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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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.


Capiotti K.M.,Pontifical Catholic University of Rio Grande do Sul | Capiotti K.M.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Menezes F.P.,Pontifical Catholic University of Rio Grande do Sul | Nazario L.R.,Pontifical Catholic University of Rio Grande do Sul | And 9 more authors.
Neurotoxicology and Teratology | Year: 2011

Adenosine receptors are the most important biochemical targets of caffeine, a common trimethylxanthine found in food and beverages. Adenosine plays modulatory action during the development through adenosine receptors and their intracellular pathways activation. In this study, we aimed to evaluate if caffeine gave to zebrafish in the very first steps of development is able to affect its direct targets, through the adenosine receptors mRNA expression evaluation, and latter indirect targets, through evaluation of the pattern of dopamine and cAMP-regulated phosphoprotein and brain-derived neurotrophic factor (BDNF) mRNA expression. Here, we demonstrate that zebrafish express adenosine receptor subtypes (A1, A2A1, A2A2 and A2B) since 24. h post-fertilization (hpf) and that caffeine exposure is able to affect the expression of these receptors. Caffeine exposure from 1. hpf is able to increase A1 expression at 72-96. hpf and A2A1 expression at 72. hpf. No alterations occurred in A2A2 and A2B expression after caffeine treatment. DARPP-32, a phosphoprotein involved in adenosine intracellular pathway is also expressed since 24. hpf and early exposure to caffeine increased DARPP-32 expression at 168. hpf. We also evaluate the expression of BDNF as one of the targets of adenosine intracellular pathway activation. BDNF was also expressed since 24. hpf and caffeine treatment increased its expression at 48 and 72. hpf. No morphological alterations induced by caffeine treatment were registered by the check of general body features and total body length. Assessment of tactile sensibility also demonstrated no alterations by caffeine treatment. Altogether, these results suggest that caffeine is able to affect expression of its cellular targets since early phases of development in zebrafish without affect visible features. The up-regulation of direct and indirect targets of caffeine presents as a compensatory mechanism of maintenance of adenosinergic modulation during the developmental phase. © 2011 Elsevier Inc.


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.


Siebel A.M.,Grande Rio University | Siebel A.M.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Piato A.L.,Grande Rio University | Piato A.L.,Chapecó Region Community University | And 6 more authors.
Pharmacology Biochemistry and Behavior | Year: 2013

Adenosine is an endogenous modulator of brain functions, which presents anticonvulsant properties. In addition, its levels can be increased during neural injury. The modulation of extracellular adenosine levels by ectonucleotidase and adenosine deaminase (ADA) activities may represent a key mechanism in the control of epileptogenesis. In the present study, we investigated the effects of acute seizure episodes and antiepileptic drug (AED) treatments on ectonucleotidases and ADA activities in adult zebrafish brain. Our data have demonstrated that pentylenetetrazole (PTZ)-induced seizures did not alter ATP, ADP, and AMP hydrolysis in brain membrane fractions. However, there was a significant increase on ecto-ADA and soluble ADA activities in PTZ-treated animals immediately after a clonus-like convulsion and loss of posture, which are typical behavioral changes observed in Stage 3. Furthermore, our results have demonstrated that AED pretreatments prevented the stimulatory effect promoted by PTZ exposure on ADA activities. The PTZ and AED treatments did not promote alterations on ADA gene expression. Interestingly, when exposed to PTZ, animals pretreated with AEDs showed longer latency to reach the clonus-like seizure status, which is an effect that matches the suppression of the increase of ADA activity promoted by the AEDs. These data suggest that the adenosine deamination could be involved in the control of seizure development in zebrafish and may be modulated by AED treatments. © 2012 Elsevier Inc.


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.


Menezes F.P.,Laboratorio Of Neuroquimica E Psicofarmacologia | Kist L.W.,Laboratorio Of Biologia Genomica E Molecular | Bogo M.R.,Laboratorio Of Biologia Genomica E Molecular | Bonan C.D.,Laboratorio Of Neuroquimica E Psicofarmacologia | And 3 more authors.
Zebrafish | Year: 2015

Imbalances in glutamatergic signaling have been proposed as the cause of several neurological disturbances. The use of MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, to mimic features of these neurological disorders is effective both in mammals and in fish. However, the variability of the subunits comprising the NMDA receptor during development alters the pharmacokinetic properties of the receptor and leads to different responses to this drug. Here, we evaluated the locomotor response of zebrafish to MK-801 (1, 5, and 20 μM) through the development (30 days postfertilization [dpf] to 2 years postfertilization [ypf]). The NMDA receptor subunit gene expression was also analyzed through the development (7 dpf to 2 ypf). Zebrafish displayed an age-related response to MK-801 with a higher response at 60 and 120 dpf. The magnitude of hyperlocomotion promoted by MK-801 seems to be less powerful for zebrafish in relation to rodents. The verification of expression levels in zebrafish NMDA receptor subunits shows that NR1.1 had a slight reduction throughout the development, while the NR2 subunits, especially NR2A.2 and NR2C.1, vary their expression levels according to the stage of development. The time-specific locomotor response to MK-801 through the development could be a consequence of differential NMDA receptor subunit expression. This result of developmental response to MK-801 is a crucial component in the consolidation of zebrafish as a suitable model to study glutamatergic neurotransmission in early phases. © 2015, 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.


Barichello T.,Laboratorio Of Microbiologia Experimental | Barichello T.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | Generoso J.S.,Laboratorio Of Microbiologia Experimental | Generoso J.S.,Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm | And 5 more authors.
Oxidative Medicine and Cellular Longevity | Year: 2013

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-B-inducing kinase, resulting in the nuclear translocation of NF-B 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•, O 2 •, and H 2O2. This formation generates oxidative and nitrosative stress, subsequently, lipid peroxidation, mitochondrial damage, and BBB breakdown, which contributes to cell injury during pneumococcal meningitis. © 2013 Tatiana Barichello et al.


PubMed | Pontifical Catholic University of Rio Grande do Sul and Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm
Type: | Journal: 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 111mM 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 (0.05ng/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 111mM 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.


PubMed | Pontifical Catholic University of Rio Grande do Sul, Instituto Nacional Of Ciencia E Tecnologia Translacional Em Medicina Inct Tm and Grande Rio University
Type: | Journal: Reproductive toxicology (Elmsford, N.Y.) | Year: 2015

The effects of ethanol exposure on extracellular adenosine sources in zebrafish were evaluated. In the acute treatment, the embryos were exposed to 2% ethanol on day 1 post-fertilization (dpf). In the chronic treatment, the exposure was continued for 2h/day up to 6 dpf. Ecto-5-nucleotidase activity was assessed by colorimetric method and gene expression determined by RT-qPCR in 7 dpf zebrafish. Body length, ocular distance and surface area of the eyes were registered in animals acutely exposed to ethanol and pretreated with AOPCP (5-500 nM), an ecto-5-nucleotidase inhibitor, or dipyridamole (10-100 M), a blocker of nucleoside transport. Both ethanol exposures promoted increased ecto-5-nucleotidase activity, impaired locomotion and morphology. Ecto-5-nucleotidase expression was not affected. AOPCP promoted mild prevention of morphological defects caused by acute treatment, while dipyridamole worsened these defects. Early ethanol exposure altered adenosinergic tonus, especially through nucleoside transporters, contributing to morphological defects produced by ethanol in zebrafish.

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