Danubia Santos | Faculdade Hélio Rocha (original) (raw)

Papers by Danubia Santos

Pharmacology, biochemistry, and behavior, 2014

Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and n... more Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and neuroprotective effects. In a previous study, our group demonstrated that this endogenous nucleoside displays antidepressant-like properties in a predictive animal model. Based on the role of oxidative stress in modulating depressive disorders as well as on the association between the neuroprotective and antioxidant properties of guanosine, here we investigated if its antidepressant-like effect is accompanied by a modulation of hippocampal oxidant/antioxidant parameters. Adult Swiss mice were submitted to an acute restraint stress protocol, which is known to cause behavioral changes that are associated with neuronal oxidative damage. Animals submitted to ARS exhibited an increased immobility time in the forced swimming test (FST) and the administration of guanosine (5mg/kg, p.o.) or fluoxetine (10mg/kg, p.o., positive control) before the exposure to stressor prevented this alteration. Mor...

Toxicology in Vitro, 2009

This study investigated the hemolytic and genotoxic effect of different organoselenium and organo... more This study investigated the hemolytic and genotoxic effect of different organoselenium and organotellurium compounds in human blood cells, as simple tests for screening the toxicity of organochalcogenides. For osmotic fragility (OF) test, samples of total blood were incubated with the organochalcogens at 4, 8, 50, 75 and 100 lM or vehicle (DMSO) for 90 min at 37°C. The EC 50 values for hemolysis were significantly increased in erythrocytes exposed to diphenyl selenide

Genotoxicity of organoselenium compounds in human leukocytes in vitro

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2009

DNA damage and cell viability of human leukocytes cells were examined as simple tests for screeni... more DNA damage and cell viability of human leukocytes cells were examined as simple tests for screening the potential toxicity of organoselenium compounds. Leukocytes were incubated with different organoselenium compounds at 4, 10, 40 and 100 microM or vehicle (DMSO) for 3h at 37 degrees C before of in vitro assays. Cell viability was determined by Trypan blue exclusion. DNA damage was assessed using the alkaline comet assay with silver staining. The exposure of leukocytes to (S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate, (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate, (S)-2-amino-1-diselenide-3-methylpropanyl, (S)-2-amino-1-diselenide-3-phenylpropanyl, 3',3-ditrifluoromethyl diphenyl diselenide, 4',4-dimethoxy diphenyl diselenide, 4',4-dichloro diphenyl diselenide and 2',2,4',4,6',6-hexamethyl diphenyl diselenide, in the range of 10-100muM, induced a significant increase in Damage Index (DI). The genotoxic effect of all compounds was associated with high frequencies of cells with damage level 4 and all compounds caused a decrease in cell viability. Our results suggest that the selenium compounds tested were genotoxic and cytotoxic to human leukocytes cells in vitro and that the organoselenium amino acid derivatives ((S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate, (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate, (S)-2-amino-1-diselenide-3-methylpropanyl and (S)-2-amino-1-diselenide-3-phenylpropanyl) were more genotoxic than aromatic derivatives (3',3-ditrifluoromethyl diphenyl diselenide, 4',4-dimethoxy diphenyl diselenide, 4',4-dichloro diphenyl diselenide and 2',2,4',4,6',6-hexamethyl diphenyl diselenide). These effects may be linked to the pro-oxidant activity exhibited by selenium compounds when used in relatively high concentrations.

Succinobucol versus probucol: Higher efficiency of succinobucol in mitigating 3-NP-induced brain mitochondrial dysfunction and oxidative stress in vitro

Mitochondrion, 2013

This study evaluated and compared the potential protective effects of probucol and succinobucol, ... more This study evaluated and compared the potential protective effects of probucol and succinobucol, two lipid-lowering compounds with anti-inflammatory and antioxidant properties, on oxidative stress and mitochondrial dysfunction induced by 3-nitropropionic acid (3-NP, a succinate dehydrogenase (SDH) inhibitor largely used as model of Huntington's disease) in rat brain mitochondria-enriched synaptosomes. 3-NP caused significant inhibition of mitochondrial complex II activity, induced mitochondrial dysfunction and oxidative stress. Probucol and succinobucol prevented oxidative stress, but only succinobucol was able to prevent the mitochondrial dysfunction induced by 3-NP. Succinobucol, which did not recover complex II inhibition, was able to protect against 3-NP-induced decreased of MTT reduction, indicating that SDH is not the only enzyme responsible for MTT reduction. The present findings suggest that succinobucol might be a novel strategy to slow or halt oxidative events in neurodegenerative conditions.

Protective Effects of Ascorbic Acid on Behavior and Oxidative Status of Restraint-Stressed Mice

Journal of Molecular Neuroscience, 2013

Studies have demonstrated an association between stressful conditions and the onset of clinical d... more Studies have demonstrated an association between stressful conditions and the onset of clinical depression. Considering the antidepressant-like properties of ascorbic acid in both experimental and clinical approaches, we evaluated the beneficial effect of this vitamin on restraint stress-induced behavioral and neurochemical alterations. Acute restraint stress caused a depressive-like behavior in the forced swimming test, accompanied by increased lipid peroxidation (cerebral cortex and hippocampus); increased superoxide dismutase (cerebral cortex and hippocampus), glutathione reductase (cerebral cortex), and glutathione peroxidase (cerebral cortex and hippocampus) activities; and elevated expression of Bcl-2 (hippocampus). Oral administration of ascorbic acid (1 mg/kg) or fluoxetine (10 mg/kg) 1 h before restraint stress prevented the stress-induced increase on immobility time in the forced swimming test. Moreover, this vitamin reduced lipid peroxidation to control levels and restored the activity of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Ascorbic acid had no effect on the increased level of Bcl-2 induced by stress. Glutathione levels, glycogen synthase kinase-3β phosphorylation, and Bax expression were not altered by stress or ascorbic acid administration. Besides reinforcing the antioxidant potential of ascorbic acid, our results support the notion that oxidative stress plays a role in the pathogenesis and treatment of stress-induced depression.

Experimental Neurology, 2013

Experimental and epidemiological studies have shown the close relationship between stressful even... more Experimental and epidemiological studies have shown the close relationship between stressful events, depression, and cognitive impairment. Folic acid has been reported to present antidepressant-like effects in both experimental and clinical approaches. However, the mechanisms mediating such effects are not understood. In the present study, we evaluated if folic acid administration to mice could protect against restraint stress-induced depressive-like behavior and cognitive deficit. Considering that oxidative stress has been pointed as a key event involved with depressive disorders, cerebrocortical and hippocampal oxidative stress-related parameters, such as the activities of antioxidant enzymes (mainly those related to the hydroperoxide-detoxifying system) and markers of lipid peroxidation, were also investigated. Restraint stress induced depressive-like behavior in the forced swimming test and memory impairment in the object recognition test, without altering locomotor activity of mice. Folic acid (50 mg/kg, p.o.) was able to prevent the stress-induced increase on immobility time in the forced swimming test, but did not prevent memory impairment. Moreover, restraint stress increased thiobarbituric acid reactive substance levels, and catalase, glutathione peroxidase and glutathione reductase activities in the cerebral cortex and hippocampus, and superoxide dismutase activity in the hippocampus. Folic acid treatment restored the activity of the antioxidant enzymes and reduced lipid peroxidation in the hippocampus. Glutathione, a non-enzymatic antioxidant, was not altered by stress and/or folic acid administration. Together, the results of the present work reinforce the notion that folic acid displays a specific antidepressant profile in the restraint stress paradigm that may be at least partly due to its antioxidant role.

Basic & Clinical Pharmacology & Toxicology, 2010

Malathion is an organophosphate (OP) pesticide whose toxicity depends on its bioactivation to mal... more Malathion is an organophosphate (OP) pesticide whose toxicity depends on its bioactivation to malaoxon. Human malathion poisoning has been treated with oximes (mainly pralidoxime) in an attempt to reactivate OP-inhibited acetylcholinesterase (AChE). However, pralidoxime has shown unsatisfactory therapeutic effects in malathion poisoning and its routine use has been questioned. In this study, we evaluated the in vitro potency of standards and newly developed oximes in reactivating malaoxon-inhibited AChE derived from mouse brain supernatants. Malaoxon displayed a concentration-dependent inhibitory effect on mouse brain AChE (IC 50 = 2.36 lM), and pralidoxime caused a modest reactivating effect (30% of reactivation at 600 lM). Obidoxime and trimedoxime, as well as K047 and K075, displayed higher reactivating effects (from 55% to 70% of reactivation at 600 lM) when compared with pralidoxime. The results show that obidoxime, trimedoxime, K074 and K075 present higher reactivating effects on malaoxon-inhibited AChE under in vitro conditions when compared with pralidoxime. Taking into account the unsatisfactory effects of pralidoxime as antidotal treatment in malathion poisonings, the present results suggest that obidoxime, trimedoxime, K074 and K075 might be interesting therapeutic strategies to reactivate malaoxon-inhibited AChE in malathion poisonings.

Evaluation of the biological effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative of aspartic acid

Archives of Toxicology, 2011

(S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative, sh... more (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative, showed remarkable glutathione peroxidase (GPx)-like activity, attesting to its antioxidant potential. However, the stability and toxicity of this compound has not yet been investigated. The present study was designed to investigate the pharmacological/toxicological properties of this compound in vitro and in vivo. In vitro, this telluroamino acid derivative significantly blocked spontaneous and Fe(II)-induced TBARS formation in rat brain homogenates, demonstrating high antioxidant activity. In addition, it exhibited GPx-like and thiol oxidase activities. However, when subcutaneously administered to mice, (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate indicated genotoxic and mutagenic effect in adult male mice. Considering the differential effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate in vitro and in vivo, additional experiments are needed to elucidate the mechanism(s) by which this compound displays its antioxidant/toxicological effects.

Agmatine has been recently emerged as a novel candidate to assist the conventional pharmacotherap... more Agmatine has been recently emerged as a novel candidate to assist the conventional pharmacotherapy of depression. The acute restraint stress (ARS) is an unavoidable stress situation that may cause depressive-like behavior in rodents. In this study, we investigated the potential antidepressant-like effect of agmatine (10 mg/kg, administered acutely by oral route) in the forced swimming test (FST) in non-stressed mice, as well as its ability to abolish the depressive-like behavior and hippocampal antioxidant imbalance induced by ARS. Agmatine reduced the immobility time in the mouse FST (1-100 mg/kg) in non-stressed mice. ARS caused an increase in the immobility time in the FST, indicative of a depressive-like behavior, as well as hippocampal lipid peroxidation, and an increase in the activity of hippocampal superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, reduced catalase (CAT) activity and increased SOD/CAT ratio, an index of pro-oxidative conditions. Agmatine was effective to abolish the depressive-like behavior induced by ARS and to prevent the ARS-induced lipid peroxidation and changes in SOD, GR and CAT activities and in SOD/CAT activity ratio. Hippocampal levels of reduced glutathione (GSH) were not altered by any experimental condition. In conclusion, the present study shows that agmatine was able to abrogate the ARS-induced depressive-like behavior and the associated redox hippocampal imbalance observed in stressed restraint mice, suggesting that its antidepressant-like effect may be dependent on its ability to maintain the pro-/anti-oxidative homeostasis in the hippocampus.

Pharmacology, biochemistry, and behavior, 2014

Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and n... more Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and neuroprotective effects. In a previous study, our group demonstrated that this endogenous nucleoside displays antidepressant-like properties in a predictive animal model. Based on the role of oxidative stress in modulating depressive disorders as well as on the association between the neuroprotective and antioxidant properties of guanosine, here we investigated if its antidepressant-like effect is accompanied by a modulation of hippocampal oxidant/antioxidant parameters. Adult Swiss mice were submitted to an acute restraint stress protocol, which is known to cause behavioral changes that are associated with neuronal oxidative damage. Animals submitted to ARS exhibited an increased immobility time in the forced swimming test (FST) and the administration of guanosine (5mg/kg, p.o.) or fluoxetine (10mg/kg, p.o., positive control) before the exposure to stressor prevented this alteration. Mor...

Toxicology in Vitro, 2009

This study investigated the hemolytic and genotoxic effect of different organoselenium and organo... more This study investigated the hemolytic and genotoxic effect of different organoselenium and organotellurium compounds in human blood cells, as simple tests for screening the toxicity of organochalcogenides. For osmotic fragility (OF) test, samples of total blood were incubated with the organochalcogens at 4, 8, 50, 75 and 100 lM or vehicle (DMSO) for 90 min at 37°C. The EC 50 values for hemolysis were significantly increased in erythrocytes exposed to diphenyl selenide

Genotoxicity of organoselenium compounds in human leukocytes in vitro

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2009

DNA damage and cell viability of human leukocytes cells were examined as simple tests for screeni... more DNA damage and cell viability of human leukocytes cells were examined as simple tests for screening the potential toxicity of organoselenium compounds. Leukocytes were incubated with different organoselenium compounds at 4, 10, 40 and 100 microM or vehicle (DMSO) for 3h at 37 degrees C before of in vitro assays. Cell viability was determined by Trypan blue exclusion. DNA damage was assessed using the alkaline comet assay with silver staining. The exposure of leukocytes to (S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate, (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate, (S)-2-amino-1-diselenide-3-methylpropanyl, (S)-2-amino-1-diselenide-3-phenylpropanyl, 3',3-ditrifluoromethyl diphenyl diselenide, 4',4-dimethoxy diphenyl diselenide, 4',4-dichloro diphenyl diselenide and 2',2,4',4,6',6-hexamethyl diphenyl diselenide, in the range of 10-100muM, induced a significant increase in Damage Index (DI). The genotoxic effect of all compounds was associated with high frequencies of cells with damage level 4 and all compounds caused a decrease in cell viability. Our results suggest that the selenium compounds tested were genotoxic and cytotoxic to human leukocytes cells in vitro and that the organoselenium amino acid derivatives ((S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate, (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate, (S)-2-amino-1-diselenide-3-methylpropanyl and (S)-2-amino-1-diselenide-3-phenylpropanyl) were more genotoxic than aromatic derivatives (3',3-ditrifluoromethyl diphenyl diselenide, 4',4-dimethoxy diphenyl diselenide, 4',4-dichloro diphenyl diselenide and 2',2,4',4,6',6-hexamethyl diphenyl diselenide). These effects may be linked to the pro-oxidant activity exhibited by selenium compounds when used in relatively high concentrations.

Succinobucol versus probucol: Higher efficiency of succinobucol in mitigating 3-NP-induced brain mitochondrial dysfunction and oxidative stress in vitro

Mitochondrion, 2013

This study evaluated and compared the potential protective effects of probucol and succinobucol, ... more This study evaluated and compared the potential protective effects of probucol and succinobucol, two lipid-lowering compounds with anti-inflammatory and antioxidant properties, on oxidative stress and mitochondrial dysfunction induced by 3-nitropropionic acid (3-NP, a succinate dehydrogenase (SDH) inhibitor largely used as model of Huntington's disease) in rat brain mitochondria-enriched synaptosomes. 3-NP caused significant inhibition of mitochondrial complex II activity, induced mitochondrial dysfunction and oxidative stress. Probucol and succinobucol prevented oxidative stress, but only succinobucol was able to prevent the mitochondrial dysfunction induced by 3-NP. Succinobucol, which did not recover complex II inhibition, was able to protect against 3-NP-induced decreased of MTT reduction, indicating that SDH is not the only enzyme responsible for MTT reduction. The present findings suggest that succinobucol might be a novel strategy to slow or halt oxidative events in neurodegenerative conditions.

Protective Effects of Ascorbic Acid on Behavior and Oxidative Status of Restraint-Stressed Mice

Journal of Molecular Neuroscience, 2013

Studies have demonstrated an association between stressful conditions and the onset of clinical d... more Studies have demonstrated an association between stressful conditions and the onset of clinical depression. Considering the antidepressant-like properties of ascorbic acid in both experimental and clinical approaches, we evaluated the beneficial effect of this vitamin on restraint stress-induced behavioral and neurochemical alterations. Acute restraint stress caused a depressive-like behavior in the forced swimming test, accompanied by increased lipid peroxidation (cerebral cortex and hippocampus); increased superoxide dismutase (cerebral cortex and hippocampus), glutathione reductase (cerebral cortex), and glutathione peroxidase (cerebral cortex and hippocampus) activities; and elevated expression of Bcl-2 (hippocampus). Oral administration of ascorbic acid (1 mg/kg) or fluoxetine (10 mg/kg) 1 h before restraint stress prevented the stress-induced increase on immobility time in the forced swimming test. Moreover, this vitamin reduced lipid peroxidation to control levels and restored the activity of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Ascorbic acid had no effect on the increased level of Bcl-2 induced by stress. Glutathione levels, glycogen synthase kinase-3β phosphorylation, and Bax expression were not altered by stress or ascorbic acid administration. Besides reinforcing the antioxidant potential of ascorbic acid, our results support the notion that oxidative stress plays a role in the pathogenesis and treatment of stress-induced depression.

Experimental Neurology, 2013

Experimental and epidemiological studies have shown the close relationship between stressful even... more Experimental and epidemiological studies have shown the close relationship between stressful events, depression, and cognitive impairment. Folic acid has been reported to present antidepressant-like effects in both experimental and clinical approaches. However, the mechanisms mediating such effects are not understood. In the present study, we evaluated if folic acid administration to mice could protect against restraint stress-induced depressive-like behavior and cognitive deficit. Considering that oxidative stress has been pointed as a key event involved with depressive disorders, cerebrocortical and hippocampal oxidative stress-related parameters, such as the activities of antioxidant enzymes (mainly those related to the hydroperoxide-detoxifying system) and markers of lipid peroxidation, were also investigated. Restraint stress induced depressive-like behavior in the forced swimming test and memory impairment in the object recognition test, without altering locomotor activity of mice. Folic acid (50 mg/kg, p.o.) was able to prevent the stress-induced increase on immobility time in the forced swimming test, but did not prevent memory impairment. Moreover, restraint stress increased thiobarbituric acid reactive substance levels, and catalase, glutathione peroxidase and glutathione reductase activities in the cerebral cortex and hippocampus, and superoxide dismutase activity in the hippocampus. Folic acid treatment restored the activity of the antioxidant enzymes and reduced lipid peroxidation in the hippocampus. Glutathione, a non-enzymatic antioxidant, was not altered by stress and/or folic acid administration. Together, the results of the present work reinforce the notion that folic acid displays a specific antidepressant profile in the restraint stress paradigm that may be at least partly due to its antioxidant role.

Basic & Clinical Pharmacology & Toxicology, 2010

Malathion is an organophosphate (OP) pesticide whose toxicity depends on its bioactivation to mal... more Malathion is an organophosphate (OP) pesticide whose toxicity depends on its bioactivation to malaoxon. Human malathion poisoning has been treated with oximes (mainly pralidoxime) in an attempt to reactivate OP-inhibited acetylcholinesterase (AChE). However, pralidoxime has shown unsatisfactory therapeutic effects in malathion poisoning and its routine use has been questioned. In this study, we evaluated the in vitro potency of standards and newly developed oximes in reactivating malaoxon-inhibited AChE derived from mouse brain supernatants. Malaoxon displayed a concentration-dependent inhibitory effect on mouse brain AChE (IC 50 = 2.36 lM), and pralidoxime caused a modest reactivating effect (30% of reactivation at 600 lM). Obidoxime and trimedoxime, as well as K047 and K075, displayed higher reactivating effects (from 55% to 70% of reactivation at 600 lM) when compared with pralidoxime. The results show that obidoxime, trimedoxime, K074 and K075 present higher reactivating effects on malaoxon-inhibited AChE under in vitro conditions when compared with pralidoxime. Taking into account the unsatisfactory effects of pralidoxime as antidotal treatment in malathion poisonings, the present results suggest that obidoxime, trimedoxime, K074 and K075 might be interesting therapeutic strategies to reactivate malaoxon-inhibited AChE in malathion poisonings.

Evaluation of the biological effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative of aspartic acid

Archives of Toxicology, 2011

(S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative, sh... more (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative, showed remarkable glutathione peroxidase (GPx)-like activity, attesting to its antioxidant potential. However, the stability and toxicity of this compound has not yet been investigated. The present study was designed to investigate the pharmacological/toxicological properties of this compound in vitro and in vivo. In vitro, this telluroamino acid derivative significantly blocked spontaneous and Fe(II)-induced TBARS formation in rat brain homogenates, demonstrating high antioxidant activity. In addition, it exhibited GPx-like and thiol oxidase activities. However, when subcutaneously administered to mice, (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate indicated genotoxic and mutagenic effect in adult male mice. Considering the differential effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate in vitro and in vivo, additional experiments are needed to elucidate the mechanism(s) by which this compound displays its antioxidant/toxicological effects.

Agmatine has been recently emerged as a novel candidate to assist the conventional pharmacotherap... more Agmatine has been recently emerged as a novel candidate to assist the conventional pharmacotherapy of depression. The acute restraint stress (ARS) is an unavoidable stress situation that may cause depressive-like behavior in rodents. In this study, we investigated the potential antidepressant-like effect of agmatine (10 mg/kg, administered acutely by oral route) in the forced swimming test (FST) in non-stressed mice, as well as its ability to abolish the depressive-like behavior and hippocampal antioxidant imbalance induced by ARS. Agmatine reduced the immobility time in the mouse FST (1-100 mg/kg) in non-stressed mice. ARS caused an increase in the immobility time in the FST, indicative of a depressive-like behavior, as well as hippocampal lipid peroxidation, and an increase in the activity of hippocampal superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, reduced catalase (CAT) activity and increased SOD/CAT ratio, an index of pro-oxidative conditions. Agmatine was effective to abolish the depressive-like behavior induced by ARS and to prevent the ARS-induced lipid peroxidation and changes in SOD, GR and CAT activities and in SOD/CAT activity ratio. Hippocampal levels of reduced glutathione (GSH) were not altered by any experimental condition. In conclusion, the present study shows that agmatine was able to abrogate the ARS-induced depressive-like behavior and the associated redox hippocampal imbalance observed in stressed restraint mice, suggesting that its antidepressant-like effect may be dependent on its ability to maintain the pro-/anti-oxidative homeostasis in the hippocampus.