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1.
J Neurochem ; 153(4): 495-509, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32031241

RESUMO

Current theories on the role of serotonin (5-HT) in vertebrate defensive behavior suggest that this monoamine increases anxiety but decreases fear, by acting at different levels of the neuroaxis. This paradoxical, dual role of 5-HT suggests that a serotonergic tone inhibits fear responses, while an acute increase in 5-HT would produce anxiety-like behavior. However, so far no evidence for a serotonergic tone has been found. Using zebrafish alarm responses, we investigate the participation of phasic and tonic 5-HT levels in fear-like behavior, as well as in behavior after stimulation. Conspecific alarm substance (CAS) increased bottom-dwelling and erratic swimming, and animals transferred to a novel environment after CAS exposure (post-exposure behavior) showed increased bottom-dwelling and freezing. Clonazepam blocked CAS effects during and after exposure. Acute fluoxetine dose-dependently decreased fear-like behavior, but increased post-exposure freezing. Metergoline had no effect on fear-like behavior, but blocked the effects of CAS on post-exposure behavior; similar effects were observed with para-chlorophenylalanine. Finally, CAS was shown to decrease the activity of monoamine oxidase in the zebrafish brain after exposure. These results suggest that phasic and tonic serotonin encode an aversive expectation value, switching behavior toward cautious exploration/risk assessment/anxiety when the aversive stimulus is no longer present.


Assuntos
Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Inibidores de Captação de Serotonina/farmacologia , Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Relação Dose-Resposta a Droga , Medo/psicologia , Feminino , Masculino , Natação/fisiologia , Peixe-Zebra
2.
Biochimie ; 168: 297-306, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31770565

RESUMO

The main function of AChE is the hydrolysis of the neurotransmitter acetylcholine (ACh) at the neuromuscular and in cholinergic brain synapses. In some pathologies, loss of cholinergic neurons may be associated with a deficiency of ACh in specific brain areas. Consequently, the study of new safe drugs that inhibit AChE is important, because they can increase ACh levels in the synaptic cleft without adverse effects. Here, we evaluated the effects of JM-20 (a benzodiazepine-dihydropyridine hybrid molecule) on cholinesterase (ChE) activities from distinct sources (AChE from Electrophorus electricus (EeAChE), human erythrocyte membranes (HsAChE (ghost)), total erythrocyte (HsAChE (erythrocyte)) and BChE from plasma (HsBChE) and purified enzyme from the horse (EcBChE)). Kinetic parameters were determined in the presence of 0.05-1.6 mM of substrate concentration. The interactions ChEs with JM-20 were performed using molecular docking simulations. JM-20 inhibited all tested AChE but not BChE. The IC50 values were 123 nM ± 0.2 (EeAChE), 158 nM ± 0.1 (ghost HsAChE), and 172 nM ± 0.2 (erythrocytic HsAChE). JM-20 caused a mixed type of inhibition (it altered Km and Vmax of AChE). The molecular docking indicated the binding poses and the most plausible active isomer of JM-20. Besides giving important data for future drug design, our results help us understand the mode of action of JM-20 as a specific inhibitor of AChE enzymes.


Assuntos
Acetilcolinesterase/metabolismo , Benzodiazepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Niacina/análogos & derivados , Animais , Desenho de Fármacos , Electrophorus , Cavalos , Humanos , Cinética , Niacina/farmacologia
3.
Pharmacol Biochem Behav ; 186: 172790, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31499145

RESUMO

Binge drinking is characterized by excessive alcohol consumption in a short period of time and is associated with a poor quality of life. Zebrafish are commonly used to investigate neurochemical, behavioral, and genetic parameters associated with ethanol (EtOH) exposure. However, few studies have used zebrafish as a model to investigate binge EtOH exposure. In order to elucidate the potential neurobehavioral impairments evoked by binge EtOH exposure in zebrafish, animals were immersed in 1.4% EtOH for 30 min three consecutive times with intervals of one week. Neurobehavioral parameters were analyzed immediately following the third exposure, as well as 2 and 9 days later. Brain choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were reduced 9 days after the treatment. Thiobarbituric acid-reactive species and dichlorodihydrofluorescein levels were increased immediately after the treatment, but both returned to normal levels 2 days after the treatment. Catalase and glutathione reductase were impaired 2 and 9 days after the treatment. No alteration was observed in superoxide dismutase and glutathione peroxidase activities. EtOH treatment did not alter brain expression of inflammatory genes such as il-1ß, il-10, and tnf-α. Zebrafish displayed anxiolytic-like behavior immediately after the last exposure, though there was no behavioral alteration observed 9 days after the treatment. Therefore, binge EtOH exposure in zebrafish leads to long lasting brain cholinergic alteration, probably related to oxidative stress immediately after the exposure, which is independent of classical inflammatory markers.


Assuntos
Etanol/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Peixe-Zebra/fisiologia , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Colina O-Acetiltransferase/metabolismo , Etanol/farmacologia
4.
J Trace Elem Med Biol ; 53: 62-68, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30910208

RESUMO

Previous findings showed that the nanoencapsulation of diphenyl diselenide [(PhSe)2], an organoselenium compound, provided superior biological effects and lower toxicological potential than its free form in vitro. However, few studies reported the behavioral and biochemical effects of this nanocapsules formulation in vivo. Zebrafish (Danio rerio) has emerged as a useful animal model to determine the pharmacological and toxicological effects of nanoparticles. Here, we evaluated the behavioral and brain oxidative effects after zebrafish exposure to (PhSe)2-loaded nanocapsules. Formulations were prepared by interfacial deposition of preformed polymer method and later tested at concentrations ranging from 0.1 to 2.0 µM. Both locomotor and exploratory activities were assessed in the novel tank diving test. Moreover, brain oxidative status was determined by measuring thiobarbituric acid-reactive substance levels, glutathione peroxidase, glutathione redutase and glutathione S-transferase activities. (PhSe)2-loaded nanocapsules showed no alteration on travelled distance, immobility, and erratic swimming, suggesting the absence of behavioral impairments. Interestingly, the higher concentration tested had anxiolytic-like effects, since animals spent more time in the top area and showed a decreased thigmotaxis behavior. Biochemical analysis demonstrated that the concentrations used in this study did not affect oxidative stress-related parameters in brain samples, reinforcing the low toxicological potential of the formulation. In conclusion, the exposure to (PhSe)2-loaded nanocapsules caused no locomotor impairments as well as did not modify the oxidative status of zebrafish brain, indicating that this formulation is probably non-toxic and promising for future pharmacological studies.


Assuntos
Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/farmacologia , Encéfalo/efeitos dos fármacos , Nanocápsulas/administração & dosagem , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Polímeros/administração & dosagem , Peixe-Zebra/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Masculino
5.
Pharmacol Biochem Behav ; 165: 1-8, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29241648

RESUMO

Caffeine is a substance present in several foods and drinks of common western diet. Although high caffeine concentrations induce anxiogenic properties in various species, the influence of the different baselines of anxiety levels on caffeine-mediated responses is poorly understood. The short-fin wild-type (WT) and leopard (leo) zebrafish populations present significant behavioral differences, in which leo shows exacerbated anxiety-like responses. Since behavioral neurophenotyping may be easily assessed in adult zebrafish by associating temporal and spatial three-dimensional reconstructions of locomotion, we investigated the effects of caffeine on exploration and anxiety-like behavior of WT and leo zebrafish. Moreover, the whole-body cortisol content was assessed in the absence and presence of caffeine. For this purpose, animals were acutely exposed to caffeine (25, 50, 100 and 200mg/L) for 15min and further tested in the novel tank. Endpoint data and 3D reconstruction plots revealed that caffeine was anxiogenic in both WT and leo populations by altering vertical swimming, freezing, and erratic movements depending on the concentration. Prominent anxiogenic effects during habituation to novelty were observed in WT, suggesting a fundamental role of the phenotype in caffeine-mediated neurobehavioral responses. Although untreated leo showed higher baseline cortisol levels than control WT, caffeine increased whole-body cortisol in both populations. Moreover, caffeine induced aberrant swimming profiles in WT and leo following 200mg/L exposure, which could reflect nonspecific toxicity and/or seizure-like behaviors. Collectively, our novel findings show that caffeine effects in zebrafish differ in a population-dependent manner.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Peixe-Zebra/fisiologia , Animais , Ansiedade/induzido quimicamente , Comportamento Exploratório , Feminino , Reação de Congelamento Cataléptica , Hidrocortisona/análise , Locomoção , Masculino , Fenótipo , Especificidade da Espécie , Natação
6.
Neurotoxicol Teratol ; 65: 14-18, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29122710

RESUMO

Ethanol alters the homeostasis between excitatory and inhibitory neurotransmitters and its intoxication reveals adenosine as responsible to modify several responses including signal transduction. Zebrafish has been recently investigated for knowledge the prolonged effect of ethanol on behavioral and biochemical parameters. The aim of this study was to evaluate the soluble and membrane adenosine deaminase activities and gene expression in zebrafish brain. Animals were exposed to 0.5% ethanol for 7, 14, and 28days. There were no significant changes in ADA activity from soluble fraction after all treatments. However, we verified a decrease of ADA activity in membrane fraction after 28days (44%) of ethanol exposure. ADA1 was not altered whereas mRNA transcript levels for ADAL presented an increase after 28days of ethanol exposure (34%). ADA2-1 showed a decrease (26%) followed by an increase (17%) of transcripts after 14 and 28days of ethanol exposure, respectively. However, ADA2-1 truncated alternative splice isoform (ADA2-1/T) demonstrated a reduction after 28days (20%). ADA2-2 was decreased (22%) followed by an increase (109%) of transcripts after 14 and 18days of ethanol exposure, respectively. Altogether, the purine catabolism promoted by ADA may be an important target of the chronic toxicity induced for ethanol.


Assuntos
Adenosina Desaminase/metabolismo , Encéfalo/efeitos dos fármacos , Etanol/toxicidade , Expressão Gênica/efeitos dos fármacos , Peixe-Zebra/metabolismo , Adenosina Desaminase/genética , Animais , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Peixe-Zebra/genética
7.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 105-111, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28602852

RESUMO

Repeated ethanol (EtOH) consumption induces neurological disorders in humans and is considered an important public health problem. The physiological effects of EtOH are dose- and time-dependent, causing relevant changes in the social behavior. In addition, alcohol-induced oxidative stress has been proposed as a key mechanism involved in EtOH neurotoxicity. Here we investigate for the first time whether repeated EtOH exposure (REE) alters the social behavior of zebrafish and influences brain oxidation processes. Animals were exposed to water (control group) or 1% (v/v) EtOH (EtOH group) for 8 consecutive days (20min per day). EtOH was added directly to the tank water. At day 9, the social behavior and biochemical parameters were assessed. REE increased shoal cohesion by reducing inter-fish and farthest neighbor distances. SOD and CAT activities, as well as NPSH levels decreased in brain tissue. Moreover, REE increased lipid peroxidation suggesting oxidative damage. In summary, changes in oxidation processes may play a role in the CNS effects of EtOH, influencing the social behavior of zebrafish. Furthermore, in a translational neuroscience perspective, our data reinforces the utility of zebrafish to clarify the biochemical and behavioral effects of intermittent EtOH administration.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Comportamento Social , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Peixe-Zebra
8.
Environ Sci Pollut Res Int ; 24(9): 8759-8768, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28213707

RESUMO

Hydropower offers a reliable source of electricity in several countries, and Brazil supplies its energy needs almost entirely through hydropower plants. Nevertheless, hydropower plants comprise large buildings and water reservoirs and dams, resulting in huge ecological disruptions. Here, we analyzed the impact of four hydropower reservoirs construction in metals and pesticides incidence and the cytotoxic and genotoxic potential of sediment elutriate of rivers from southern Brazil. Our analyses have evidenced the elevated incidence of different metals (lead, iron, cadmium, and chrome) and pesticides (methyl parathion, atrazine, and 2,4-dichlorophenoxyacetic acid). We showed that Allium cepa exposed to sediment elutriates did not change the seed germination rate and mitotic index. However, roots from Allium cepa exposed to reservoirs sediment elutriates showed increased occurrence of chromosomal aberrations and nuclear abnormalities. Therefore, the results obtained in our study indicate that sediment from reservoirs present elevated concentration of metals and pesticides and a significant genotoxic potential. Taken together, our data support that hydropower reservoirs represent an environmental scenario that could impact surrounding wildlife and population.


Assuntos
Aberrações Cromossômicas/induzido quimicamente , Metais Pesados/toxicidade , Cebolas/efeitos dos fármacos , Resíduos de Praguicidas/toxicidade , Centrais Elétricas , Poluentes Químicos da Água/toxicidade , Brasil , Sedimentos Geológicos/química , Metais Pesados/análise , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Índice Mitótico , Cebolas/genética , Resíduos de Praguicidas/análise , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Rios/química , Poluentes Químicos da Água/análise
9.
Toxicol Mech Methods ; 27(4): 307-317, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28110610

RESUMO

Methylglyoxal (MG) is a reactive dicarbonyl metabolite originated mainly from glucose degradation pathway that plays an important role in the pathogenesis of diabetes mellitus (DM). Reactions of MG with biological macromolecules (proteins, DNA and lipids) can induce cytotoxicity and apoptosis. Here, human erythrocytes, leukocytes and platelets were acutely exposed to MG at concentration ranging from 0.025 to 10 mM. Afterwards, hemolysis and osmotic fragility in erythrocytes, DNA damage and cell viability in leukocytes, and the activity of purinergic ecto-nucleotidases in platelets were evaluated. The levels of glycated products from leukocytes and free amino groups from erythrocytes and platelets were also measured. MG caused fragility of membrane, hemolysis and depletion of amino groups in erythrocytes. DNA damage, loss of cell viability and increased levels of glycated products were observed in leukocytes. In platelets, MG inhibited the activity of enzymes NTPDase, 5'-nucleotidase and adenosine deaminase (ADA) without affecting the levels of free amino groups. Our findings provide insights for understanding the mechanisms involved in MG acute toxicity towards distinct blood cells.


Assuntos
Plaquetas/efeitos dos fármacos , Dano ao DNA , Eritrócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Aldeído Pirúvico/toxicidade , 5'-Nucleotidase/metabolismo , Adenosina Desaminase/metabolismo , Adulto , Plaquetas/enzimologia , Plaquetas/patologia , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Relação Dose-Resposta a Droga , Eritrócitos/enzimologia , Eritrócitos/patologia , Feminino , Hemólise/efeitos dos fármacos , Humanos , Leucócitos/enzimologia , Leucócitos/patologia , Masculino , Fragilidade Osmótica/efeitos dos fármacos
10.
Zebrafish ; 14(1): 51-59, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27672711

RESUMO

In this study, we show that an adaptation of the spinning test can be used as a model to study the exercise-exhaustion-recovery paradigm in fish. This forced swimming test promotes a wide range of changes in the hypothalamus-pituitary-interrenal axis functioning, intermediary metabolism, as well in fish behavior at both exercise and recovery periods. Our results pointed that this adapted spinning test can be considered a valuable tool for evaluating drugs and contaminant effects on exercised fish. This can be a suitable protocol both to environmental-to evaluate contaminants that act in fish energy mobilization and recovery after stressors-and translational perspectives-effects of drugs on exercised or stressed humans.


Assuntos
Glucose/análise , Hidrocortisona/análise , Condicionamento Físico Animal/métodos , Natação , Peixe-Zebra/fisiologia , Animais , Comportamento Animal , Creatina Quinase/análise , Metabolismo Energético , Modelos Animais , Estresse Fisiológico , Peixe-Zebra/sangue
11.
Zebrafish ; 13(3): 217-25, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27045850

RESUMO

By means of scientometric indicators, this study investigated the characteristics of scientific production and research collaboration involving zebrafish (Danio rerio) in Brazilian Science indexed by the Web of Science (WoS). Citation data were collected from the WoS and data regarding Impact Factor (IF) were gathered from journals in the Journal Citation Reports. Collaboration was evaluated according to coauthorship data, creating representative nets with VOSviewer. Zebrafish has attained remarkable importance as an experimental model organism in recent years and an increase in scientific production with zebrafish is observed in Brazil and around the world. The citation impact of the worldwide scientific production is superior when compared to the Brazilian scientific production. However, the citation impact of the Brazilian scientific production is consistently increasing. Brazil does not follow the international trends with regard to publication research fields. The state of Rio Grande do Sul has the greatest number of articles and the institution with the largest number of publications is Pontifícia Universidade Católica do Rio Grande do Sul. Journals' average IF is higher in Brazilian publications with international coauthorship, and around 90% of articles are collaborative. The Brazilian institutions presenting the greatest number of collaborations are Pontifícia Universidade Católica do Rio Grande do Sul, Universidade Federal do Rio Grande do Sul, Fundação Universidade Federal de Rio Grande, and Universidade de São Paulo. These data indicate that Brazilian research using zebrafish presents a growth in terms of number of publications, citation impact, and collaborative work.


Assuntos
Pesquisa Biomédica , Peixe-Zebra , Animais , Brasil , Internacionalidade , Editoração
12.
Biores Open Access ; 5(1): 1-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26862467

RESUMO

Ethanol is a widely consumed drug, which acts on the central nervous system to induce behavioral alterations ranging from disinhibition to sedation. Recent studies have produced accumulating evidence for the therapeutic role of probiotic bacteria in behavior. We aimed to investigate the effect of Lactobacillus rhamnosus GG (LGG) on the behavior of adult zebrafish chronically exposed to ethanol. Adult wild-type zebrafish were randomly divided into four groups, each containing 15 fish. The following groups were formed: Control (C), received unsupplemented feed during the trial period; Probiotic (P), fed with feed supplemented with LGG; Ethanol (E), received unsupplemented feed and 0.5% of ethanol directly added to the tank water; and Probiotic+Ethanol (P+E), group under ethanol exposure (0.5%) and fed with LGG supplemented feed. After 2 weeks of exposure, the novel tank test was used to evaluate fish behavior, which was analyzed using computer-aided video tracking. LGG alone did not alter swimming behavior of the fish. Ethanol exposure led to robust behavioral effects in the form of reduced anxiety levels, as indicated by increased vertical exploration and more time spent in the upper region of the novel tank. The group exposed to ethanol and treated with LGG behaved similarly to animals exposed to ethanol alone. Taken together, these results show that zebrafish behavior was not altered by LGG per se, as seen in murine models. This was the first study to investigate the effects of a probiotic diet on behavior after a chronic ethanol exposure.

13.
Mol Neurobiol ; 53(1): 200-209, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25421208

RESUMO

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.


Assuntos
Trifosfato de Adenosina/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Metionina/farmacologia , Adenosina/metabolismo , Adenosina Trifosfatases/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Animais , Glicina N-Metiltransferase/deficiência , Hidrólise/efeitos dos fármacos , Peixe-Zebra
14.
Artigo em Inglês | MEDLINE | ID: mdl-26229543

RESUMO

The jaboticaba tree, Plinia trunciflora (O. Berg) Kausel, is popularly named "jabuticabeira" in Brazil and is used in folk medicine to treat diabetes and chronic inflammation of the tonsils, but studies evaluating the central effects of this species are limited. This study evaluated the antidepressant-like and antioxidant effects of P. trunciflora (PT) aqueous extract, in which five different anthocyanins were identified. PT showed significant ferric-reduction power and DPPH radical scavenging activity in vitro and reduced lipid peroxidation both in vitro and ex vivo. At the behavioural level, PT (400 and 800 mg/kg, i.p.) dose-dependently reduced immobility time in the tail suspension test in Swiss male mice. The identification of bioactive compounds accompanied by the in vitro and ex vivo antioxidant activity of PT suggests that these activities might be related to the antidepressant-like activity of P. trunciflora.

15.
Biomed Res Int ; 2015: 870389, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25685814

RESUMO

Alzheimer's disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski's rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) from Equus ferus (EfBChE), with IC50 ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.


Assuntos
Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase , Bases de Dados de Proteínas , Simulação de Acoplamento Molecular , Acetilcolina/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Equidae/metabolismo , Humanos
16.
PLoS One ; 9(12): e114233, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25469630

RESUMO

In this study, the protective effects of diphenyl diselenide [(PhSe)2] on quinclorac- induced toxicity were investigated in silver catfish (Rhamdia quelen). The fish were fed for 60 days with a diet in the absence or in the presence of 3.0 mg/Kg (PhSe)2. Animals were further exposed to 1 mg/L quinclorac for 8 days. At the end of experimental period, fish were euthanized and biopsies from liver and gills, as well as blood samples, were collected. The cortisol and metabolic parameters were determined in plasma, and those enzyme activities related to osmoregulation were assayed in the gills. In liver, some important enzyme activities of the intermediary metabolism and oxidative stress-related parameters, such as thiobarbituric acid-reactive substance (TBARS), protein carbonyl, catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), nonprotein thiols (NPSH) and ascorbic acid contents were also evaluated. Compared to the control group, quinclorac exposure significantly decreased hepatosomatic index and increased cortisol and lactate values in plasma. Moreover, the activities of fructose biphosphatase (FBPase), glucose-6-phosphate dehydrogenase (G6Pase), glycogen phosphorilase (GPase) and aspartate aminotransferase (AST) were significantly increased in liver. Quinclorac also induced lipid peroxidation while the activity of SOD, NPSH and ascorbic acid levels decreased in the liver. However, dietary (PhSe)2 reduced the herbicide-induced effects on the studied parameters. In conclusion, (PhSe)2 has beneficial properties based on its ability to attenuate toxicity induced by quinclorac by regulating energy metabolism and oxidative stress-related parameters.


Assuntos
Derivados de Benzeno/administração & dosagem , Peixes-Gato/metabolismo , Herbicidas/toxicidade , Compostos Organosselênicos/administração & dosagem , Substâncias Protetoras/administração & dosagem , Quinolinas/toxicidade , Animais , Ácido Ascórbico/metabolismo , Catalase/genética , Catalase/metabolismo , Dieta , Suplementos Nutricionais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Estresse Oxidativo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
17.
Aquat Toxicol ; 156: 269-73, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25245382

RESUMO

Fluoxetine is one of the most prescribed psychotropic medications, and is an agent of increasing interest for environmental toxicology. Fish and other aquatic organisms are excellent models to study neuroactive small molecules like fluoxetine. However, prone to variance due to experimental factors, data obtained in these models need to be interpreted with caution, using proper experimental protocols, study designs, validated endpoints as well as well-established models and tests. Choosing the treatment protocol and dose range for fluoxetine and other serotonergic drugs is critical for obtaining valid test results and correct data interpretation. Here we discuss the value of aquatic models to study fluoxetine effects, based on prior high-quality research, and outline the directions of future translational studies in the field. We review fluoxetine-evoked phenotypes in acute vs. chronic protocols, discussing them in the contact of complex role of serotonin in behavioral regulation. We conclude that zebrafish and other aquatic models represent a useful in-vivo tool for fluoxetine pharmacology and (eco)toxicology research.


Assuntos
Organismos Aquáticos/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Ecotoxicologia/normas , Fluoxetina/toxicidade , Animais , Modelos Animais , Serotonina/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra
18.
Toxicol In Vitro ; 28(5): 822-8, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24681127

RESUMO

Ethanol (EtOH) and its metabolite, acetaldehyde (ALD), induce deleterious effects on central nervous system (CNS). Here we investigate the in vitro toxicity of EtOH and ALD (concentrations of 0.25%, 0.5%, and 1%) in zebrafish brain structures [telencephalon (TE), opticum tectum (OT), and cerebellum (CE)] by measuring the functionality of glutamate transporters, MTT reduction, and extracellular LDH activity. Both molecules decreased the activity of the Na(+)-dependent glutamate transporters in all brain structures. The strongest glutamate uptake inhibition after EtOH exposure was 58% (TE-1%), and after ALD, 91% (CE-1%). The results of MTT assay and LDH released demonstrated that the actions of EtOH and its metabolite are concentration and structure-dependent, in which ALD was more toxic than EtOH. In summary, our findings demonstrate a differential toxicity in vitro of EtOH and ALD in zebrafish brain structures, which can involve changes on glutamatergic parameters. We suggest that this species may be an interesting model for assessing the toxicological actions of alcohol and its metabolite in CNS.


Assuntos
Acetaldeído/toxicidade , Encéfalo/efeitos dos fármacos , Etanol/toxicidade , Peixe-Zebra , Animais , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Feminino , Ácido Glutâmico/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino
19.
Toxicol Appl Pharmacol ; 272(3): 681-9, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23933163

RESUMO

The use of zebrafish (Danio rerio) is increasing as an intermediate preclinical model, to prioritize drug candidates for mammalian testing. As the immune system of the zebrafish is quite similar to that of mammals, models of inflammation are being developed for the screening of new drugs. The characterization of these models is crucial for studies that seek for mechanisms of action and specific pharmacological targets. It is well known that copper is a metal that induces damage and cell migration to hair cells of lateral line of zebrafish. Extracellular nucleotides/nucleosides, as ATP and adenosine (ADO), act as endogenous signaling molecules during tissue damage by exerting effects on inflammatory and immune responses. The present study aimed to characterize the inflammatory status, and to investigate the involvement of the purinergic system in copper-induced inflammation in zebrafish larvae. Fishes of 7 days post-fertilization were exposed to 10 µM of copper for a period of 24 h. The grade of oxidative stress, inflammatory status, copper uptake, the activity and the gene expression of the enzymes responsible for controlling the levels of nucleotides and adenosine were evaluated. Due to the copper accumulation in zebrafish larvae tissues, the damage and oxidative stress were exacerbated over time, resulting in an inflammatory process involving IL-1ß, TNF-α, COX-2 and PGE2. Within the purinergic system, the mechanisms that control the ADO levels were the most involved, mainly the reactions performed by the isoenzyme ADA 2. In conclusion, our data shed new lights on the mechanisms related to copper-induced inflammation in zebrafish larvae.


Assuntos
Cobre/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Nucleosídeos de Purina/fisiologia , Nucleotídeos de Purina/fisiologia , Animais , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/fisiopatologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/metabolismo , Estresse Oxidativo/fisiologia , Peixe-Zebra/embriologia
20.
Mem Inst Oswaldo Cruz ; 107(2): 170-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22415254

RESUMO

Trichomonas vaginalis is a parasite of the human urogenital tract that causes trichomonosis, the most prevalent non-viral sexually transmitted disease. Ectonucleoside triphosphate diphosphohydrolase (NTPDase) family members, which hydrolyse extracellular ATP and ADP and ecto-5'-nucleotidase, which hydrolyses AMP, have been characterised in T. vaginalis. For trichomonad culture, the growth medium is supplemented with 10% serum, which is an important source of nutrients, such as adenosine. Here, we investigated the ATP metabolism of T. vaginalis trophozoites from long-term cultures and clinical isolates under limited bovine serum conditions (1% serum). The specific enzymatic activities were expressed as nmol inorganic phosphate (Pi) released/min/mg protein, the gene expression patterns were determined by reverse transcriptase-polymerase chain reaction, the extracellular adenine nucleotide hydrolysis was analysed by high performance liquid chromatography and the cell cycle analysis was assessed by flow cytometry. Serum limitation led to the profound activation of NTPDase and ecto-5'-nucleotidase activities. Furthermore, the levels of NTPDase A and B transcripts increased and extracellular ATP metabolism was activated, which led to enhanced ATP hydrolysis and the formation of ADP and AMP. Moreover, the cell cycle was arrested at the G0/G1 stage, which suggested adenosine uptake. Our data suggest that under conditions of serum limitation, NTPDase and ecto-5'-nucleotidase play a role in providing the adenosine required for T. vaginalis growth and that this process contributes to the establishment of parasitism.


Assuntos
5'-Nucleotidase/metabolismo , Trifosfato de Adenosina/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Trichomonas vaginalis/enzimologia , Animais , Bovinos , Ciclo Celular , Cromatografia Líquida de Alta Pressão , Feminino , Citometria de Fluxo , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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