Behavioural Brain Research - Antioxidant administration prevents memory impairment in an animal model of maple syrup urine disease
Giselli Scaini, Brena Teodorak, Isabela Jeremias, Morais MO, Francielle Mina, Dominguini D, Bruna Pescador, Clarissa Comim, Patricia Schuck, Gustavo Ferreira, João Quevedo e Emilio Streck
Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder resulting from deficiency of branched-chain α-keto acid dehydrogenase complex leading to branched chain amino acids (BCAA) leucine, isoleucine, and valine accumulation as well as their corresponding transaminated branched-chain α-keto acids. MSUD patients present neurological dysfunction and cognitive impairment. Here, we investigated whether acute and chronic administration of a BCAA pool causes impairment of acquisition and retention of avoidance memory in young rats. We have used two administration protocols. Acute administration consisted of three subcutaneous administrations of the BCAA pool (15.8 μL/g body weight at 1-h intervals) containing 190 mmol/L leucine, 59 mmol/L isoleucine, and 69 mmol/L valine or saline solution (0.85% NaCl; control group) in 30 days old Wistar rats. Chronic administration consisted of two subcutaneous administrations of BCAA pool for 21 days in 7 days old Wistar rats. N-acetylcysteine (NAC; 20 mg/kg) and deferoxamine (DFX; 20 mg/kg) co administration influence on behavioral parameters after chronic BCAA administration was also investigated. BCAA administration induced long-term memory impairment in the inhibitory avoidance and CMIA (continuous multiple-trials step-down inhibitory avoidance) tasks whereas with no alterations in CMIA retention memory. Inhibitory avoidance alterations were prevented by NAC and DFX. BCAA administration did not impair the neuropsychiatric state, muscle tone and strength, and autonomous function evaluated with the SHIRPA (SmithKline/Harwell/ImperialCollege/RoyalHospital/Phenotype Assessment) protocol. Taken together, our results indicate that alterations of motor activity or emotionality probably did not contribute to memory impairment after BCAA administration and NAC and DFX effects suggest that cognition impairment after BCAA administration may be caused by oxidative brain damage.
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Molecular Medicine - Gastrin-releasing peptide receptor antagonism induces protection from lethal sepsis: involvement of toll-like receptor 4 signaling
Fabricia Petronilho, Francieli Vuolo, Galant LS, Larissa Constantino, Cristiane Daminai Tomasi, Giombelli VR, Claudio De Souza, Da Silva S, Barbeiro DF, Soriano FG, Emiilio Streck, Cristiane Ritter, Zanotto-Filho A, Mateus Augusto Pasquali, Gelain DP, Rybarczyk-Filho JL, José Claudio Moreira, Block NL, Rafael Roesler, Gilberto Schwartsmann, Schally AV, Felipe Dal-Pizzol
In sepsis, TLR-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide receptor (GRPR) antagonist, RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to LPS or TNF-α and, RC-3095 (10ng/ml). Male Wistar rats were subjected to CLP and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 hours we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h and plasma was collected before and after RC-3095 administration and, in a different set of patients with SIRS or sepsis, GRP plasma levels were determined. RC-3095 inhibited TLR-4, ERK1/2, JNK, and Akt, decreased activation of AP-1, NF-kB and IL-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-α. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung, reduced systemic cytokines, and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP, which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving, at least, inhibition of TLR-4 signaling.
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Experimental Diabetes Research - Increased oxidative stress and imbalance in antioxidant enzymes in the brains of alloxan-induced diabetic rats
Luciane Ceretta, Gislaine Réus, Helena Mendes Abelaira, Karine Ribeiro, Giovanni Zappellini, Francine F. Felisbino, Amanda Steckert, Felipe Dal-Pizzol e João Quevedo
Diabetes Mellitus (DM) is associated with pathological changes in the central nervous system (SNC) as well as alterations in oxidative stress. Thus, the main objective of this study was to evaluate the effects of the animal model of diabetes induced by alloxan on memory and oxidative stress. Diabetes was induced in Wistar rats by using a single injection of alloxan (150 mg/kg), and fifteen days after induction, the rats memory was evaluated through the use of the object recognition task. The oxidative stress parameters and the activity of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT) were measured in the rat brain. The results showed that diabetic rats did not have alterations in their recognition memory. However, the results did show that diabetic rats had increases in the levels of superoxide in the prefrontal cortex, and in thiobarbituric acid reactive species (TBARS) production in the prefrontal cortex and in the amygdala in submitochondrial particles. Also, there was an increase in protein oxidation in the hippocampus and striatum, and in TBARS oxidation in the striatum and amygdala. The SOD activity was decreased in diabetic rats in the striatum and amygdala. However, the CAT activity was increased in the hippocampus taken from diabetic rats. In conclusion, our findings illustrate that the animal model of diabetes induced by alloxan did not cause alterations in the animals' recognition memory, but it produced oxidants and an imbalance between SOD and CAT activities, which could contribute to the pathophysiology of diabetes.
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Journal of Psychiatric Research - The administration of olanzapine and fluoxetine has synergistic effects on intracellular survival pathways in the rat brain
Gislaine Réus, Helena Mendes Abelaira, Fabiano Agostinho, Karine Ribeiro, Marcelo Vitto, Thais F. Luciano, Claudio de Souza e João Quevedo
Recently, several studies have emerged suggesting a role of the intracellular survival pathways in the treatment of mood disorders. In addition, the beneficial effects of using a combination of antipsychotics and antidepressants have been shown. With this in mind, we evaluated the effects of the acute administration of fluoxetine (FLX), olanzapine (OLZ) and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), cAMP response element-binding (CREB), Protein Kinase B (PKB, Akt), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated death promoter (BAD) in the rat brain. Adult Wistar rats received an acute injection of OLZ (3 or 6 mg/kg) and/or FLX (12.5 or 25 mg/kg), and were evaluated for Akt, BDNF, CREB, Bcl-2 and BAD protein levels in the prefrontal cortex, hippocampus and striatum. Our results showed that treatment with FLX and OLZ alone or in combination increased the Akt, CREB, BDNF, Bcl-2 and BAD levels in the prefrontal cortex, hippocampus and striatum. However, the combination of FLX and OLZ at high doses was associated with a greater increase in the levels of Akt in the prefrontal cortex, and did not have an effect on the levels of BAD in any of the brain areas that we evaluated. Finally, these findings further support the hypothesis that treatment with FLX and OLZ alone or in combination exert neuroprotective effects, and that intracellular survival pathways could be involved in the therapeutic effects of combining antipsychotic and antidepressant drugs in mood disorders.
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Environmental Science and Pollution Research International - Kinetic analysis of constructed systems for the recovery of contaminated areas by acid mine drainage
Erlon Mendes, Erilson Barros, Jairo Zocche, Nadja Zim Alexandre, Sergio Galatto, Marcos Back, Jader Lima Pereira, Jonas Frasseto, Elidio Angioletto.
Flowing of the acid mine drainage may contaminate the adjacent water bodies causing substantial changes in the aquatic ecosystem. This aspect is the most relevant problem in the southern of Santa Catarina once the contaminated areas are inserted in the watershed of the Araranguá, Urussanga, and Tubarão rivers, increasing the need for recovery studies. These areas are between Criciúma, Içara, Urussanga, Siderópolis, Lauro Müller, Orleans, and Alfredo Wagner towns where a conservation unit exist called the Environmental Preservation Area of Baleia Franca. Aiming to compare the kinetics of the ash derived from burning coal and to neutralize acid mine drainage, different neutralizer, limestone, fly, and bottom ash, was mounted on a pilot scale experiment. DISCUSSION: The transport parameters showed the same order of infiltration and dispersion: fly ash < bottom ash < limestone. The order of measured alkalinity was: limestone < fly ash < bottom ash, with pH values of 9.34, 12.07, and 12.25, respectively. The limestone kinetics of acidic drainage neutralization was first order with reaction rate constant k = 0.0963 min(-1), bottom ash was 3/4 with k = 0.0723 mol(1/4) L(-1/4) min(-1), and the fly ash had higher order kinetics, 4/3, with reaction rate constant k = 27.122 L(1/3) mol(-1/3) min(-1). However, by mathematical modeling, it was found that due to a combination of transport and kinetics, only limestone treatment reached a pH above 6 within 5 years, corresponding to the ideal as planned.
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