Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm

Porto Alegre, Brazil

Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm

Porto Alegre, Brazil
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Vuaden F.C.,Federal University of Rio Grande do Sul | Savio L.E.B.,Federal University of Rio Grande do Sul | Rico E.P.,Federal University of Rio Grande do Sul | Mussulini B.H.M.,Federal University of Rio Grande do Sul | And 6 more authors.
Molecular Neurobiology | Year: 2016

Hypermethioninemic patients may exhibit different neurological dysfunctions, and the mechanisms underlying these pathologies remain obscure. Glutamate and ATP are important excitatory neurotransmitters co-released at synaptic clefts, and whose activities are intrinsically related. Adenosine—the final product of ATP breakdown—is also an important neuromodulator. Here, we investigated the effects of long-term (7-day) exposure to 1.5 or 3 mM methionine (Met) on glutamate uptake in brain tissues (telencephalon, optic tectum, and cerebellum) and on ATP, ADP, and AMP catabolism by ecto-nucleotidases found in brain membrane samples, using a zebrafish model. Also, we evaluated the expression of ecto-nucleotidase (ntdp1, ntdp2mg, ntdp2mq, ntdp2mv, ntdp3, and nt5e) and adenosine receptor (adora1, adora2aa, adora2ab, adora2b) genes in the brain of zebrafish exposed to Met. In animals exposed to 3.0 mM Met, glutamate uptake in the telencephalon decreased significantly. Also, ATP and ADP (but not AMP) catabolism decreased significantly at both Met concentrations tested. The messenger RNA (mRNA) levels of ntpd genes and of the adenosine receptors adora1 and adora2aa increased significantly after Met exposure. In contrast, adora2ab mRNA levels decreased after Met exposure. Our data suggest that glutamate and ATP accumulate at synaptic clefts after Met exposure, with potential detrimental effects to the nervous system. This phenomenon might explain, at least in part, the increased susceptibility of hypermethioninemic patients to neurological symptoms. © 2014, Springer Science+Business Media New York.


Cognato G.P.,Grande Rio University | Bortolotto J.W.,Grande Rio University | Blazina A.R.,Grande Rio University | Christoff R.R.,Grande Rio University | And 5 more authors.
Neurobiology of Learning and Memory | Year: 2012

The interest in the behavioral features of zebrafish has significantly increased over the past two decades. However, most available protocols have used longer training periods and have been based on reinforcement/ reward or avoidance. The Y-Maze memory task has the advantage of using a simple and rapid training session, but it has not been established in zebrafish. Here, we have characterized this task for zebrafish, with the addition of pharmacological interventions in the acquisition and consolidation memory phases. The results show that zebrafish spend more time in the novel arm than in the other arms of the Y-Maze, both in response to novelty and spatial memory training-test intervals (TTIs). We have also studied the involvement of the glutamatergic and cholinergic systems with pre- and post-training treatments with the NMDA receptor antagonist MK-801 (20 μM) and the cholinergic blocker scopolamine (200 μM). After 1h of TTI, pre-training MK-801 and scopolamine-treated fish reduced their exploration of the novel arm when compared to the control group, with no changes in their locomotor activity. Post-training of MK-801 treatment also impaired their Y-Maze performance, while post-training of any scopolamine treatment failed to affect novel arm exploration. In conclusion, the Y-Maze memory task can be reliably used for zebrafish, providing a new, rapid, and preference/avoidance independent task for the study of memory in this teleost. In addition, our results highlight the implication of the glutamatergic and cholinergic systems in the memory of zebrafish. © 2012 Elsevier Inc.


Piato A.L.,Grande Rio University | Capiotti K.M.,Grande Rio University | Tamborski A.R.,Grande Rio University | Oses J.P.,Catholic University of Pelotas | And 8 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2011

Zebrafish (Danio rerio) have emerged as a promising model organism to study development, toxicology, pharmacology, and neuroscience, among other areas. Despite the increasing number of studies using zebrafish, behavioral studies with this species are still elementary when compared to rodents. The aim of this study was to develop a model of unpredictable chronic stress (UCS) in zebrafish. We evaluated the effects of UCS protocol during 7 or 14. days on behavioral and physiological parameters. The effects of stress were evaluated in relation to anxiety and exploratory behavior, memory, expression of corticotrophin-releasing factor (CRF) and glucocorticoid receptor (GR), and cortisol levels. As expected, UCS protocol increased the anxiety levels, impaired cognitive function, and increased CRF while decreased GR expression. Moreover, zebrafish submitted to 7 or 14. days of UCS protocol presented increased cortisol levels. The protocol developed here is a complementary model for studying the neurobiology and the effects of chronic stress in behavioral and physiological parameters. In addition, this protocol is less time consuming than standard rodent models commonly used to study chronic stress. These results confirm UCS in zebrafish as an adequate model to preclinical studies of stress, although further studies are warranted to determine its predictive validity. © 2010 Elsevier Inc.


Richetti S.K.,Grande Rio University | Richetti S.K.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Rosemberg D.B.,Federal University of Rio Grande do Sul | Ventura-Lima J.,Grande Rio University | And 5 more authors.
NeuroToxicology | Year: 2011

Pollution is a world problem with immeasurable consequences. Heavy metal compounds are frequently found as components of anthropogenic pollution. Here we evaluated the effects of the treatment with cadmium acetate, lead acetate, mercury chloride, and zinc chloride in acetylcholinesterase activity and gene expression pattern, as well as the effects of these treatments in antioxidant competence in the brain of an aquatic and well-established organism for toxicological analysis, zebrafish (Danio rerio, Cyprinidae). Mercury chloride and lead acetate promoted a significant decrease in acetylcholinesterase activity whereas they did not alter the gene expression pattern. In addition, the antioxidant competence was decreased after exposure to mercury chloride. The data presented here allowed us to hypothesize a signal transmission impairment, through alterations in cholinergic transmission, and also in the antioxidant competence of zebrafish brain tissue as some of the several effects elicited by these pollutants. © 2010 Elsevier Inc.


Richetti S.K.,Grande Rio University | Richetti S.K.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Blank M.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Blank M.,Grande Rio University | And 10 more authors.
Behavioural Brain Research | Year: 2011

Demographic aging gives rise to a growing population with age-associated behavioral and cognitive deficits that may be associated at least partially to the increasing prevalence of neurodegenerative disorders, such as Alzheimer's disease (AD). In this disease, it has been observed a decrease in the cholinergic system, which is crucial to memory formation. Scopolamine-induced amnesic effect, through the disruption of the cholinergic neurotransmission, is one of the approaches used to investigate the mechanisms involved in cognitive impairment observed in AD. The aim of our study was to investigate the potential protective role of quercetin and rutin against scopolamine-induced inhibitory avoidance memory deficits in zebrafish. Scopolamine (200. μM dissolved in the tank water for 1. h) given pre-training hindered memory formation while both quercetin and rutin pretreatments (50. mg/kg, single injection, i.p.) prevented the scopolamine-induced amnesia. None of the compounds affected zebrafish general locomotor activity. Together, these results contribute to the increase of the knowledge about plant compounds applicability as medicines to prevent and treat neurodegenerative diseases, like Alzheimer's disease. © 2010 Elsevier B.V.


Seibt K.J.,Grande Rio University | Piato A.L.,Grande Rio University | da Luz Oliveira R.,Grande Rio University | da Luz Oliveira R.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | And 6 more authors.
Behavioural Brain Research | Year: 2011

Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Studies have demonstrated that these behavioral changes are, in some cases, sensitive to remediation by antipsychotic drugs. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs and to discover new pharmacological targets. In the current study we investigated the ability of antipsychotic drugs to reverse schizophrenia-like symptoms produced by the NMDA receptor antagonist MK-801. Results showed that MK-801 (5. μM) given pre-training hindered memory formation while both atypical antipsychotics sulpiride (250. μM) and olanzapine (50. μM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9. μM) was ineffective to reverse those behavioral deficits. Therefore, MK-801-treated zebrafish showed some behavioral features observed in schizophrenia, such as cognitive and social interaction deficits, which were reverted by current available atypical drugs. © 2011 Elsevier B.V.


Gebauer D.L.,Grande Rio University | Pagnussat N.,Grande Rio University | Piato A.L.,Grande Rio University | Schaefer I.C.,Grande Rio University | And 3 more authors.
Pharmacology Biochemistry and Behavior | Year: 2011

There is growing interest in zebrafish as a model organism in behavioral pharmacology research. Several anxiety behaviors have been characterized in zebrafish, but the effect of anxiolytic drugs on these parameters has been scarcely studied. The purpose of this work was to assess the predictive validity of acute treatment with anxiolytic drugs on behavioral parameters of anxiety. In the first task we simultaneously observed behavior of adult zebrafish on four parameters: height in the tank, locomotion, color, and shoal cohesion. The second task was the assessment of light/dark preference for 5 min. The benzodiazepines clonazepam, bromazepam, diazepam, and a moderate dose of ethanol significantly reduced shoal cohesion. Buspirone specifically increased zebrafish exploration of higher portions of the tank. In the light/dark task, all benzodiazepines, buspirone, and ethanol increased time spent in the light compartment. After treatment with anxiolytics, fish typically spent more than 60 s and rarely less than 40 s in the light compartment whereas controls (n = 45) spent 33.3 ± 14.4 s and always less than 60 s in the light compartment. Propranolol had no clear effects in these tasks. These results suggest that light/dark preference in zebrafish is a practical, low-cost, and sensitive screening task for anxiolytic drugs. Height in the tank and shoal cohesion seem to be useful behavioral parameters in discriminating different classes of these drugs. © 2011 Elsevier Inc. All rights reserved.


Carini J.P.,Federal University of Rio Grande do Sul | Klamt F.,Federal University of Rio Grande do Sul | Klamt F.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Bassani V.L.,Federal University of Rio Grande do Sul
RSC Advances | Year: 2014

Cancer is the major public health problem worldwide; consequently, the search for new chemotherapeutic drugs is constant. Most of these agents are derived from natural sources, which are the major consistent basis for the search for modern anticancer medicines. In this context, numerous studies indicate flavonoids as a potential new class of secondary metabolites for anticancer therapy. In this review, special attention was addressed to flavonoids present in Achyrocline satureioides, a widely used medicinal plant with several and a well established range of biological properties. Two of these flavonoids are extensively studied for anticancer therapy, quercetin and luteolin, followed by 3-O-methylquercetin. Achyrobichalcone, recently isolated from A. satureioides by our group, can also represent a promising chemotherapeutic biomolecule due to its similarity with other cytotoxic bichalcones to cancer cell lines. The anticancer properties of these flavonoids, specially quercetin and luteolin, type of cell death, mechanisms and molecular targets involved were described. In general, these effects were observed due to the inhibition of cell proliferation, cell cycle arrest, apoptosis, inhibition of angiogenesis, prevention of migration/metastasis and overcoming multidrug resistance, alone or in combination with commonly used chemotherapeutic drugs. All these successful findings in preclinical studies suggest that these flavonoids are promising biomolecules for the development of new anticancer drugs in the future.


Blazina A.R.,Grande Rio University | Vianna M.R.,Grande Rio University | Vianna M.R.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Lara D.R.,Grande Rio University
Zebrafish | Year: 2013

The increasing use of adult zebrafish in behavioral studies has created the need for new and improved protocols. Our investigation sought to evaluate the swimming behavior of zebrafish against a water current using the newly developed Spinning Task. Zebrafish were individually placed in a beaker containing a spinning magnetic stirrer and their latency to be swept into the whirlpool was recorded. We characterized that larger fish (>4 cm) and lower rpm decreased the swimming time in the Spinning Task. There was also a dose-related reduction in swimming after acute treatment with haloperidol, valproic acid, clonazepam, and ethanol, which alter coordination. Importantly, at doses that reduced swimming time in the Spinning Task, these drugs influenced absolute turn angle (ethanol increased and the other drugs decreased), but had no effect of distance travelled in a regular water tank. These results suggest that the Spinning Task is a useful protocol to add information to the assessment of zebrafish motor behavior. © Mary Ann Liebert, Inc.


Capiotti K.M.,Pontifical Catholic University of Rio Grande do Sul | De Moraes D.A.,Pontifical Catholic University of Rio Grande do Sul | Menezes F.P.,Pontifical Catholic University of Rio Grande do Sul | Kist L.W.,Pontifical Catholic University of Rio Grande do Sul | And 5 more authors.
Behavioural Brain Research | Year: 2014

Diabetes mellitus, which causes hyperglycemia, affects the central nervous system and can impairs cognitive functions, such as memory. The aim of this study was to investigate the effects of hyperglycemia on memory as well as on the activity of acethylcholinesterase. Hyperglycemia was induced in adult zebrafish by immersion in glucose 111. mM by 14 days. The animals were divided in 4 groups: control, glucose-treated, glucose-washout 7-days and glucose-washout 14-days. We evaluated the performance in inhibitory avoidance task and locomotor activity. We also determined acethylcholinesterase activity and gene expression from whole brain. In order to counteract the effect of hyperglycemia underlined by effects on acethylcholinesterase activity, we treated the animals with galantamine (0.05. ng/g), an inhibitor of this enzyme. Also we evaluated the gene expression of insulin receptor and glucose transporter from zebrafish brain. The hyperglycemia promoted memory deficit in adult zebrafish, which can be explained by increased AChE activity. The ache mRNA levels from zebrafish brain were decrease in 111. mM glucose group and returned to normal levels after 7 days of glucose withdrawal. Insulin receptors (. insra-. 1, insra-2, insrb-1 and insrb-2) and glut-3 mRNA levels were not significantly changed. Our results also demonstrated that galantamine was able to reverse the memory deficit caused by hyperglycemia, demonstrating that these effects involve modulation of AChE activity. These data suggest that the memory impairment induced by hyperglycemia is underlined by the cholinergic dysfunction caused by the mechanisms involving the control of acetylcholinesterase function and gene expression. © 2014 Elsevier B.V.

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