National Institute for Translational Medicine

Porto Alegre, Brazil

National Institute for Translational Medicine

Porto Alegre, Brazil
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Figueiredo L.S.,University of Porto | Figueiredo L.S.,National Institute for Translational Medicine | Dornelles A.S.,National Institute for Translational Medicine | Dornelles A.S.,Federal University of Rio Grande do Sul | And 10 more authors.
Neurobiology of Learning and Memory | Year: 2015

Healthy neuronal function and synaptic modification require a concert of synthesis and degradation of proteins. Increasing evidence indicates that protein turnover mediated by proteasome activity is involved in long-term synaptic plasticity and memory. However, its role in different phases of memory remains debated, and previous studies have not examined the possible requirement of protein degradation in recognition memory. Here, we show that the proteasome inhibitor, lactacystin (LAC), infused into the CA1 area of the hippocampus at two specific time points during consolidation, impairs 24-retention of memory for object recognition in rats. Administration of LAC after retrieval did not affect retention. These findings provide the first evidence for a requirement of proteasome activity in recognition memory, indicate that protein degradation in the hippocampus is necessary during selective time windows of memory consolidation, and further our understanding of the role of protein turnover in memory formation. © 2015 Elsevier Inc.


Roesler R.,Federal University of Rio Grande do Sul | Roesler R.,National Institute for Translational Medicine | Kent P.,University of Ottawa | Kent P.,Ottawa Health Research Institute | And 7 more authors.
Reviews in the Neurosciences | Year: 2012

Mammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide (GRP) act by activating NMB receptors (NMBR, BB1) and GRP receptors (GRPR, BB2), respectively. These two bombesin receptors are members of the G-protein-coupled receptor (GPCR) superfamily. In the brain, NMBR and GRPR are highly expressed in the brain areas involved in memory processing and emotional responses, such as the hippocampus and the amygdaloid nuclei. An increasing number of pharmacological and genetic studies in rodents indicate that NMBRs and GRPRs in brain regions including the dorsal hippocampus, the nucleus tractus solitarius, the basolateral amygdala, and cortical areas, regulate memory formation and expression, particularly for memories related to emotionally arousing tasks. GRPR signaling interacts with multiple protein kinase pathways as well as with other neurotransmitter, hormone, and growth factor systems in influencing memory formation. Together with evidence from human studies, the findings from rodent experiments suggest that bombesin receptors may be therapeutic targets in brain disorders involving memory dysfunction and anxiety.


Nor C.,Federal University of Rio Grande do Sul | Nor C.,National Institute for Translational Medicine | Sassi F.A.,Federal University of Rio Grande do Sul | Sassi F.A.,National Institute for Translational Medicine | And 11 more authors.
Molecular Neurobiology | Year: 2013

Increasing evidence suggests that alterations in epigenetic mechanisms regulating chromatin state play a role in the pathogenesis of medulloblastoma (MB), the most common malignant brain tumor of childhood. Histone deacetylase (HDAC) inhibitors, which increase chromatin relaxation, have been shown to display anticancer activities. Here we show that the HDAC inhibitor sodium butyrate (NaB) markedly increases cell death and reduces colony formation in human MB cell lines. In addition, NaB increased the mRNA expression of Gria2, a neuronal differentiation marker, in D283 and DAOY cells and reduced the number of neurospheres in D283 cell cultures. Finally, NaB reduced the viability of D283 cells when combined with etoposide. These data show that NaB displays pronounced inhibitory effects on the survival of human MB cells and suggest that NaB might potentiate the effects of etoposide. In addition, our study suggests that HDAC inhibition might promote the neuronal differentiation of MB cells and provides the first evidence that an HDAC inhibitor might suppress the expansion or survival of MB cancer stem cells. © 2013 Springer Science+Business Media New York.


Brietzke E.,University of Sao Paulo | Moreira C.L.R.L.,University of Sao Paulo | Duarte S.V.B.,University of Sao Paulo | Nery F.G.,University of Sao Paulo | And 4 more authors.
Comprehensive Psychiatry | Year: 2012

Background: Recent evidence suggests an association between migraine and bipolar disorder (BD), although the impact of this association in the clinical course of BD is relatively unknown. Objective: This study aimed to compare 2 groups of individuals with BD (with vs without comorbid migraine) and evaluate differences in severity of clinical course. Methods: Three hundred thirty-nine adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined bipolar I or II disorder were enrolled and divided into 2 groups: with and without comorbid migraine. Demographic and clinical data were obtained using standardized interviews. Results: Patients with comorbid migraines had more mood episodes, especially those with depressive polarity. In addition, comorbid migraine was associated with a higher prevalence of psychiatric and general medical comorbidities. Differences between the 2 groups in number of lifetime hospitalizations for depression/mania, rates of rapid cycling, and history of suicide attempts were not observed after Bonferroni correction. Conclusions: Comorbid migraine seems to be associated with poor outcomes in BD. Additional studies should be conducted to investigate shared vulnerabilities and pathophysiologic mechanisms as well as treatment optimization of both illnesses. © 2012 Elsevier Inc.


Brietzke E.,University of Sao Paulo | Mansur R.B.,University of Sao Paulo | Soczynska J.K.,University of Toronto | Kapczinski F.,Federal University of Rio Grande do Sul | And 3 more authors.
Journal of Affective Disorders | Year: 2012

Background: The high prevalence, recurrence rate, chronicity, and illness burden in bipolar disorder (BD) are well documented. Moreover, insufficient response with conventional pharmacological and manual-based psychosocial interventions, as well as evidence of illness progression and acceleration, invite the need for early detection and primary prevention. Methods: Herein we comprehensively review extant studies reporting on a bipolar prodrome. The overarching aim is to propose a predictive algorithm (i.e. prediction of BD in at-risk populations) integrating genetic (i.e. family history), environmental (e.g. childhood maltreatment) and biological markers (i.e. BDNF, inflammatory and oxidative stress markers). Computerized databases i.e. Pubmed, PsychInfo, Cochrane Library and Scielo were searched using the followed terms: bipolar disorder cross-referenced with prodromal, preclinical, at risk mental states, clinical high risk, ultra high risk, biomarkers, brain-derived neurotrophic factor, inflammation, cytokines, oxidative stress, prediction and predictive model. Results: Available evidence indicates that a prodrome to bipolar disorder exists. Commonly encountered features preceding the onset of a manic episode are affective lability, irritability, anger, depression, anxiety, substance use disorders, sleep disorders, as well as disturbances in attention and cognition. Non-specificity and insufficient sensitivity have hampered the development of an adequate prediction algorithm. Limitations: Limitations include biases associated with retrospective studies, poor characterization of clinical high risk, inadequacy of prospective studies regarding sample selection and absence of specificity of risk states. Conclusion: We propose a hypothetical prediction algorithm that is combinatorial in approach that attempts to integrate family history, early adversity, and selected biomarkers. © 2012 Elsevier B.V.


Brietzke E.,University of Sao Paulo | Kapczinski F.,Federal University of Rio Grande do Sul | Kapczinski F.,National Institute for Translational Medicine | Grassi-Oliveira R.,National Institute for Translational Medicine | And 4 more authors.
Expert Review of Neurotherapeutics | Year: 2011

Bipolar disorder (BD) is associated with substantial morbidity, as well as premature mortality. Available evidence indicates that 'stress-sensitive' chronic medical disorders, such as cardiovascular disease, obesity and Type 2 diabetes mellitus, are critical mediators and/or moderators of BD. Changes in physiologic systems implicated in allostasis have been proposed to impact brain structures and neurocognition, as well as medical comorbidity in this population. For example, abnormalities in insulin physiology, for example, insulin resistance, hyperinsulinemia and central insulinopenia, are implicated as effectors of allostatic load in BD. Insulins critical role in CNS physiological (e.g., neurotrophism and synaptic plasticity) and pathophysiological (e.g., neurocognitive deficits, pro-apoptosis and amyloid deposition) processes is amply documented. This article introduces the concept that insulin is a mediator of allostatic load in the BD and possibly a therapeutic target. © 2011 Expert Reviews Ltd.


Freire R.C.,Federal University of Rio de Janeiro | Freire R.C.,National Institute for Translational Medicine | Perna G.,San Benedetto Hospital | Nardi A.E.,Federal University of Rio de Janeiro | Nardi A.E.,National Institute for Translational Medicine
Harvard Review of Psychiatry | Year: 2010

Objective: Our objective is to summarize the new findings concerning the respiratory subtype (RS) of panic disorder (PD) since its first description. Methods: Two searches were made in the Institute for Scientific Information Web of Science: with the keywords "panic disorder" and "respiratory symptoms," and all articles that cited Briggs and colleagues' 1993 article "Subtyping of Panic Disorder by Symptom Profile" (Br J Psychiatry 1993;163:2019). Altogether, 133 articles were reviewed. Results: We describe and discuss RS epidemiology, genetics, psychopathology, demographic features, clinical features, correlations with the respiratory system, traumatic suffocation history, provocative tests, and nocturnal panic. Compared to patients with the nonrespiratory subtype (non-RS), the RS patients had higher familial history of PD, lower comorbidity with depression, longer duration of illness, lower neuroticism scores, and higher scores in severity scales, such as the Panic and Agoraphobia Scale, Panic-Agoraphobia Spectrum scale and the Clinical Global Impression scale. Tests to induce panic attacks, such as those with CO2, hyperventilation, and caffeine, produce panic attacks in a higher proportion of RS patients than non-RS patients. Differences in the subtypes' improvement with the pharmacologic treatment were found. There are also some controversial findings regarding the RS, including the age of onset of PD, and alcohol and tobacco use in RS patients. Conclusions: Some characteristics, such as the increased sensitivity to CO2 and the higher familial history of PD, clearly distinguish the RS from the non-RS. Nevertheless, there are also controversial findings. More studies are needed to determine the validity of the RS subtype. © 2010 President and Fellows of Harvard College.


Blank M.,Federal University of Rio Grande do Sul | Blank M.,National Institute for Translational Medicine | Blank M.,Federal University of Santa Catarina | Dornelles A.S.,Federal University of Rio Grande do Sul | And 10 more authors.
Neurobiology of Learning and Memory | Year: 2014

Histone acetylation, a type of chromatin modification that allows increased gene transcription and can be pharmacologically promoted by histone deacetylase (HDAC) inhibitors (HDACis), has been consistently associated with promoting memory formation in the hippocampus. The basolateral nucleus of the amygdala (BLA) is a brain area crucially involved in enabling hormones and drugs to influence memory formation. Here, we show that BLA activity is required for memory enhancement by intrahippocampal administration of an HDACi. Two different HDACis, sodium butyrate (NaB) and trichostatin A (TSA), differentially enhanced the retention of memory for inhibitory avoidance (IA) when administered to the dorsal hippocampus after training. TSA showed a biphasic pattern of response during consolidation, in which infusions given immediately or 3. h after training produced memory enhancement, whereas no effect was observed when it was infused 1.5 or 6. h posttraining. Muscimol (MUS)-induced unilateral functional inactivation of the BLA prevented the enhancement of memory retention produced by posttraining infusion of TSA into the ipsilateral hippocampus. TSA did not affect IA extinction or reconsolidation. These results indicate that HDACis can increase IA memory retention when given into the hippocampus, and, most importantly, BLA activity is necessary for enabling HDACi-induced influences on memory formation. © 2014 Elsevier Inc.


Roesler R.,Federal University of Rio Grande do Sul | Roesler R.,National Institute for Translational Medicine | Schwartsmann G.,Federal University of Rio Grande do Sul | Schwartsmann G.,National Institute for Translational Medicine
Frontiers in Endocrinology | Year: 2012

Neuropeptides acting on specific cell membrane receptors of the G protein-coupled receptor (GPCR) superfamily regulate a range of important aspects of nervous and neuroendocrine function. Gastrin-releasing peptide (GRP) is a mammalian neuropeptide that bindstotheGRPreceptor(GRPR, BB2). Increasing evidence indicates that GRPR-mediated signaling in the central nervous system (CNS) plays an important role in regulating brain function, including aspects related to emotional responses, social interaction, memory, and feeding behavior. In addition, some alterations in GRP or GRPR expression or function have been described in patients with neurodegenerative, neurodevelopmental, and psychiatric disorders, as well as in brain tumors. Findings from preclinical models are consistent with the view that the GRPR might play a role in brain disorders, and raise the possibility that GRPR agonists might ameliorate cognitive and social deficits associated with neurological diseases, while antagonists may reduce anxiety and inhibit the growth of some types of brain cancer. Further preclinical and translational studies evaluating the potential therapeutic effects of GRPR ligands are warranted. © 2012 Roesler and Schwarts-mann.


Grande I.,Federal University of Rio Grande do Sul | Grande I.,University of Barcelona | Fries G.R.,Federal University of Rio Grande do Sul | Kunz M.,Federal University of Rio Grande do Sul | And 2 more authors.
Psychiatry Investigation | Year: 2010

The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in ortion with mood episodes and the potential use of serum BDNF as a biomarker in BD. Psychiatry Investig 2010;7:243-250 © Korean Neuropsychiatric Association.

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