studies in between-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in depression compared to healthy controls. Figure S15. Funnel plot of included studies in between-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in euthymia compared to healthy controls. Figure S16. Funnel plot of included studies in within-group meta-analyses of peripheral BDNF level in participants with bipolar disorder in mania before and after treatment. Figure S17. Funnel plot of included studies in within-group meta-analyses of peripheral BDNF levels in participants with bipolar disorder in depression before and after treatment. (PDF 567 kb)

Objectives: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats. Methods: Young male Wistar rats received a single injection of fenproporex (6.25, 12.5, or 25 mg/kg intraperitoneally) or polysorbate 80 (control group). Two hours after the last injection, the rats were killed by decapitation and the brain was removed for evaluation of Na+, K+-ATPase activity. Results: Fenproporex decreased Na+, K+-ATPase activity in the striatum of young rats at doses of 6.25, 12.5, and 25 mg/kg and increased enzyme activity in the hypothalamus at the same doses. Na+, K+-ATPase activity was not affected in the hippocampus or prefrontal cortex. Conclusion: Fenproporex administration decreased Na+, K+-ATPase activity in the striatum even in low doses. However, in the hypothalamus, Na+, K+-ATPase activity was increased. Changes in this enzyme might be the result of the effects of fenproporex on neuronal excitability.

BACKGROUND: Suicide is a public health problem worldwide. Estimates have indicated that over 1 million people commit suicide every year all over the world. Brazil has a moderate suicide death rate (4.1 per 100,000 inhabitants), but the fact that it is a large country leads to the coexistence of diverse characteristics and levels of development across the different Brazilian regions. In this sense, the South region has been shown to present suicide rates above the national average. OBJECTIVE: To estimate the profile of suicide in municipalities comprising the Santa Catarina Coal Mining Region from 1980 to 2007. METHODS: This ecological, time-series, descriptive study sought to characterize epidemiological aspects related to suicide method, marital status, sex, age, and occupation in the municipalities of the region in the years 1980 to 2007. RESULTS: A total of 474 suicides occurred in the period, yielding a mean death rate of 10.83 per 100,000 inhabitants. There was a predominance of males, at a 5:1 ratio, and a peak rate in the 55-64-year age group (11.31 per 100,000 inhabitants). The suicide method most commonly used was hanging (72%) and the most frequent occupation was hard labor work (11.60%); in relation to marital status, married subjects (48%) were the ones with the highest rates of suicide. CONCLUSIONS: The Santa Catarina Coal Mining Region has suicide mortality rates above the national average. This study highlights specific characteristics of suicide in the region and may contribute to the development of preventive measures. INTRODUÇÃO: O suicídio é um problema mundial de saúde pública. Estimativas apontam que, anualmente, mais de 1 milhão de pessoas cometem suicídio em todo o mundo. O Brasil possui um coeficiente mediano de suicídio (4,1 por 100 mil habitantes), porém o fato de ser um país de grandes dimensões faz com que características e níveis de desenvolvimento variem grandemente em diferentes regiões. Nesse aspecto, o sul do país se destaca por possuir índices acima da média nacional. OBJETIVOS: Estimar o perfil do suicídio nos municípios da Região Carbonífera Catarinense no período de 1980 a 2007. METODOLOGIA: Estudo ecológico, temporal, descritivo, que buscou caracterizar os aspectos epidemiológicos em relação aos meios empregados para cometer suicídio, estado civil, gênero, faixa etária e ocupação nos municípios da região nos anos de 1980 a 2007. RESULTADOS: Ocorreram 474 suicídios no período, o que gerou um coeficiente médio de 10,83 por 100.000 habitantes. Houve predomínio masculino, na proporção de 5:1, e pico na faixa etária entre 55 e 64 anos (11,31 por 100.000 habitantes). O meio mais utilizado foi o enforcamento (72%), e a ocupação mais frequente foi a dos trabalhadores braçais (11,60%); em relação ao estado civil, os casados foram os que mais cometeram suicídio (48%). CONCLUSÃO: A Região Carbonífera Catarinense apresenta coeficientes de mortalidade por suicídio acima da média nacional. O presente estudo destaca características próprias do suicídio na região, podendo contribuir para o desenvolvimento de ações preventivas.

Pneumococcal meningitis is a life-threatening disease characterized by an acute purulent infection affecting the pia mater, the arachnoid, and the subarachnoid spaces. Streptococcus pneumoniae crosses the blood-brain barrier (BBB) by both transcellular traversal and disruption of the intraepithelial tight junctions to allow intercellular traversal. During multiplication, pneumococci release their bacterial products, which are highly immunogenic and may lead to an increased inflammatory response in the host. Thus, these compounds are recognized by antigen-presenting cells through the binding of toll-like receptors. These receptors induce the activation of myeloid differentiation factor 88 (MyD88), which interacts with various protein kinases, including IL-1 receptor-associated kinase-4 (IRAK4), which is phosphorylated and dissociated from MyD88. These products also interact with tumor necrosis factor receptor-associated factor 6 dependent signaling pathway (TRAF6). This cascade provides a link to NF-κB-inducing kinase, resulting in the nuclear translocation of NF-κB leading to the production of cytokines, chemokines, and other proinflammatory molecules in response to bacterial stimuli. Consequently, polymorphonuclear cells are attracted from the bloodstream and then activated, releasing large amounts of NO•, O2•, and H2O2. This formation generates oxidative and nitrosative stress, subsequently, lipid peroxidation, mitochondrial damage, and BBB breakdown, which contributes to cell injury during pneumococcal meningitis.

Electroconvulsive therapy (ECT) is a wellestablished psychiatric treatment for severe depression. Despite its clinical utility, post-ECT memory deficits are a common side effect. Neuronal plasticity and memory consolidation are intimately related to the expression of immediate early genes (IEG), such as Egr1, Fos and Arc. Changes in IEG activation have been postulated to underlie long-term neuronal adaptations following electroconvulsive seizures (ECS), an animal model of ECT. To test this hypothesis, we used real-time PCR to examine the effect of acute and chronic ECS (8 sessions, one every other day) on the long-term ([24 h) expression of IEG Egr1, Fos and Arc in the hippocampus, a brain region implicated both in the pathophysiology of depression as well as in memory function. We observed a transient increase in Egr1 and Fos expression immediately after ECS, followed by a long-term decrease of IEGlevels after both acute and chronic ECS.Aseparate group of animals, submitted to the same chronic ECS protocol and then subjected to open field or passive avoidance tasks, confirmed robust memory deficits 2 weeks after the last chronic ECS. The possible role of IEG downregulation on long-term learning deficits observed following ECS are discussed.

OBJECTIVE: The present study aims to investigate the effects of ouabain intracerebroventricular injection on BDNF levels in the amygdala and hippocampus of Wistar rats. METHODS: Animals received a single intracerebroventricular injection of ouabain (10-3 and 10-2 M) or artificial cerebrospinal fluid and immediately, 1h, 24h, or seven days after injection, BDNF levels were measured in the rat's amygdala and hippocampus by sandwich-ELISA (n = 8 animals per group). RESULTS: When evaluated immediately, 3h, or 24h after injection, ouabain in doses of 10-2 and 10-3 M does not alter BDNF levels in the amygdala and hippocampus. However, when evaluated seven days after injection, ouabain in 10-2 and 10-3 M, showed a significant reduction in BDNF levels in both brain regions evaluated. DISCUSSION: In conclusion, we propose that the ouabain decreased BDNF levels in the hippocampus and amygdala when assessed seven days after administration, supporting the Na/K ATPase hypothesis for bipolar illness. OBJETIVO: O presente estudo tem como objetivo investigar os efeitos da injeção intracerebroventricular de ouabaína sobre os níveis de BDNF na amígdala e no hipocampo de ratos Wistar. MÉTODOS: Os animais receberam uma única injeção intracerebroventricular de ouabaína (10-3 and 10-2 M) ou fluido cerebroespinhal artificial e, imediatamente, 3h, 24h ou sete dias após a injeção, os níveis de BDNF foram mensurados na amígdala e hipocampo dos ratos por ELISA sandwich (n = 8 animais por grupo). RESULTADOS: Quando avaliados imediatamente após a injeção, 3h ou 24h, ouabaína nas doses 10-2 e 10-3 M não alterou os níveis de BDNF em ambas as estruturas avaliadas. Entretanto, quando avaliados sete dias após a injeção, ouabaína nas doses 10-2 e 10-3 M mostrou uma significante redução nos níveis de BDNF em amígdala e hipocampo. CONCLUSÃO: Em conclusão, propõe-se que a administração de ouabaína diminuiu os níveis de BDNF em amígdala e hipocampo quando avaliados sete dias após a injeção, suportando a hipótese da participação da Na/K ATPase no transtorno bipolar.

OBJETIVO: Um amplo corpo de evidência oriundo de estudos experimentais indica que a sepse se associa com um aumento da produção de espécies de oxigênio reativo, depleção de antioxidantes, e acúmulo de marcadores de estresse oxidativo. Além disto, a disfunção mitocondrial foi implicada na patogênese da síndrome de disfunção de múltiplos órgãos. A citrato sintase é uma enzima que se localiza no interior das células, na matriz mitocondrial, sendo uma etapa importante do ciclo de Krebs; esta enzima foi utilizada como um marcador enzimático quantitativo da presença de mitocôndrias intactas. Assim, investigamos a atividade da citrato sintase no cérebro de ratos submetidos ao modelo sepse com de ligadura e punção do ceco. MÉTODOS: Em diferentes horários (3, 6, 12, 24 e 48 horas) após cirurgia de ligadura e punção do ceco, seis ratos foram sacrificados por decapitação, sendo seus cérebros removidos e dissecados o hipocampo, estriato, cerebelo, córtex cerebral e córtex pré-frontal, e utilizados para determinação da atividade de citrato sintase. RESULTADOS: Verificamos que a atividade de citrato sintase no córtex pré-frontal estava inibida após 12, 24 e 48 horas da ligadura e punção do ceco. No córtex cerebral, esta atividade estava inibida após 3, 12, 24 e 48 horas da ligadura e punção do ceco. Por outro lado a citrato sintase não foi afetada no hipocampo, estriato e cerebelo até 48 horas após a ligadura e punção do ceco. CONCLUSÃO: Considerando-se que é bem descrito o comprometimento da energia decorrente da disfunção mitocondrial na sepse, e que o estresse oxidativo desempenha um papel essencial no desenvolvimento da sepse, acreditamos que o comprometimento da energia pode também estar evolvido nestes processos. Se a inibição da citrato sintase também ocorre em um modelo de sepse, é tentador especular que a redução do metabolismo cerebral pode provavelmente estar relacionada com a fisiopatologia desta doença. OBJECTIVE: An extensive body of evidence from experimental studies indicates that sepsis is associated with increased reactive oxygen species production, depletion of antioxidants, and accumulation of markers of oxidative stress. Moreover, mitochondrial dysfunction has been implicated in the pathogenesis of multiple organ dysfunction syndrome (MODS). Citrate synthase is an enzyme localized in the mitochondrial matrix and an important component of the Krebs cycle; consequently, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase activity in the brains of rats submitted to a cecal ligation puncture model of sepsis. METHODS: At several times points (3, 6, 12, 24 and 48 hours) after the cecal ligation puncture operation, six rats were killed by decapitation. Their brains were removed, and the hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex were dissected and used to determine citrate synthase activity. RESULTS: We found that citrate synthase activity in the prefrontal cortex was inhibited 12, 24 and 48 hours after cecal ligation puncture. In the cerebral cortex, citrate synthase activity was inhibited 3, 12, 24 and 48 hours after cecal ligation puncture. Citrate synthase was not affected in the hippocampus, striatum or cerebellum up to 48 hours after cecal ligation puncture. CONCLUSION: Considering that energy impairment due to mitochondrial dysfunction in sepsis has been well described and that oxidative stress plays a crucial role in sepsis development, we believe that energy impairment may also be involved in these processes. If citrate synthase inhibition also occurs in a sepsis model, it is tempting to speculate that a reduction in brain metabolism may be related to the pathophysiology of this disease.

OBJECTIVE: Bipolar disorder is a severe, recurrent, and often chronic psychiatric illness associated with significant functional impairment, morbidity, and mortality. Creatine kinase is an important enzyme, particularly for cells with high and fluctuating energy requirements, such as neurons, and is a potential marker of brain injury. The aim of the present study was to compare serum creatine kinase levels between bipolar disorder patients, in the various phases (depressive, manic, and euthymic), and healthy volunteers. METHOD: Forty-eight bipolar patients were recruited: 18 in the euthymic phase; 17 in the manic phase; and 13 in the depressive phase. The control group comprised 41 healthy volunteers. The phases of bipolar disorder were defined as follows: euthymic-not meeting the DSM-IV criteria for a mood episode and scoring < 8 on the Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS); manic-scoring < 7 on the HDRS and > 7 on the YMRS; depressive-scoring > 7 on the HDRS and < 7 on the YMRS. Patients in mixed phases were excluded. Blood samples were collected from all participants. RESULTS: Creatine kinase levels were higher in the manic patients than in the controls. However, we observed no significant difference between euthymic and depressive patients in terms of the creatine kinase level. CONCLUSION: Our results suggest that the clinical differences among the depressive, manic, and euthymic phases of bipolar disorder are paralleled by contrasting levels of creatine kinase. However, further studies are needed in order to understand the state-dependent differences observed in serum creatine kinase activity. OBJETIVO: O transtorno do humor bipolar é uma doença psiquiátrica grave, recorrente e crônica associada a significativo prejuízo funcional, morbidade e mortalidade. A creatina quinase tem sido proposta como um marcador de dano cerebral. A creatina quinase é uma enzima importante principalmente para células que necessitam de uma grande quantidade de energia, como os neurônios. O objetivo do presente estudo foi comparar os níveis de creatina quinase entre as fases depressiva, maníaca e eutímica de pacientes com transtorno do humor bipolar. MÉTODO: Para avaliação dos níveis de creatina quinase no soro, 48 pacientes bipolares foram recrutados; 18 estavam eutímicos, 17 estavam em mania e 13 em episódio depressivo. Foi feita também uma comparação com um grupo controle que incluiu 41 voluntários saudáveis. Grupo eutimia: foram incluídos os pacientes que não cumpriam os critérios do DSM-IV para episódios de humor e deveriam ter a pontuação inferior a oito nas escalas de avaliação de mania (YMRS) e depressão (HDRS); grupo mania: foram incluídos os pacientes que apresentavam YMRS > 7 e HDRS < 7; grupo depressão: foram incluídos os pacientes que apresentavam HDRS > 7 e YMRS < 7. Os pacientes em episódios mistos não foram incluídos no estudo. Amostras de sangue foram coletadas de todos os participantes. RESULTADOS: Durante a mania, os níveis de creatina quinase foram aumentados em comparação com voluntários saudáveis. Entretanto, não houve diferença significativa nos níveis de creatina quinase em pacientes eutímicos e depressivos, quando comparados com o grupo controle. CONCLUSÃO: Nossos resultados sugerem que as fases maníaca, depressiva e eutímica do transtorno do humor bipolar, além de apresentarem sintomatologia distinta, também podem ser diferenciadas pelo nível de creatina quinase presente no sangue do paciente. Entretanto, mais estudos são necessários para entender as diferenças observadas na atividade da creatina quinase durante as fases do transtorno do humor bipolar.

Objetivo: O transtorno do humor bipolar é uma doença psiquiátrica grave, recorrente e crônica associada a significativo prejuízo funcional, morbidade e mortalidade. A creatina quinase tem sido proposta como um marcador de dano cerebral. A creatina quinase é uma enzima importante principalmente para células que necessitam de uma grande quantidade de energia, como os neurônios. O objetivo do presente estudo foi comparar os níveis de creatina quinase entre as fases depressiva, maníaca e eutímica de pacientes com transtorno do humor bipolar. Método: Para avaliação dos níveis de creatina quinase no soro, 48 pacientes bipolares foram recrutados; 18 estavam eutímicos, 17 estavam em mania e 13 em episódio depressivo. Foi feita também uma comparação com um grupo controle que incluiu 41 voluntários saudáveis. Grupo eutimia: foram incluídos os pacientes que não cumpriam os critérios do DSM-IV para episódios de humor e deveriam ter a pontuação inferior a oito nas escalas de avaliação de mania (YMRS) e depressão (HDRS); grupo mania: foram incluídos os pacientes que apresentavam YMRS > 7 e HDRS < 7; grupo depressão: foram incluídos os pacientes que apresentavam HDRS > 7 e YMRS < 7. Os pacientes em episódios mistos não foram incluídos no estudo. Amostras de sangue foram coletadas de todos os participantes. Resultados: Durante a mania, os níveis de creatina quinase foram aumentados em comparação com voluntários saudáveis. Entretanto, não houve diferença significativa nos níveis de creatina quinase em pacientes eutímicos e depressivos, quando comparados com o grupo controle. Conclusão: Nossos resultados sugerem que as fases maníaca, depressiva e eutímica do transtorno do humor bipolar, além de apresentarem sintomatologia distinta, também podem ser diferenciadas pelo nível de creatina quinase presente no sangue do paciente. Entretanto, mais estudos são necessários para entender as diferenças observadas na atividade da creatina quinase durante as fases do transtorno do humor bipolar. Objective: Bipolar disorder is a severe, recurrent, and often chronic psychiatric illness associated with significant functional impairment, morbidity, and mortality. Creatine kinase is an important enzyme, particularly for cells with high and fluctuating energy requirements, such as neurons, and is a potential marker of brain injury. The aim of the present study was to compare serum creatine kinase levels between bipolar disorder patients, in the various phases (depressive, manic, and euthymic), and healthy volunteers. Method: Forty-eight bipolar patients were recruited: 18 in the euthymic phase; 17 in the manic phase; and 13 in the depressive phase. The control group comprised 41 healthy volunteers. The phases of bipolar disorder were defined as follows: euthymic—not meeting the DSM-IV criteria for a mood episode and scoring < 8 on the Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS); manic—scoring < 7 on the HDRS and > 7 on the YMRS; depressive—scoring > 7 on the HDRS and < 7 on the YMRS. Patients in mixed phases were excluded. Blood samples were collected from all participants. Results: Creatine kinase levels were higher in the manic patients than in the controls. However, we observed no significant difference between euthymic and depressive patients in terms of the creatine kinase level. Conclusion: Our results suggest that the clinical differences among the depressive, manic, and euthymic phases of bipolar disorder are paralleled by contrasting levels of creatine kinase. However, further studies are needed in order to understand the state-dependent differences observed in serum creatine kinase activity.

Objetivo: Medicina translacional pode ser descrita como a aplicação integrada de ferramentas farmacológicas inovadoras, biomarcadores, métodos e tecnologias clínicas e delineamentos de pesquisa para aumentar o conhecimento a respeito das doenças. A pesquisa translacional oferece uma oportunidade para aplicar os achados de pesquisa básica na clínica cotidiana. O Instituto Nacional de Ciência e Tecnologia – Medicina Translacional foi criado com seis centros (Universidade Federal do Rio Grande do Sul, Universidade de São Paulo- Ribeirão Preto, Universidade Federal do Rio de Janeiro, Pontifícia Universidade Católica do Rio Grande do Sul, Universidade Estadual de Santa Catarina e uma core facility que serve a todos os centros). Os objetivos deste projeto são divididos em quatro dimensões: institucional, pesquisa, formação de recursos humanos e transferência de tecnologia para a comunidade e setor produtivo. Método: Neste artigo, são apresentadas algumas das estratégias utilizadas para atingir os objetivos do Instituto Nacional de Ciência e Tecnologia – Medicina Translacional: 1) Desenvolvimento de modelos animais para o transtorno bipolar; 2) Estratégias de investigação neurocomportamental e disfunções cognitivas dos transtornos cerebrais; 3) Modelos experimentais de funcionamento cerebral e comportamento, proliferação celular e câncer; 4) Teste de Simulação de Falar em Público e 5) Realidade Virtual para indução de Pânico e Agorafobia. Conclusão: O Instituto Nacional de Ciência e Tecnologia – Medicina Translacional possui como foco principal o desenvolvimento de metodologias mais úteis para aumentar a aplicabilidade dos conhecimentos da pesquisa básica em medicina. Objective: Translational medicine has been described as the integrated application of innovative pharmacology tools, biomarkers, clinical methods, clinical technologies and study designs to improve the understanding of medical disorders. In medicine, translational research offers an opportunity for applying the findings obtained from basic research to every-day clinical applications. The National Science and Technology Institute for Translational Medicine is comprised of six member institutions (Universidade Federal do Rio Grande do Sul, Universidade de São Paulo-Ribeirão Preto, Universidade Federal do Rio de Janeiro, Pontifícia Universidade Católica do Rio Grande do Sul, Universidade Estadual de Santa Catarina and a core facility that serves all centers). The objectives of the project are divided into four areas: Institutional, Research, Human Resources and Technology for the Community and Productive Sector. Method: In this manuscript, we describe some of the approaches used to attain the main objectives of the National Science and Technology Institute for Translational Medicine, which include the development of 1) animal models for bipolar disorder; 2) strategies to investigate neurobehavioral function and cognitive dysfunction associated with brain disorders; 3) experimental models of brain function and behavior, neuropsychiatric disorders, cell proliferation, and cancer; 4) Simulated Public Speaking and 5) Virtual reality simulation for inducing panic disorder and agoraphobia. Conclusion: The main focus of the National Science and Technology Institute for Translational Medicine is the development of more useful methods that allow for a better application of basic research-based knowledge to the medical field.9

OBJECTIVE: Clinical findings suggest that ketamine may be used for the treatment of major depression. The present study aimed to compare behavioral effects and brain Creatine kinase activity in specific brain regions after administration of ketamine and imipramine in rats. METHOD: Rats were acutely given ketamine or imipramine and antidepressant-like activity was assessed by the forced swimming test; Creatine kinase activity was measured in different regions of the brain. RESULTS: The results showed that ketamine (10 and 15mg/kg) and imipramine (20 and 30mg/kg) reduced immobility time when compared to saline group. We also observed that ketamine (10 and 15mg/kg) and imipramine (20 and 30mg/kg) increased Creatine kinase activity in striatum and cerebral cortex. Ketamine at the highest dose (15mg/kg) and imipramine (20 and 30mg/kg) increased Creatine kinase activity in cerebellum and prefrontal cortex. On the other hand, hippocampus was not affected. CONCLUSION: Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, the modulation of energy metabolism (like increase in Creatine kinase activity) by antidepressants could be an important mechanism of action of these drugs. OBJETIVO: Vários achados clínicos sugerem que a cetamina apresenta efeito antidepressivo. O presente estudo tem como objetivo comparar efeitos comportamentais e a atividade da creatina quinase em regiões específicas do encéfalo após a administração de cetamina e imipramina em ratos. MÉTODO: Ratos Wistar receberam uma administração aguda de cetamina ou imipramina e a atividade antidepressiva foi avaliada pelo teste de nado forçado; a atividade da creatina quinase foi medida em diferentes regiões encefálicas. RESULTADOS: Os resultados mostraram que a cetamina (10 e 15mg/kg) e a imipramina (20 e 30mg/kg) diminuíram o tempo de imobilidade quando comparados ao grupo salina. Também foi observado que a cetamina (10 e 15mg/kg) e a imipramina (20 e 30mg/kg) aumentaram a atividade da creatina quinase no estriado e córtex cerebral. A dose mais alta de cetamina (15mg/kg) e a imipramina (20 e 30mg/kg) aumentaram a atividade da creatina quinase no cerebelo e córtex pré-frontal. Por outro lado, o hipocampo não foi alterado. CONCLUSÃO: Considerando que a diminuição no metabolismo provavelmente está envolvida na fisiopatologia da depressão, a modulação do metabolismo energético (como um aumento na atividade da creatina quinase) por antidepressivos pode ser um importante mecanismo de ação destes fármacos.

Sepsis and its complications are the leading causes of mortality in intensive care units, accounting for 10-50% of deaths. Intensive care unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration, and/or global loss of cognitive function. In the present study, we investigated behavioral alterations in sepsis-surviving rats. One hundred and ten male Wistar rats (3-4 months, 250-300 g) were submitted to cecal ligation and puncture (CLP), and 44 were submitted to sham operation. Forty-four rats (40%) survived after CLP, and all sham-operated animals survived and were used as control. Twenty animals of each group were used in the object recognition task (10 in short-term memory and 10 in long-term memory), 12 in the plus-maze test and 12 in the forced swimming test. Ten days after surgery, the animals were submitted individually to an object recognition task, plus-maze and forced swimming tests. A significant impairment of short- and long-term recognition memory was observed in the sepsis group (recognition index 0.75 vs 0.55 and 0.74 vs 0.51 for short- and long-term memory, respectively (P < 0.05). In the elevated plus-maze test no difference was observed between groups in any of the parameters assessed. In addition, sepsis survivors presented an increase in immobility time in the forced swimming test (180 vs 233 s, P < 0.05), suggesting the presence of depressive-like symptoms in these animals after recovery from sepsis. The present results demonstrated that rats surviving exposure to CLP, a classical sepsis model, presented recognition memory impairment and depressive-like symptoms but not anxietylike behavior.

(João Quevedo - Estudo do Processamento das Memórias de Curta e Longa Duração) - Este trabalho apresenta a compilação dos 4 principais experimentos carreados ao longo de 1999-2002: 3 deles envolvem o modelo animal e um quarto utilizase de voluntários humanos. Entretanto, o uso desses diferentes paradigmas não prejudica a unidade do conjunto. O Capítulo 1 apresenta sucintamente o marco teórico dos 4 trabalhos. Inicialmente são discutidos aspectos modulatórios da consolidação da memória. Após, alguns elementos da bioquímica da consolidação da memória são apresentados no intuito de permitir establecer um entendimento das vias da PKA e da MAPK e suas correlações com a via final comum – a síntese protéica. Adicionalmente, a dissociação STM e LTM é discutida a partir do referencial farmacológico. Uma última unidade apresenta conceitos primitivos do papel da amígdala na modulação da memória e das evidências da implicação das emoções, via amígdala, na modulação da memória em humanos. Os experimentos utilizando a esquiva inibitória como paradigma e o rato como sujeito ocupam os Capítulos 2, 3 e 4. No Capítulo 2 é apresentado um corpo de resultados que permite observar uma dissecção farmacológica da STM e LTM. Os dados demonstram um envolvimento de fenômenos dependentes de PKA em ambas STM e LTM, dependentes de MAPK apenas na STM, e dependentes de síntese protéica apenas na LTM. O Capítulo 3 apresenta um trabalho realizado em colaboração com o Prof. Steven P. R. Rose (Open University, UK), que envolve a determinação dos momentos sensíveis à inibição da síntese protéica na consolidação da LTM. Foram observados dois momentos: um inicial, junto ao treino, e um tardio apos 3h. Além disso, foi possível demonstrar que um treino prévio de baixa intensidade, mas não a pré-exposição ao aparato, pode impedir o estabelecimento de amnésia induzida pelo bloqueio da síntese protéica. O Capítulo 4 estende os achados com anisomicina observados no Capítulo 3, estudando também o inibidor da PKA, Rp-cAMPs, e o inibidor da MAPKK, PD 098059. Os dados obtidos confirmam também para essas cascatas a indução em um treino prévio de baixa intensidade de algum fenômeno celular de longa duração que torna o aprendizado de um segundo treino independente de PKA, MAPK ou síntese protéica. O estudo da dissociação da STM e LTM foi ampliado, agora no modelo humano, no experimento descrito no Capítulo 6. Nesse experimento, observamos uma clara influência do conteúdo emocional na LTM, mas a ausência desse efeito na STM. A discussão geral (Capítulo 7) busca integrar esses achados descritos nos capítulos anteriores dentro da nova perspectiva molecular da neurobiologia da memória. Além disso, abre discussão acerca de possíveis novas possibilidades de pesquisa.

A total of 182 young adult male Wistar rats were bilaterally implanted with cannulae into the CA1 region of the dorsal hippocampus and into the amygdaloid nucleus, the entorhinal cortex, and the posterior parietal cortex. After recovery, the animals were trained in a stepdown inhibitory avoidance task. At various times after training (0, 30, 60 or 90 min) the animals received a 0.5-μl microinfusion of vehicle (saline) or 0.5 μg of muscimol dissolved in the vehicle. A retention test was carried out 24 h after training. Retention test performance was hindered by muscimol administered into both the hippocampus and amygdala at 0 but not at 30 min posttraining. The drug was amnestic when given into the entorhinal cortex 30, 60 or 90 min after training, or into the parietal cortex 60 or 90 min after training, but not before. These findings suggest a sequential entry in operation, during the posttraining period, of the hippocampus and amygdala, the entorhinal cortex, and the posterior parietal cortex in memory processing.

Submitted by MARCIA ROVADOSCHI (marciar@unifra.br) on 2019-09-17T17:19:20Z No. of bitstreams: 2 Dissertacao_KarstynKistBakof_VersaoParcial.pdf: 760023 bytes, checksum: cdc25d2c6b320d5d006164a6e1482d23 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Made available in DSpace on 2019-09-17T17:19:20Z (GMT). No. of bitstreams: 2 Dissertacao_KarstynKistBakof_VersaoParcial.pdf: 760023 bytes, checksum: cdc25d2c6b320d5d006164a6e1482d23 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2019-07-31 The older population is increasing in the world and concomitant with there are an enhance in the neurodegenerative disease, characterized by a progressive decline in the areas of cognition and behavior. While the disease progresses, there is the demand for a special care, an important activity performed by caregivers. Caring someone impacts on the quality of life of the caregivers and the burden experienced daily can cause emotional changes and physical overload, reflecting somatic diseases, social isolation, higher prevalence of psychiatric illness, such as depression and stress, characteristics of the Burnout Syndrome. Psychological stress has been associated with an increased risk of developing depression and studies suggest that caffeine may act as a protective factor for this disorder. The present work is arranged in two chapters and aims to evaluated the influence of stress and depression on the physical and mental health of caregivers of the elderly with neurodegenerative disease. Chapter 1 presents the field study, where 81 caregivers (family members or professional) of the elderly with neurodegenerative diseases from community, recruited from July 2018 to April 2019. Caregivers were evaluated for stress and depressive symptoms using psychological questionnaires (Hamilton Depressive Rating Scale and Lipp’s Inventory of Stress Symptoms for adults). Also, they answered a 72-hours Recall to evaluate caffeine intake and collected saliva for the measurement of salivary biomarkers. The field study showed that stress and depression symptoms are present in more than half of the population and that stress was associated with educational level, tobacco use and frequency of DNA damage. However, stress and depression indexes did not show association with caffeine consumption and other salivary biomarkers. Chapter 2 presents the narrative review from the scientific literature with the search in the PubMed, LILACS, SciELO, Web of Science and Scopus databases for publications between 2008 and 2018, with the following descriptors: [“Burnout prevalence” or “Burnout Syndrome” or “Burnout“ and (“caregivers” and “dementia”) or (“dementia elderly”)]. For review, 10 studies were included in the English language, because they present the prevalence of Burnout Syndrome using questionnaires appropriate for the evaluation of this syndrome. The majority shows a high prevalence of Burnout syndrome in caregivers of the elderly with dementia. The present dissertation corroborates the hypothesis that caregivers of the elderly with neurodegenerative diseases are exposed daily to stressful situations, increments knowledge about the impact of educational level as a preventive of psychological symptoms. Nevertheless, it indicates that investigated salivary biomarkers do not have a pattern of association of psychological stress with the burden of care in these caregivers. A população idosa está crescendo consideravelmente em todo o mundo e concomitantemente com este crescimento, ocorre o aumento das doenças neurodegenerativas, caracterizada por um declínio progressivo nas áreas de cognição e comportamento. Com a progressão da doença, surge a demanda por cuidados especiais, atividade importante desempenhada pelos cuidadores. Esta atividade impacta na qualidade de vida destes cuidadores e a sobrecarga de trabalho que enfrentam diariamente pode causar alterações emocionais e sobrecarga física, refletindo, por sua vez, em maior número em doenças somáticas, isolamento social, maior prevalência de doenças psiquiátricas como depressão e estresse, próprios da Síndrome de Burnout. O estresse psicológico tem sido associado a um aumento no risco de desenvolver a depressão e estudos sugerem que a cafeína possa agir como fator de proteção para esta patologia. Este trabalho, está disposto em dois capítulos e objetiva avaliar a influência do estresse e depressão na saúde física e mental de cuidadores de idosos com doenças neurodegenerativas. O capítulo 1 apresenta o estudo de campo, onde foram recrutados 81 cuidadores (familiares ou profissionais) de idosos com doenças neurodegenerativas da comunidade, de julho 2018 a abril de 2019. Os cuidadores foram avaliados quanto aos sintomas de estresse e depressão por meio das respostas aos questionários psicológicos (Escala Hamilton de Depressão e Inventário de Sintomas de Stress para adultos de Lipp). Também, responderam a um recordatório alimentar de 72 horas para avaliação do consumo de cafeína, e a coleta de saliva para a mensuração de biomarcadores salivares. O estudo de campo mostrou que os sintomas de estresse e depressão estão presentes em mais da metade da população e que o estresse foi associado ao nível educacional, uso de cigarro e frequência de danos no DNA, no entanto os índices de estresse e depressão não apresentaram associação com o consumo de cafeína e os biomarcadores salivares. O Capítulo 2 apresenta a revisão narrativa realizada a partir da literatura científica com a busca nas bases de dados PubMed, LILACS, SciELO, Web of Science e Scopus, para publicações entre 2008 e 2018, com os seguintes descritores: [“Burnout prevalence” or “Burnout Syndrome” or “Burnout“ and (“caregivers” and “dementia”) or (“dementia elderly”)]. Para a revisão bibliográfica, foram incluídos 10 estudos na língua inglesa, por apresentarem a prevalência da Síndrome de Burnout com uso de questionários próprios para a avaliação dessa síndrome. A grande maioria, apresentou uma elevada prevalência de Síndrome de Burnout em cuidadores de idosos com demência. A presente dissertação corrobora com a hipótese de que os cuidadores de idosos com doenças neurodegenerativas são expostos diariamente a situações estressoras, incrementa o conhecimento sobre o impacto do nível educacional como preventivo dos sintomas psicológicos. Contudo, indica que os biomarcadores salivares investigados não possuem um padrão de associação do estresse psicológico com o fardo do cuidado nestes cuidadores.