Teses em Neurociências e Biologia Celular (Doutorado) - PPGNBC/ICB

URI Permanente para esta coleçãohttps://repositorio.ufpa.br/handle/2011/2390

O Doutorado Acadêmico pertence ao Programa de Pós-Graduação em Neurociências e Biologia Celular (PPGNBC) do Instituto de Ciências Biológicas (ICB) da Universidade Federal do Pará (UFPA).

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Acesso aberto (Open Access)
Alterações oxidativas e inflamatórias induzidas pela dapsona no sangue e no córtex pré-frontal de camundongos: efeitos do ácido alfa-lipóico
(Universidade Federal do Pará, 2018-12-14) GOMES, Bruno Alexandre Quadros; MONTEIRO, Marta Chagas; http://lattes.cnpq.br/6710783324317390
Dapsone (DDS), a drug used in leprosy multidrug therapy, can cause many adverse reactions and intoxications, inducing the generation of reactive oxygen species (ROS) and imbalance in the redox state, increase methemoglobin (MetHb) formation, hemolysis and release of heme and iron free, which may interfere with redox homeostasis in more vulnerable regions, such as prefrontal cortex (PFC), causing neurotoxicity and even neuroinflammation. In this sense, antioxidant compounds with chelating properties such as α-lipoic acid (ALA) may play a key role in combating or preventing these alterations. Thus, this work aims to evaluate the effect of DDS on MetHb formation, peripheral oxidative stress, and oxidative changes and neuroinflammation in PFC, as well as, effects of ALA. For this, was induced MetHb formation in Swiss mice with DDS 40mg/kg ip for 5 days. Two hours after DDS administration, ALA was given at two concentrations (12.5 and 25 mg/kg). Besides MetHb percentage, total equivalent antioxidant capacity (TEAC), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) thiobarbituric acid reactive substances (TBARS), and iron concentrations in blood and PFC were evaluated, as well as, IL-1β, IL-17, and IL-4 cytokine concentrations, and de F4/80+, GFAP, and BDNF expression in PFC. Our results show that DDS induces the MetHb formation in red blood cells of mice, however, ALA was able to prevent or reverse the oxidation of hemoglobin induced by DDS at two used concentrationns. DDS reduced antioxidant capacity (TEAC) in plasma and red blood cells; decreased erythrocyte GSH, CAT, and SOD; and increased TBARS and plasma iron; however, ALA at two concentrations increased or reestablished TEAC in plasma and red blood cells at baseline levels. In addition to increasing or reestablishing GSH levels, SOD, and CAT in red blood cells, and decreased TBARS and iron levels, mainly in euthanized animals 4h after treatment. Curiously ALA 50mg/kg increased plasma iron concentrations. The treatment with DDS 40mg/kg also reduced TEAC, GSH, SOD e CAT in the PFC of the mice and increased TBARS and iron, characterizing oxidative stress, mainly in euthanized animals in 24h after treatment. Treatment with ALA increased or restored TEAC and GSH; and increased SOD and CAT in 12,5mg/kg concentration in euthanized animals 4h after treatment, as well as reducing TBARS levels and decreasing or preventing iron overload, mainly in euthanized animals 24h after treatment. DDS also promoting microglial and astrocyte activation in PFC, through F4/80+ e GFAP expression., with increased IL-1β and IL-4 production, and BDNF reduction, on the other hand, ALA 25mg/kg reduced GFAP and IL-1β expression, besides increased BDNF, suggesting that DDS also can cause neuroinflammation, and ALA presents antioxidant and anti-inflammatory properties against toxicity caused by DDS. These results suggest that ALA is promising and plays an important role in the prevention and/or formation of MetHb, reestablishment of redox balance and iron concentrations in both blood and PFC. Thus, ALA may be a usefull adjuvant therapy in DDS-induced toxicity, with lower toxicity and increasing adherence to treatment of leprosy patients.
Acesso aberto (Open Access)
Avaliação do efeito da fração lipídica extraída de Agaricus brasiliensis antioxidante e imunomoduladora in vitro e em modelo de sepse letal em murino
(Universidade Federal do Pará, 2021-01) LIMA, Kely Campos Navegantes; MONTEIRO, Marta Chagas; http://lattes.cnpq.br/6710783324317390; https://orcid.org/0000-0002-3328-5650
Sepsis is defined as a potentially fatal organ dysfunction caused by a dysregulated host immune response to an infection. During sepsis, dysregulation of the host response occurs with the excessive release of pro-inflammatory mediators, generation of reactive species with depletion of antioxidant defenses and cellular damage. As a result, the patient develops organ dysfunction. In this context, our group proposes the A.brasiliensis Lipid Fraction (FLAb) as a possible therapy for sepsis considering its immunomodulatory and systemic antioxidant activity in a murine sepsis model. Thus, the present study aimed to evaluate the activity of FLAb isolated in vitro and to evaluate the effect of treatment with FLAb alone or associated with the antibiotic ertapenem (F-Erta) on coagulation, antioxidant and immunomodulatory parameters in the lethal sepsis model in murine. For this, FLAb was kindly provided by Dr. Herta Dalla- Santa from UNICENTRO. In the present study, the antioxidant capacity of different concentrations of FLAb (1.25 and 5 μg/mL) was evaluated and in a RAW 264.7-Luc macrophage cell line, cytotoxicity, phagocytic capacity, nitric oxide, NF-κB activity and cytokines TNF-α and IL-6 were evaluated.The survival rates were analyzed 7 days in a model of CLP sepsis in swiss albino mice (Mus musculus), and treated with CLP+Salt (0.9%), CLP+FLAb (0.2mg/Kg), CLP+F-erta (0.2mg) /Kg; 30mg/Kg). For evaluation of on coagulation, antioxidant and immunomodulatory parameters, the mice were treated by 6 and/or 24h after CLP. In vitro, FLAb show antioxidant and anti-inflammatory activity in both concentrations. In vivo, all CLP+Salt animals died within a maximum of 48 hours while the FLAb and F-Erta treated groups survived the 7 days. During this period, clinical parameters of these animals were evaluated, the septic animals treated with saline showed piloerection, with little active level of consciousness and most of the time they were stopped in the cage, some of them had ocular secretion. In addition, animals treated with saline showed significant weight loss, reduced water and feed consumption resulting in death. The FLAb and F-Erta groups were active, with normal appearance, with normal breathing and heart rate, in addition to consuming water and food within normal limits. In the inflammatory site, peritoneal cavity, the treatment with FLAb showed an anti-inflammatory effect, decreased reactive oxygen species (ROS) and increased GSH antioxidant activity and protected from cell damage, maintaining neutrophil recruitment and nitric oxide levels (NO), reducing the bacterial load. Regarding coagulation parameters (platelet count, tp and ttpa), treatment with FLAb and F-Erta eliminated the bacterial load and protected the animals from tissue damage. In the liver, 6 hours after CLP the treatment with FLAb and F-ERTA was observed in the biochemical parameters protective effect, in addition, it presented immunomodulatory, antimicrobial and antioxidant activity preventing liver damage. In the parameters evaluated in the heart, the treatment with FLAb and F-ERTA after CLP protected the animals from cardiac damage through immunomodulatory, antimicrobial and antioxidant activity. In this sense, FLAb alone showed promise as a treatment and/or adjunct in sepsis, in addition to preventing organic dysfunction in septic animals.

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