National Institute of Science and Technology for Translational Medicine

Porto Alegre, Brazil

National Institute of Science and Technology for Translational Medicine

Porto Alegre, Brazil
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Do Val-da Silva R.A.,University of Sao Paulo | Peixoto-Santos J.E.,University of Sao Paulo | Kandratavicius L.,University of Sao Paulo | Kandratavicius L.,National Institute of Science and Technology for Translational Medicine | And 14 more authors.
Frontiers in Pharmacology | Year: 2017

The present study reports the behavioral, electrophysiological, and neuropathological effects of cannabidiol (CBD), a major non-psychotropic constituent of Cannabis sativa, in the intrahippocampal pilocarpine-induced status epilepticus (SE) rat model. CBD was administered before pilocarpine-induced SE (group SE+CBDp) or before and after SE (group SE+CBDt), and compared to rats submitted only to SE (SE group), CBD, or vehicle (VH group). Groups were evaluated during SE (behavioral and electrophysiological analysis), as well as at days one and three post-SE (exploratory activity, electrophysiological analysis, neuron density, and neuron degeneration). Compared to SE group, SE+CBD groups (SE+CBDp and SE+CBDt) had increased SE latency, diminished SE severity, increased contralateral afterdischarge latency and decreased relative powers in delta (0.5-4 Hz) and theta (4-10 Hz) bands. Only SE+CBDp had increased vertical exploratory activity 1-day post SE and decreased contralateral relative power in delta 3 days after SE, when compared to SE group. SE+CBD groups also showed decreased neurodegeneration in the hilus and CA3, and higher neuron density in granule cell layer, hilus, CA3, and CA1, when compared to SE group. Our findings demonstrate anticonvulsant and neuroprotective effects of CBD preventive treatment in the intrahippocampal pilocarpine epilepsy model, either as single or multiple administrations, reinforcing the potential role of CBD in the treatment of epileptic disorders. © 2017 Do Val-da Silva, Peixoto-Santos, Kandratavicius, De Ross, Esteves, De Martinis, Alves, Scandiuzzi, Hallak, Zuardi, Crippa and Leite.


Zuardi A.W.,University of Sao Paulo | Zuardi A.W.,National Institute of Science and Technology for Translational Medicine | Rodrigues N.P.,University of Sao Paulo | Silva A.L.,University of Sao Paulo | And 7 more authors.
Frontiers in Pharmacology | Year: 2017

The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg), and CBD (100, 300, and 900 mg). The subjects were underwent a test of public speaking in a real situation (TPSRS) where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes) after administration of the drug/placebo, as time 0: -5 (baseline), 80 (pre-test), 153 (speech), and 216 (post-speech). Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase. © 2017 Zuardi, Rodrigues, Silva, Bernardo, Hallak, Guimarães and Crippa.


Genaro K.,University of Sao Paulo | Fabris D.,University of Sao Paulo | Arantes A.L.F.,University of Sao Paulo | Zuardi A.W.,University of Sao Paulo | And 4 more authors.
Frontiers in Pharmacology | Year: 2017

Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection. Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg). Conditioned place preference (CPP) paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg) inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL) injected into the rACC reduced mechanical allodynia in a dose-dependent manner. CBD (5 nmol/0.25 μL) did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally,CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness. Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. In addition, the study gives further support to the notion that the sensorial and affective dimensions of pain may be differentially modulated by CBD. © 2017 Genaro, Fabris, Arantes, Zuardi, Crippa and Prado.


Senger M.R.,Oswaldo Cruz Institute FIOCRUZ | Senger M.R.,Federal University of Rio Grande do Sul | Seibt K.J.,Pontifical Catholic University of Rio Grande do Sul | Seibt K.J.,National Institute of Science and Technology for Translational Medicine | And 7 more authors.
Cell Biology and Toxicology | Year: 2011

Aluminum is a metal that is known to impact fish species. The zebrafish has been used as an attractive model for toxicology and behavioral studies, being considered a model to study environmental exposures and human pathologies. In the present study, we have investigated the effect of aluminum exposure on brain acetylcholinesterase activity and behavioral parameters in zebrafish. In vivo exposure of zebrafish to 50 μg/L AlCl3 for 96 h at pH 5.8 significantly increased (36%) acetylthiocholine hydrolysis in zebrafish brain. There were no changes in acetylcholinesterase (AChE) activity when fish were exposed to the same concentration of AlCl3 at pH 6.8. In vitro concentrations of AlCl3 varying from 50 to 250 μM increased AChE activity (28% to 33%, respectively). Moreover, we observed that animals exposed to AlCl3 at pH 5.8 presented a significant decrease in locomotor activity, as evaluated by the number of line crossings (25%), distance traveled (14.1%), and maximum speed (24%) besides an increase in the absolute turn angle (12.7%). These results indicate that sublethal levels of aluminum might modify behavioral parameters and acetylcholinesterase activity in zebrafish brain. © Springer Science+Business Media B.V. 2011.


Lemes G.A.F.,Grande Rio University | Kist L.W.,Pontifical Catholic University of Rio Grande do Sul | Bogo M.R.,Pontifical Catholic University of Rio Grande do Sul | Bogo M.R.,National Institute of Science and Technology for Translational Medicine | Yunes J.S.,Grande Rio University
Journal of Venomous Animals and Toxins Including Tropical Diseases | Year: 2015

Background: Toxic cyanobacterial blooms are recurrent in Patos Lagoon, in southern Brazil. Among cyanotoxins, [D-Leu1] microcystin-LR is the predominant variant whose natural cycle involves water and sediment compartments. This study aimed to identify and isolate from sediment a bacterial strain capable of growing on [D-Leu1] microcystin-LR. Sediment and water samples were collected at two distinct aquatic spots: close to the Oceanographic Museum (P1), in Rio Grande City, and on São Lourenço Beach (P2), in São Lourenço do Sul City, southern Brazil.Methods: [D-Leu1] microcystin-LR was isolated and purified from batch cultures ofMicrocystis aeruginosastrain RST9501. Samples of water and sediment from Rio Grande and São Lourenço do Sul were collected. Bacteria from the samples were allowed to grow in flasks containing solely [D-Leu1] microcystin-LR. This strain named DMSX was isolated on agar MSM with 8 g L-1glucose and further purified on a cyanotoxin basis growth. Microcystin concentration was obtained by using the ELISA immunoassay for microcystins whereas bacterial count was performed by epifluorescence microscopy. The genusPseudomonaswas identified by DNA techniques.Results: Although several bacterial strains were isolated from the samples, only one, DMXS, was capable of growing on [D-Leu1] microcystin-LR. The phylogenetic analysis of the 16S rRNA gene from DMXS strain classified the organism asPseudomonas aeruginosa. DMXS strain incubated with [D-Leu1] microcystin-LR lowered the amount of toxin from 1 μg.L-1to < 0.05 μg.L-1. Besides, an increase in the bacterial count-from 71 × 105bacteria.mL-1to 117 × 105bacteria.mL-1-was observed along the incubation.Conclusions: The use of bacteria isolated from sediment for technological applications to remove toxic compounds is viable. Studies have shown that sediment plays an important role as a source of bacteria capable of degrading cyanobacterial toxins. This is the first Brazilian report on a bacterium-of the genusPseudomonas-that can degrade [D-Leu1] microcystin-LR, the most frequent microcystin variant in Brazilian freshwaters. © 2015 Lemes et al.; licensee BioMed Central.

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