National Institute for Translational Medicine INCT TM

Rio de Janeiro, Brazil

National Institute for Translational Medicine INCT TM

Rio de Janeiro, Brazil

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Roesler R.,Federal University of Rio Grande do Sul | Roesler R.,National Institute for Translational Medicine INCT TM | Kent P.,University of Ottawa | Kent P.,Ottawa Health Research Institute | And 6 more authors.
Neurobiology of Learning and Memory | Year: 2014

Neuropeptides act as signaling molecules that regulate a range of aspects of brain function. Gastrin-releasing peptide (GRP) is a 27-amino acid mammalian neuropeptide, homolog of the amphibian peptide bombesin. GRP acts by binding to the GRP receptor (GRPR, also called BB2), a member of the G-protein coupled receptor (GPCR) superfamily. GRP produced by neurons in the central nervous system (CNS) plays a role in synaptic transmission by activating GRPRs located on postsynaptic membranes, influencing several aspects of brain function. Here we review the role of GRP/GRPR as a system mediating both stress responses and the formation and expression of memories for fearful events. GRPR signaling might integrate the processing of stress and fear with synaptic plasticity and memory, serving as an important component of the set of neurobiological systems underlying the enhancement of memory storage by aversive information. © 2013 Elsevier Inc.


Wegner M.,University of Bern | Helmich I.,University Institute of Health Sciences | Machado S.,Federal University of Rio de Janeiro | Machado S.,National Institute for Translational Medicine INCT TM | And 7 more authors.
CNS and Neurological Disorders - Drug Targets | Year: 2014

Anxiety and depression are the most frequently diagnosed psychological diseases showing a high co-morbidity. They have a severe impact on the lives of the persons concerned. Many meta-analytical studies suggested a positive anxiolytic and depression-reducing effect of exercise programs. The aim of the present article is to synthesize metaanalyses on the effects of exercise on anxiety and depression and to describe average effect sizes. For this purpose 37 meta-analyses were included reporting 50 effect sizes for anxiety scores of 42,264 participants and depression scores of 48,207 persons. The average documented anxiolytic effect of exercise in these reviews was small, 0.34. In contrast, the effect of exercise on depression was significantly higher and at a moderate level, 0.56. Data of randomized controlled trials suggest higher sizes for the effect of exercise on anxiety and depression leading to increases up to moderate and large effects, respectively. Additionally, exercise seems to be more beneficial for patients compared to participants within a non-clinical, normal range of psychological disease. Especially for the effect of exercise on anxiety, more high quality meta-analyses of randomized controlled trials are needed. Finally, possible neurobiological explanations are suggested for the positive effect of exercise on psychological disorders like anxiety and depression. © 2014 Bentham Science Publishers.


Freire R.C.,Federal University of Rio de Janeiro | Freire R.C.,National Institute for Translational Medicine INCT TM | Machado S.,Federal University of Rio de Janeiro | Machado S.,National Institute for Translational Medicine INCT TM | And 5 more authors.
CNS and Neurological Disorders - Drug Targets | Year: 2014

The aim of this review was to summarize the recent evidences regarding the pharmacological treatment of panic disorder (PD). The authors performed a review of the literature regarding the pharmacological treatment of PD since the year 2000. The research done in the last decade brought strong evidences of effectiveness for paroxetine, venlafaxine, sertraline, fluvoxamine, citalopram, fluoxetine, clonazepam, and the relatively novel agent escitalopram. There are evidences indicating that the other new compounds inositol, duloxetine, mirtazapine, milnacipran, and nefazodone have antipanic properties and may be effective compounds in the treatment of PD. The effectiveness of reboxetine and anticonvulsants is a subject of controversy. In addition to selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines and atypical antipsychotics may be valid alternatives in the treatment of PD. Recent data indicate that augmentation strategies with aripiprazole, olanzapine, pindolol or clonazepam may be effective. D-cycloserine is a promising agent in the augmentation of cognitive behavioral therapy. © 2014 Bentham Science Publishers.


Mochcovitch M.D.,Federal University of Rio de Janeiro | Mochcovitch M.D.,National Institute for Translational Medicine INCT TM | Nardi A.E.,National Institute for Translational Medicine INCT TM | Nardi A.E.,Federal University of Rio de Janeiro | And 2 more authors.
Revista Brasileira de Psiquiatria | Year: 2012

Introduction: Since the first publication of Cloninger ́s psychobiological model of personality, the relationship between temperament and character dimensions and psychiatric disorders has been widely studied. The exact nature of this interaction, however, is still unclear. Different models have been proposed (state-dependency, vulnerability, continuous spectrum etc). Objective: To analyze the relationship between temperament and character dimensions with depression and panic disorder. Method: Systematic review on interventional studies published up until December 2011 on MEDLINE and ISI databases. Also, a brief review on genetic studies is hereby undertaken, aiming to discuss the gene-environment interaction in relation to this topic. Results: Thirteen studies were included: 10 related to depression and 3 to panic disorder (or unspecific anxiety symptoms). All of them showed association between high harm avoidance (HA) and low selfdirectedness (SD) with depression and anxiety symptoms. Longitudinal studies demonstrated that these traits may not be just state-dependent. Conclusions: HA and SD dimensions are associated with both the occurrence of depressive and anxiety symptoms. There is also some evidence to suggest that high HA and low SD indicates susceptibility to depression. Longitudinal studies are not sufficient to affirm the same about panic disorder up to the present moment. ©2012 Elsevier Editora Ltda. All rights reserved.


Wild L.B.,University of Porto | Wild L.B.,Pontifical Catholic University of Rio Grande do Sul | De Lima D.B.,University of Porto | Balardin J.B.,University of Porto | And 9 more authors.
Journal of Neurology | Year: 2013

The primary purpose of this study was to investigate the effect of dual-tasking on cognitive performance and gait parameters in patients with idiopathic Parkinson's disease (PD) without dementia. The impact of cognitive task complexity on cognition and walking was also examined. Eighteen patients with PD (ages 53-88, 10 women; Hoehn and Yahr stage I-II) and 18 older adults (ages 61-84; 10 women) completed two neuropsychological measures of executive function/attention (the Stroop Test and Wisconsin Card Sorting Test). Cognitive performance and gait parameters related to functional mobility of stride were measured under single (cognitive task only) and dual-task (cognitive task during walking) conditions with different levels of difficulty and different types of stimuli. In addition, dual-task cognitive costs were calculated. Although cognitive performance showed no significant difference between controls and PD patients during single or dual-tasking conditions, only the patients had a decrease in cognitive performance during walking. Gait parameters of patients differed significantly from controls at single and dual-task conditions, indicating that patients gave priority to gait while cognitive performance suffered. Dual-task cognitive costs of patients increased with task complexity, reaching significantly higher values then controls in the arithmetic task, which was correlated with scores on executive function/attention (Stroop Color-Word Page). Baseline motor functioning and task executive/attentional load affect the performance of cognitive tasks of PD patients while walking. These findings provide insight into the functional strategies used by PD patients in the initial phases of the disease to manage dual-task interference. © 2012 Springer-Verlag Berlin Heidelberg.


Nor C.,University of Michigan | Nor C.,Federal University of Rio Grande do Sul | Nor C.,National Institute for Translational Medicine INCT TM | Zhang Z.,University of Michigan | And 7 more authors.
Neoplasia (United States) | Year: 2014

Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs). These unique cells, named here cancer stem cells (CSCs), proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6)] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan- squamous cell carcinoma 22B (UM-SCC-22B) cells and observed that cisplatin treatment increased (P =.0013) the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDHhighCD44high)]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatinsensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDHhighCD44high immediately after surgery and plated onto ultralow attachment plates. IL-6- induced signal transducer and activator of transcription 3 (STAT3) phosphorylation (indicative of stemness) was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK) phosphorylation (indicative of differentiation processes) was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs and suggest a mechanism for resistance to cisplatin therapy in head and neck cancer. © 2014 Neoplasia Press, Inc. All rights reserved.


Roesler R.,Federal University of Rio Grande do Sul | Roesler R.,National Institute for Translational Medicine INCT TM | Schroder N.,National Institute for Translational Medicine INCT TM | Schroder N.,University of Porto
Pharmacology Biochemistry and Behavior | Year: 2011

Biological research has unraveled many of the molecular and cellular mechanisms involved in the formation of long-lasting memory, providing new opportunities for the development of cognitive-enhancing drugs. Studies of drug enhancement of cognition have benefited from the use of pharmacological treatments given after learning, allowing the investigation of mechanisms regulating the consolidation phase of memory. Modulatory systems influencing consolidation processes include stress hormones and several neurotransmitter and neuropeptide systems. Here, we review some of the findings on memory enhancement by drug administration in animal models, and discuss their implications for the development of cognitive enhancers. © 2011 Elsevier Inc.


Balardin J.B.,Pontifical Catholic University of Rio Grande do Sul | Balardin J.B.,University of Porto | Vedana G.,University of Porto | Luz C.,University of Porto | And 3 more authors.
Journal of Geriatric Psychiatry and Neurology | Year: 2011

Background: Alterations in cortisol secretion pattern seem to be involved in the associations between aging, depression, and cognitive decline. Objective: The aim of this study was to mainly assess cortisol circadian profile in older adults with subjective depressive symptoms. Methods: Salivary cortisol samples from healthy young (n = 22) and old adults (n = 22), and from older adults who self-reported depressive symptoms in Geriatric Depression Scale (n = 22) were collected at 7 AM, 4 PM, and 10 PM and were analyzed by radioimmunoassay. Results: Older adults with depressive symptoms presented the characteristic cortisol circadian pattern, but they showed higher cortisol levels at 10 PM than healthy young and elderly controls. Conclusions: Our data suggest that mild depressive symptoms could be associated with a cortisol secretion pattern previously described as being predictive of cognitive decline. © The Author(s) 2011.


Dornelles A.S.,University of Porto | Garcia V.A.,University of Porto | De Lima M.N.M.,University of Porto | Vedana G.,University of Porto | And 5 more authors.
Neurochemical Research | Year: 2010

Abnormally high levels of iron are observed in the brain of patients suffering from neurodegenerative disorders. The mechanisms involved in iron accumulation in neurodegenerative disorders remain poorly understood. In the present study we investigated the effects of aging and neonatal iron overload on the mRNA expression of proteins critically involved in controlling iron homeostasis. Wistar rat pups received a single daily dose of vehicle or iron (10 mg/kg of b.w. of Fe2+), at postnatal days 12-14. The expression of Transferrin Receptor (TfR), H-Ferritin, and IRP2 were analyzed by a semi-quantitative reverse transcriptase polymerase chain reaction assay in cortex, hippocampus and striatum of rats sacrificed at three different ages (15-day-old; 90-day-old and 2-year old rats). Results indicate that TfR, H-ferritin, and IRP2 mRNA expression was differentially affected by aging and by neonatal iron treatment in all three brain regions. These findings might have implications for the understanding of iron homeostasis misregulation associated with neurodegenerative disorders. © Springer Science+Business Media, LLC 2009.


Schroder N.,University of Porto | Schroder N.,National Institute for Translational Medicine INCT TM | Figueiredo L.S.,University of Porto | De Lima M.N.M.,University of Porto
Journal of Alzheimer's Disease | Year: 2013

Over the last decades, studies from our laboratory and other groups using animal models have shown that iron overload, resulting in iron accumulation in the brain, produces significant cognitive deficits. Iron accumulation in the hippocampus and the basal ganglia has been related to impairments in spatial memory, aversive memory, and recognition memory in rodents. These results are corroborated by studies showing that the administration of iron chelators attenuates cognitive deficits in a variety of animal models of cognitive dysfunction, including aging and Alzheimer's disease models. Remarkably, recent human studies using magnetic resonance image techniques have also shown a consistent correlation between cognitive dysfunction and iron deposition, mostly in the hippocampus, cortical areas, and basal ganglia. These findings may have relevant implications in the light of the knowledge that iron accumulates in brain regions of patients suffering from neurodegenerative diseases. A better understanding of the functional consequences of iron dysregulation in aging and neurological diseases may help to identify novel targets for treating memory problems that afflict a growing aging population. © 2013 - IOS Press and the authors. All rights reserved.

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