João Rocha | UFSM - Universidade Federal de Santa Maria (original) (raw)

Papers by João Rocha

Research paper thumbnail of Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice

Toxicology, 2007

Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Mo... more Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Moreover, 2,3-dimercapto-1propanesulfonic acid (DMPS), a tissue-permeable metal chelator, was found to increase urinary mercury excretion and decrease mercury content in rat brain after methylmercury (MeHg) exposure. We evaluated the capability of DMPS to reduce MeHg-induced motor impairment and cerebellar toxicity in adult mice. Animals were exposed to MeHg (40 mg/L in drinking water, ad libitum) during 17 days. In the last 3 days of exposure (days 15-17), animals received DMPS injections (150 mg/kg, i.p.; once a day) in order to reverse MeHg-induced neurotoxicity. Twenty-four hours after the last injection (day 18), behavioral tests related to the motor function (open field and rotarod tasks) and biochemical analyses on oxidative stress-related parameters (cerebellar glutathione, protein thiol and malondyaldehyde levels, glutathione peroxidase and glutathione reductase activities) were carried out. Histological analyses for quantifying cellular damage and mercury deposition in the cerebellum were also performed. MeHg exposure induced a significant motor deficit, observed as decreased locomotor activity in the open field and decreased falling latency in the rotarod apparatus. DMPS treatment displayed an ameliorative effect toward such behavioral parameters. Cerebellar glutathione and protein thiol levels were not changed by MeHg or DMPS treatment. Conversely, the levels of cerebellar thiobarbituric acid reactive substances (TBARS), a marker for lipid peroxidation, were increased in MeHg-exposed mice and DMPS administration minimized such phenomenon. Cerebellar glutathione peroxidase activity was decreased in the MeHg-exposed animals, but DMPS treatment did not prevent such event. Histological analyses showed a reduced number of cerebellar Purkinje cells in MeHg-treated mice and this phenomenon was completely reversed by DMPS treatment. A marked mercury deposition in the cerebellar cortex was observed in MeHg-exposed animals (granular layer > Purkinje cells > molecular layer) and DMPS treatment displayed a significant ameliorative effect toward these phenomena. These findings indicate that DMPS displays beneficial effects on reversing MeHg-induced motor deficits and cerebellar damage in mice. Histological analyses indicate that these phenomena are related to its capability of removing mercury from cerebellar cortex.

Research paper thumbnail of Behavioral and dopaminergic damage induced by acute iron exposure in Caenorhabditis elegans

Toxicol. Res., 2015

Iron (Fe) is an important metal to organism homeostasis and exists abundantly in the environment.... more Iron (Fe) is an important metal to organism homeostasis and exists abundantly in the environment. Moderate levels of Fe obtained from food are necessary for normal cell physiology; however, abnormally high levels of Fe may have toxic effects by reducing H 2 O 2 to the highly cytotoxic hydroxyl radical (OH • ) (Fenton catalysis). Fe is a ubiquitous toxicant to the environment and also widely used in food products; however, its effects on the nervous system are not well understood. Herein, we evaluated the toxic effects of Fe using C. elegans and investigated various parameters in order to contribute to the understanding of Fe-induced toxicity and to validate this model. The Fe LD 50 of acute exposure (30 min) was 1.2 mM, and we verified that worms readily take up this metal. Furthermore, sublethal Fe concentrations significantly decreased the worms' lifespan and brood size compared to non-exposed worms. We also observed that animals exposed to Fe had decreased locomotor activity and decreased mechanical sensitivity, suggesting the possible dysfunction of the nervous system. In agreement, we found cholinergic and dopaminergic alterations in the worms. In summary, we suggest that Fe leads to selective neuronal damage, which might be the underlying cause of altered behavior and reproductive defects.

Research paper thumbnail of Organotellurium and organoselenium compounds attenuate Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress

Free Radical Biology and Medicine, 2012

Organochalcogens have been widely studied given their antioxidant activity, which confers neuropr... more Organochalcogens have been widely studied given their antioxidant activity, which confers neuroprotection, antiulcer, and antidiabetic properties. Given the complexity of mammalian models, understanding the cellular and molecular effects of organochalcogens has been hampered. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging, and in vivo live analysis of toxicity. We previously showed that manganese (Mn)-exposed worms exhibit oxidative-stress-induced neurodegeneration and life-span reduction. Here we use Mn-exposed worms as a model for an oxidatively challenged organism to investigate the underlying mechanisms of organochalcogen antioxidant properties. First, we recapitulate in C. elegans the effects of organochalcogens formerly observed in mice, including their antioxidant activity. This is followed by studies on the ability of these compounds to afford protection against Mn-induced toxicity. Diethyl-2-phenyl-2-tellurophenyl vinyl phosphonate (DPTVP) was the most efficacious compound, fully reversing the Mn-induced reduction in survival and life span. Ebselen was also effective, reversing the Mn-induced reduction in survival and life span, but to a lesser extent compared with DPTVP. DPTVP also lowered Mn-induced increases in oxidant levels, indicating that the increased survival associated with exposure to this compound is secondary to a decrease in oxidative stress. Furthermore, DPTVP induced nuclear translocation of the transcriptional factor DAF-16/FOXO, which regulates stress responsiveness and aging in worms. Our findings establish that the organochalcogens DPTVP and ebselen act as antiaging agents in a model of Mn-induced toxicity and aging by regulating DAF-16/ FOXO signaling and attenuating oxidative stress.

Research paper thumbnail of Involvement of striatal lipid peroxidation and inhibition of calcium influx into brain slices in neurobehavioral alterations in a rat model of short-term oral exposure to manganese

NeuroToxicology, 2008

Manganese is an essential element for biological systems, nevertheless occupational exposure to h... more Manganese is an essential element for biological systems, nevertheless occupational exposure to high levels of Mn can lead to neurodegenerative disorder, characterized by excessive Mn accumulation, especially in astrocytes of basal ganglia and symptoms closely resembling idiopathic Parkinson's disease (PD). The purpose of this study was to evaluate behavioral and biochemical alterations in adult rats exposed for 30 days to 10 and 25mg/mL of MnCl(2) in their drinking water. MnCl(2) intoxicated rats showed impaired locomotor activity in comparison to control animals. Furthermore, lipid peroxidation were increased, delta-aminolevulinate dehydratase (delta-ALA-D, an enzyme sensitive to pro-oxidant situations) activity was inhibited and (45)Ca(2+) influx into striatal slices was decreased in rats exposed to 25mg/mL of Mn, indicating that this brain region was markedly affected by short-term Mn exposure. In contrast, Mn exposure was not associated with characteristic extrapyramidal effects and did not modify protein oxidation, suggesting that the striatal damage represents early stages of Mn-induced damage. In addition, treatment with Mn was associated with reduced body weight gain, but there were no discernible alterations in liver and kidney function. In conclusion, Mn caused increased oxidative stress and decreased (45)Ca(2+) influx into the striatum, which are likely linked to impaired locomotor activity, but not with the occurrence of orofacial dyskinesia.

Research paper thumbnail of Hepatoprotective activity of a vinylic telluride against acute exposure to acetaminophen

European Journal of Pharmacology, 2011

Acetaminophen (APAP) hepatotoxicity has been related with several cases of cirrhosis, hepatitis a... more Acetaminophen (APAP) hepatotoxicity has been related with several cases of cirrhosis, hepatitis and suicides attempts. Notably, oxidative stress plays a central role in the hepatic damage caused by APAP and antioxidants have been tested as alternative treatment against APAP toxicity. In the present study, we observed the hepatoprotector activity of the diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP), an organotellurium compound with low toxicity and high antioxidant potential. When the dose of 200 mg/kg of APAP was used, we observed that all used doses of DPTVP were able to restore the -SH levels that were depleted by APAP. Furthermore, the increase in thiobarbituric acid reactive substances levels and in the seric alanine aminotransferase (ALT) activity and the histopathological alterations caused by APAP were restored to control levels by DPTVP (30, 50 and 100 μmol/kg). On the other hand, when the 300 mg/kg dose of APAP was used, DPTVP restored the non-proteic -SH levels and repaired the normal liver morphology of the intoxicated mice only at 50 μmol/kg. Our in vitro results point out to a scavenging activity of DPTVP against several reactive species, action that is attributed to its chemical structure. Taken together, our results demonstrate that the pharmacological action of DPTVP as a hepatoprotector is probably due to its scavenging activity related to its chemical structure.

Research paper thumbnail of A biochemical and toxicological study with diethyl 2-phenyl-2-tellurophenyl vinylphosphonate in a sub-chronic intraperitoneal treatment in mice

Life sciences, Jan 24, 2007

Diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP) is an organotellurium compound with low... more Diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP) is an organotellurium compound with low toxicity after subcutaneous administration in mice. This study evaluated possible in vivo and ex vivo toxicological effects of daily injections of DPTVP for 12 days in mice, using the intraperitoneal administration. This route potentially increases the pharmacokinetics of absorption, distribution, metabolism and toxicity of DPTVP. Treatment with DPTVP (0, 30, 50, 75, 100, 250, 350 or 500 micromol/kg) were not associated with mortality or body weight loss. Nevertheless, the liver and liver-to-body weight ratio increased in groups treated with 350 and 500 micromol/kg of DPTVP. However, plasmatic aspartate and alanine aminotransferase activities (classical markers of hepatotoxicity) were not increased after diethyl-2-phenyl-2-tellurophenyl vinylphosphonate administration. Hepatic, renal and cerebral thiobarbituric acid reactive substances (TBARS), delta-ALA-D activity and Vitamin C levels ...

Research paper thumbnail of Euphorbia tirucalli Aqueous Extract Induces Cytotoxicity, Genotoxicity and Changes in Antioxidant Gene Expression in Human Leukocytes

Toxicol. Res., 2015

Euphorbia tirucalli, popularly known as "avelós", is a toxic plant used as tea in Brazilian folk ... more Euphorbia tirucalli, popularly known as "avelós", is a toxic plant used as tea in Brazilian folk medicine as an antibacterial, antiviral and anticarcinogenic agent. However, there is no scientific report about its potential toxicity in human cells. Therefore, the objective of the present study was to evaluate the in vitro genotoxicity and cytotoxicity of aqueous extracts of E. tirucalli in human leukocytes using a comet assay and trypan blue exclusion assay, respectively. In addition, the effect of E. tirucalli on the osmotic fragility was investigated in human erythrocytes. The expressions of selected antioxidant mRNA genes (SOD2, CAT and GPx4) as well as tumor protein p53 (TP53) were evaluated by qRT-PCR. Exposure of human leukocytes to high concentrations of aqueous extracts of E. tirucalli (100-150 µg mL −1 ) caused a significant increase in DNA damage. Leukocyte viability was decreased in the presence of 50-150 µg mL −1 E. tirucalli extract.

Research paper thumbnail of Sub-acute administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate induces toxicity and oxidative stress in mice: unexpected effects of N-acetylcysteine

SpringerPlus, 2013

The organic tellurium compound (S)-dimethyl 2-(3-(phenyltellanyl) propanamide) succinate (TeAsp) ... more The organic tellurium compound (S)-dimethyl 2-(3-(phenyltellanyl) propanamide) succinate (TeAsp) exhibits thiol-peroxidase activity that could potentially offer protection against oxidative stress. However, data from the literature show that tellurium is a toxic agent to rodents. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered in parallel with TeAsp during 10 days. Mice were separated into four groups receiving daily injections of (A) vehicle (PBS 2.5 ml/kg, i.p. and DMSO 1 ml/kg, s.c.), (B) NAC (100 mg/kg, i.p. and DMSO s.c.), (C) PBS i.p. and TeAsp (92.5 μmol/kg, s.c), or (D) NAC plus TeAsp. TeAsp treatment started on the fourth day. Vehicle or NAC-treated animals showed an increase in body weight whereas TeAsp caused a significant reduction. Contrary to expected, NAC co-administration potentiated the toxic effect of TeAsp, causing a decrease in body weight. Vehicle, NAC or TeAsp did not affect the exploratory and motor activity in the open-field test a...

Research paper thumbnail of Intrahippocampal infusion of ebselen impairs retention of an inhibitory avoidance task in rats

European Journal of Pharmacology, 2002

Ebselen is a seleno-compound used in the treatment of neurological disorders involving the glutam... more Ebselen is a seleno-compound used in the treatment of neurological disorders involving the glutamatergic system. Although ebselen is currently used in clinical trials, the physiological effects of this seleno-compound are poorly known. In this study, we investigated the effects of intrahippocampal infusion of ebselen (0.1-3 nmol) in rats submitted to an inhibitory avoidance task. Ebselen (1-3 nmol) infused after the training session impaired retention of inhibitory avoidance, tested 90 min or 24 h after the training session. Moreover, ebselen also impaired the retention when infused 30 min prior to training or 10 min prior to test sessions. In summary, ebselen impaired memory consolidation, acquisition and retrieval. This amnesic effect of ebselen could be related to oxidant activity at N-methyl-D-aspartate (NMDA) receptors. Our results indicate that more studies must be performed to investigate the mechanisms of this amnesic effect and whether ebselen has a cognition-impairing effect when administered chronically.

Research paper thumbnail of Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Brain Research, 2007

The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and e... more The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F 2 -isoprostanes (F 2 -IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 μ M MeHg for 1 or 6 hours. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (ΔΨm), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that ΔΨ m is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 μ M. MeHg pretreatment (1, 5 and 10 μ M) for 30 min also inhibited the net uptake of glutamine ( 3 H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 μ M) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 μ M) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to cellular dysfunction and cell death.

Research paper thumbnail of Organotellurium and organoselenium compounds attenuate Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress

Free Radical Biology and Medicine, 2012

Organochalcogens have been widely studied given their antioxidant activity, which confers neuropr... more Organochalcogens have been widely studied given their antioxidant activity, which confers neuroprotection, antiulcer, and antidiabetic properties. Given the complexity of mammalian models, understanding the cellular and molecular effects of organochalcogens has been hampered. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging, and in vivo live analysis of toxicity. We previously showed that manganese (Mn)-exposed worms exhibit oxidative-stress-induced neurodegeneration and life-span reduction. Here we use Mn-exposed worms as a model for an oxidatively challenged organism to investigate the underlying mechanisms of organochalcogen antioxidant properties. First, we recapitulate in C. elegans the effects of organochalcogens formerly observed in mice, including their antioxidant activity. This is followed by studies on the ability of these compounds to afford protection against Mn-induced toxicity. Diethyl-2-phenyl-2-tellurophenyl vinyl phosphonate (DPTVP) was the most efficacious compound, fully reversing the Mn-induced reduction in survival and life span. Ebselen was also effective, reversing the Mn-induced reduction in survival and life span, but to a lesser extent compared with DPTVP. DPTVP also lowered Mn-induced increases in oxidant levels, indicating that the increased survival associated with exposure to this compound is secondary to a decrease in oxidative stress. Furthermore, DPTVP induced nuclear translocation of the transcriptional factor DAF-16/FOXO, which regulates stress responsiveness and aging in worms. Our findings establish that the organochalcogens DPTVP and ebselen act as antiaging agents in a model of Mn-induced toxicity and aging by regulating DAF-16/ FOXO signaling and attenuating oxidative stress.

Research paper thumbnail of Trichilia  catigua  (Catuaba)  bark  extract  exerts  neuroprotection  against oxidative  stress  induced  by  different  neurotoxic  agents  in  rat hippocampal  slices

Plant extracts have been reported to prevent various diseases associated with oxidative stress. T... more Plant extracts have been reported to prevent various diseases associated with oxidative stress. Trichilia catigua, a traditional Brazilian herbal medicine, exhibits beneficial behavioral effects in experimental models of neuropathologies and protects rat hippocampal slices from oxidative stress induced by ischemia-reperfusion injury. In the present study, we investigated the protective effects of T. catigua against hydrogen peroxide (H 2 O 2 )-, sodium nitroprusside (SNP)-, and 3-nitropropionic acid (3-NPA)induced neurotoxicity in rat hippocampal slices. Exposure of rat hippocampal slices to H 2 O 2 , SNP or 3-NPA (150-500 M) for 1 h caused significant decrease in cellular viability (evaluated by MTT reduction), increased reactive oxygen/nitrogen species in the incubation medium as well as lipid peroxidation in slices homogenates. Pre-treatment of slices with T. catigua (10-100 g/mL) for 30 min significantly attenuated the toxic effects of pro-oxidants. Phytochemical profile of T. catigua determined by high performance liquid chromatography (HPLC-DAD) indicated the presence of phenolic and flavonoid compounds. These antioxidant compounds can be involved in T. catigua neuroprotective effects. Consequently, T. catigua antioxidative properties may be useful in the prevention of cellular damage triggered by oxidative stress found in acute and chronic neuropathological situations.

Research paper thumbnail of Acute Brain Damage Induced by Acetaminophen in Mice: Effect of Diphenyl Diselenide on Oxidative Stress and Mitochondrial Dysfunction

Neurotoxicity Research, 2012

Organoselenium compounds exhibit antioxidant activity, as well as a variety of biological activit... more Organoselenium compounds exhibit antioxidant activity, as well as a variety of biological activities, with potential pharmacological and therapeutic applications. The aim of this study was to investigate the effect of diphenyl diselenide (PhSe)(2) in reversing oxidative brain damage and mitochondrial dysfunction caused by administration of acetaminophen (APAP) in mice. Mice received a toxic dose of APAP, followed by a dose of (PhSe)(2) 1 h later. Four hours after the administration of APAP, plasma was withdrawn from the mice and used for biochemical assays of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatotoxicity. Brain homogenate was examined to determine oxidative stress. Isolated brain mitochondria were examined to quantify mitochondrial transmembrane's electrical potential and mitochondrial swelling and to estimate reactive oxygen species (ROS) production. APAP administration caused an increase in plasma ALT and AST activities. APAP administration also caused a significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and dichlorofluorescein oxidation in brain homogenate. Similarly, mitochondrial swelling and ROS production increased after APAP administration. APAP treatment also caused a decrease in Na(+), K(+)- ATPase activity and in mitochondrial membrane potential. These alterations observed in the brain of APAP-treated mice were restored by (PhSe)(2). Glutathione levels were decreased by APAP, but (PhSe)(2) did not reverse this change. Treatment with (PhSe)(2) after APAP administration can reverse the neurotoxicity caused by a single toxic dose of APAP. The neuroprotective effect of (PhSe)(2) is likely associated with its antioxidant properties.

Research paper thumbnail of The antioxidant properties of different phthalocyanines

Toxicology in Vitro, 2012

Oxidative stress is involved in the etiology of several chronic diseases, including cardiovascula... more Oxidative stress is involved in the etiology of several chronic diseases, including cardiovascular disease, diabetes, cancer, and neurodegenerative disorders. From this perspective, we have evaluated the possible antioxidant capacities of five different phthalocyanines (PCs), consisting of four metallophthalocyanines (MPCs) and one simple phthalocyanine (PC) in order to explore, for the first time, the potential antioxidant activities of these compounds. Our results show that all PCs tested in this study have significant antioxidant activity in lipid peroxidation assay, providing protection from sodium nitroprusside -induced oxidative damage to supernatant from the homogenized liver, brain, e rim of mice. Compared to the non-induced control, the PCs were generally more efficient in reducing malondialdehyde levels in all assays on lipid peroxidation induced by sodium nitroprusside; the order of approximate decrease in efficiency was as follows: manganese-PC (better efficiency)>copper-PC>iron-PC>zinc-PC>PC (worst efficiency). Furthermore, the copper-PC and manganese-PC compounds exerted a significant protective effect in deoxyribose degradation assays, when employing Fe(2+), Fe(2+)+H(2)O(2), and H(2)O(2) solutions. In conclusion, all PCs tested here were shown to be promising compounds for future in vivo investigations, because of their potential antioxidant activities in vitro.

Research paper thumbnail of Cooperation of Non-Effective Concentration of Glutamatergic System Modulators and Antioxidant Against Oxidative Stress Induced by Quinolinic Acid

Neurochemical Research, 2012

Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been... more Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been hypothesized as key mechanisms contributing to quinolinic acid (QA)-induced toxicity. Thus, here we investigate if the use of diphenyl diselenide (PhSe) 2 , guanosine (GUO) and MK-801, alone or in combination, could protect rat brain slices from QA-induced toxicity. QA (1 mM) increased ROS formation, thiobarbituric acid reactive substances (TBARS) and decreased cell viability after 2 h of exposure. (PhSe) 2 (1 lM) protected against this ROS formation in the cortex and the striatum and also prevented decreases in cell viability induced by QA. (PhSe) 2 (5 lM) prevented ROS formation in the hippocampus. GUO (10 and 100 lM) blocked the increase in ROS formation caused by QA and MK-801 (20 and 100 lM) abolished the pro-oxidant effect of QA. When the noneffective concentrations were used in combination produced a decrease in ROS formation, mainly (PhSe) 2 ? GUO and (PhSe) 2 ? GUO ? MK-801. These results demonstrate that this combination could be effective to avoid toxic effects caused by high concentrations of QA. Furthermore, the data obtained in the ROS formation and cellular viability assays suggest different pathways in amelioration of QA toxicity present in the neurodegenerative process.

Research paper thumbnail of Neuroprotective Effect of Diphenyl Diselenide in a Experimental Stroke Model: Maintenance of Redox System in Mitochondria of Brain Regions

Neurotoxicity Research, 2014

Acute stroke is a major risk for morbidity and mortality in aging population. Mitochondrion has b... more Acute stroke is a major risk for morbidity and mortality in aging population. Mitochondrion has been the focus of a wide stroke-related research. This study investigated if treatment or pre-treatment with diphenyl diselenide (PhSe)2 can prevent mitochondrial damage in cerebral structures of rats induced by an ischemia and reperfusion (I/R) model. Adult male Wistar rats were assigned into five experimental groups: sham operation, ischemia/reperfusion, pre-treated + I/R, treated + I/R, and Sham + (PhSe)2. Neurological score showed the damage caused by I/R, which was partially prevented by (PhSe)2. Moreover, mitochondria of hippocampus and cortex were impaired by I/R through an increase of reactive oxygen species production, mitochondrial membrane potential (ΔΨm) and electrons flow alteration, activity of complex I deregulation as well as mitochondrial swelling. However, the ischemic damage did not induce an increase in pro-apoptotic proteins expression, but demonstrated an enhanced expression of Hsp70. The mitochondrial redox state was also altered (GSH/GSSG ratio, MnSOD, and GPx activities). Our results revealed that all treatments with (PhSe)2 significantly reduced the mitochondrial damage induced by I/R. These findings suggest that neuroprotective properties of (PhSe)2 may be attributed to the maintenance of mitochondrial redox balance.

Research paper thumbnail of Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosophila melanogaster

Free radical biology & medicine, 2014

Corrigendum to "Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosoph... more Corrigendum to "Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosophila melanogaster" [Free Radic. Biol. Med. 71 (2014) 99-108]

Research paper thumbnail of The combination of organoselenium compounds and guanosine prevents glutamate-induced oxidative stress in different regions of rat brains

This study was designed to investigate the protective effects of the combination of guanosine and... more This study was designed to investigate the protective effects of the combination of guanosine and 2 organoselenium compounds (ebselen and diphenyl diselenide) against glutamateinduced oxidative stress in different regions of rat brains. Glutamate caused an increase in reactive oxygen species (ROS) generation and a decrease in [ 3 H]-glutamate uptake in striatal, cortical, and hippocampal slices. Guanosine, ebselen, and diphenyl diselenide prevented glutamate-induced ROS production in striatal, cortical and hippocampal slices. The combination of guanosine with organoselenium compounds was more effective against glutamateinduced ROS production than the individual compounds alone. Guanosine prevented [ 3 H]glutamate uptake inhibition in striatal, cortical, and hippocampal slices. Thus, protection against the harmful effects of glutamate is possibly due to the combination of the antioxidant properties of organoselenium compounds and the stimulatory effect of guanosine on glutamate uptake. In conclusion, the combination of antioxidants and glutamatergic system modulators could be considered a potential therapy against the prooxidant effects of glutamate.

Research paper thumbnail of African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca(2+)-induced mitochondrial swelling

Asian Pacific journal of tropical biomedicine, 2013

To evaluate the antioxidant and radical scavenging activities of Solanum anguivi fruit (SAG) and ... more To evaluate the antioxidant and radical scavenging activities of Solanum anguivi fruit (SAG) and its possible effect on mitochondrial permeability transition pore as well as mitochondrial membrane potential (ΔΨm) isolated from rat liver. Antioxidant activity of SAG was assayed by using 2,2-diphenyl-1-picrylhydrazyl (DPPH), reducing power, iron chelation and ability to inhibit lipid peroxidation in both liver and brain homogenate of rats. Also, the effect of SAG on mitochondrial membrane potential and mitochondrial swelling were determined. Identification and quantification of bioactive polyphenolics was done by HPLC-DAD. SAG exhibited potent and concentration dependent free radical-scavenging activity (IC50/DPPH=275.03±7.8 μg/mL). Reductive and iron chelation abilities also increase with increase in SAG concentration. SAG also inhibited peroxidation of cerebral and hepatic lipids subjected to iron oxidative assault. SAG protected against Ca(2+) (110 μmol/L)-induced mitochondrial swe...

Research paper thumbnail of Antioxidant effect of organic purple grape juice on exhaustive exercise

Applied Physiology, Nutrition, and Metabolism, 2013

This study aimed to assess the potential protective effect of organic purple grape juice (PGJ) on... more This study aimed to assess the potential protective effect of organic purple grape juice (PGJ) on oxidative stress produced by an exhaustive exercise bout in rats. To test this hypothesis, rats were acutely treated with organic PGJ (Vitis labrusca) and subsequently submitted to an exhaustive exercise bout. Parameters of oxidative stress, such as thiobarbituric acid reactive species (TBARS) levels, 2',7',-dichlorofluorescein diacetate (DCFH-DA) oxidation, and nonprotein sulfhydryl levels (NP-SH) in the brain, skeletal muscle, and blood, were evaluated. Enzyme activity of Na(+),K(+)-ATPase, Ca(2+)-ATPase, and δ-aminolevulinate dehydratase (δ-ALA-D) in the brain, skeletal muscle, and blood were also assayed. Statistical analysis showed that the exhaustive exercise bout increased TBARS levels and DCFH-DA oxidation, and decreased NP-SH levels in rat tissue. Ca(2+)-ATPase activity was increased in groups exposed to both exercise and PGJ treatment. The results indicate that organic PGJ intake was able to protect against the oxidative damage caused by an exhaustive exercise bout in different rat tissues.

Research paper thumbnail of Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice

Toxicology, 2007

Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Mo... more Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Moreover, 2,3-dimercapto-1propanesulfonic acid (DMPS), a tissue-permeable metal chelator, was found to increase urinary mercury excretion and decrease mercury content in rat brain after methylmercury (MeHg) exposure. We evaluated the capability of DMPS to reduce MeHg-induced motor impairment and cerebellar toxicity in adult mice. Animals were exposed to MeHg (40 mg/L in drinking water, ad libitum) during 17 days. In the last 3 days of exposure (days 15-17), animals received DMPS injections (150 mg/kg, i.p.; once a day) in order to reverse MeHg-induced neurotoxicity. Twenty-four hours after the last injection (day 18), behavioral tests related to the motor function (open field and rotarod tasks) and biochemical analyses on oxidative stress-related parameters (cerebellar glutathione, protein thiol and malondyaldehyde levels, glutathione peroxidase and glutathione reductase activities) were carried out. Histological analyses for quantifying cellular damage and mercury deposition in the cerebellum were also performed. MeHg exposure induced a significant motor deficit, observed as decreased locomotor activity in the open field and decreased falling latency in the rotarod apparatus. DMPS treatment displayed an ameliorative effect toward such behavioral parameters. Cerebellar glutathione and protein thiol levels were not changed by MeHg or DMPS treatment. Conversely, the levels of cerebellar thiobarbituric acid reactive substances (TBARS), a marker for lipid peroxidation, were increased in MeHg-exposed mice and DMPS administration minimized such phenomenon. Cerebellar glutathione peroxidase activity was decreased in the MeHg-exposed animals, but DMPS treatment did not prevent such event. Histological analyses showed a reduced number of cerebellar Purkinje cells in MeHg-treated mice and this phenomenon was completely reversed by DMPS treatment. A marked mercury deposition in the cerebellar cortex was observed in MeHg-exposed animals (granular layer > Purkinje cells > molecular layer) and DMPS treatment displayed a significant ameliorative effect toward these phenomena. These findings indicate that DMPS displays beneficial effects on reversing MeHg-induced motor deficits and cerebellar damage in mice. Histological analyses indicate that these phenomena are related to its capability of removing mercury from cerebellar cortex.

Research paper thumbnail of Behavioral and dopaminergic damage induced by acute iron exposure in Caenorhabditis elegans

Toxicol. Res., 2015

Iron (Fe) is an important metal to organism homeostasis and exists abundantly in the environment.... more Iron (Fe) is an important metal to organism homeostasis and exists abundantly in the environment. Moderate levels of Fe obtained from food are necessary for normal cell physiology; however, abnormally high levels of Fe may have toxic effects by reducing H 2 O 2 to the highly cytotoxic hydroxyl radical (OH • ) (Fenton catalysis). Fe is a ubiquitous toxicant to the environment and also widely used in food products; however, its effects on the nervous system are not well understood. Herein, we evaluated the toxic effects of Fe using C. elegans and investigated various parameters in order to contribute to the understanding of Fe-induced toxicity and to validate this model. The Fe LD 50 of acute exposure (30 min) was 1.2 mM, and we verified that worms readily take up this metal. Furthermore, sublethal Fe concentrations significantly decreased the worms' lifespan and brood size compared to non-exposed worms. We also observed that animals exposed to Fe had decreased locomotor activity and decreased mechanical sensitivity, suggesting the possible dysfunction of the nervous system. In agreement, we found cholinergic and dopaminergic alterations in the worms. In summary, we suggest that Fe leads to selective neuronal damage, which might be the underlying cause of altered behavior and reproductive defects.

Research paper thumbnail of Organotellurium and organoselenium compounds attenuate Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress

Free Radical Biology and Medicine, 2012

Organochalcogens have been widely studied given their antioxidant activity, which confers neuropr... more Organochalcogens have been widely studied given their antioxidant activity, which confers neuroprotection, antiulcer, and antidiabetic properties. Given the complexity of mammalian models, understanding the cellular and molecular effects of organochalcogens has been hampered. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging, and in vivo live analysis of toxicity. We previously showed that manganese (Mn)-exposed worms exhibit oxidative-stress-induced neurodegeneration and life-span reduction. Here we use Mn-exposed worms as a model for an oxidatively challenged organism to investigate the underlying mechanisms of organochalcogen antioxidant properties. First, we recapitulate in C. elegans the effects of organochalcogens formerly observed in mice, including their antioxidant activity. This is followed by studies on the ability of these compounds to afford protection against Mn-induced toxicity. Diethyl-2-phenyl-2-tellurophenyl vinyl phosphonate (DPTVP) was the most efficacious compound, fully reversing the Mn-induced reduction in survival and life span. Ebselen was also effective, reversing the Mn-induced reduction in survival and life span, but to a lesser extent compared with DPTVP. DPTVP also lowered Mn-induced increases in oxidant levels, indicating that the increased survival associated with exposure to this compound is secondary to a decrease in oxidative stress. Furthermore, DPTVP induced nuclear translocation of the transcriptional factor DAF-16/FOXO, which regulates stress responsiveness and aging in worms. Our findings establish that the organochalcogens DPTVP and ebselen act as antiaging agents in a model of Mn-induced toxicity and aging by regulating DAF-16/ FOXO signaling and attenuating oxidative stress.

Research paper thumbnail of Involvement of striatal lipid peroxidation and inhibition of calcium influx into brain slices in neurobehavioral alterations in a rat model of short-term oral exposure to manganese

NeuroToxicology, 2008

Manganese is an essential element for biological systems, nevertheless occupational exposure to h... more Manganese is an essential element for biological systems, nevertheless occupational exposure to high levels of Mn can lead to neurodegenerative disorder, characterized by excessive Mn accumulation, especially in astrocytes of basal ganglia and symptoms closely resembling idiopathic Parkinson's disease (PD). The purpose of this study was to evaluate behavioral and biochemical alterations in adult rats exposed for 30 days to 10 and 25mg/mL of MnCl(2) in their drinking water. MnCl(2) intoxicated rats showed impaired locomotor activity in comparison to control animals. Furthermore, lipid peroxidation were increased, delta-aminolevulinate dehydratase (delta-ALA-D, an enzyme sensitive to pro-oxidant situations) activity was inhibited and (45)Ca(2+) influx into striatal slices was decreased in rats exposed to 25mg/mL of Mn, indicating that this brain region was markedly affected by short-term Mn exposure. In contrast, Mn exposure was not associated with characteristic extrapyramidal effects and did not modify protein oxidation, suggesting that the striatal damage represents early stages of Mn-induced damage. In addition, treatment with Mn was associated with reduced body weight gain, but there were no discernible alterations in liver and kidney function. In conclusion, Mn caused increased oxidative stress and decreased (45)Ca(2+) influx into the striatum, which are likely linked to impaired locomotor activity, but not with the occurrence of orofacial dyskinesia.

Research paper thumbnail of Hepatoprotective activity of a vinylic telluride against acute exposure to acetaminophen

European Journal of Pharmacology, 2011

Acetaminophen (APAP) hepatotoxicity has been related with several cases of cirrhosis, hepatitis a... more Acetaminophen (APAP) hepatotoxicity has been related with several cases of cirrhosis, hepatitis and suicides attempts. Notably, oxidative stress plays a central role in the hepatic damage caused by APAP and antioxidants have been tested as alternative treatment against APAP toxicity. In the present study, we observed the hepatoprotector activity of the diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP), an organotellurium compound with low toxicity and high antioxidant potential. When the dose of 200 mg/kg of APAP was used, we observed that all used doses of DPTVP were able to restore the -SH levels that were depleted by APAP. Furthermore, the increase in thiobarbituric acid reactive substances levels and in the seric alanine aminotransferase (ALT) activity and the histopathological alterations caused by APAP were restored to control levels by DPTVP (30, 50 and 100 μmol/kg). On the other hand, when the 300 mg/kg dose of APAP was used, DPTVP restored the non-proteic -SH levels and repaired the normal liver morphology of the intoxicated mice only at 50 μmol/kg. Our in vitro results point out to a scavenging activity of DPTVP against several reactive species, action that is attributed to its chemical structure. Taken together, our results demonstrate that the pharmacological action of DPTVP as a hepatoprotector is probably due to its scavenging activity related to its chemical structure.

Research paper thumbnail of A biochemical and toxicological study with diethyl 2-phenyl-2-tellurophenyl vinylphosphonate in a sub-chronic intraperitoneal treatment in mice

Life sciences, Jan 24, 2007

Diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP) is an organotellurium compound with low... more Diethyl-2-phenyl-2-tellurophenyl vinylphosphonate (DPTVP) is an organotellurium compound with low toxicity after subcutaneous administration in mice. This study evaluated possible in vivo and ex vivo toxicological effects of daily injections of DPTVP for 12 days in mice, using the intraperitoneal administration. This route potentially increases the pharmacokinetics of absorption, distribution, metabolism and toxicity of DPTVP. Treatment with DPTVP (0, 30, 50, 75, 100, 250, 350 or 500 micromol/kg) were not associated with mortality or body weight loss. Nevertheless, the liver and liver-to-body weight ratio increased in groups treated with 350 and 500 micromol/kg of DPTVP. However, plasmatic aspartate and alanine aminotransferase activities (classical markers of hepatotoxicity) were not increased after diethyl-2-phenyl-2-tellurophenyl vinylphosphonate administration. Hepatic, renal and cerebral thiobarbituric acid reactive substances (TBARS), delta-ALA-D activity and Vitamin C levels ...

Research paper thumbnail of Euphorbia tirucalli Aqueous Extract Induces Cytotoxicity, Genotoxicity and Changes in Antioxidant Gene Expression in Human Leukocytes

Toxicol. Res., 2015

Euphorbia tirucalli, popularly known as "avelós", is a toxic plant used as tea in Brazilian folk ... more Euphorbia tirucalli, popularly known as "avelós", is a toxic plant used as tea in Brazilian folk medicine as an antibacterial, antiviral and anticarcinogenic agent. However, there is no scientific report about its potential toxicity in human cells. Therefore, the objective of the present study was to evaluate the in vitro genotoxicity and cytotoxicity of aqueous extracts of E. tirucalli in human leukocytes using a comet assay and trypan blue exclusion assay, respectively. In addition, the effect of E. tirucalli on the osmotic fragility was investigated in human erythrocytes. The expressions of selected antioxidant mRNA genes (SOD2, CAT and GPx4) as well as tumor protein p53 (TP53) were evaluated by qRT-PCR. Exposure of human leukocytes to high concentrations of aqueous extracts of E. tirucalli (100-150 µg mL −1 ) caused a significant increase in DNA damage. Leukocyte viability was decreased in the presence of 50-150 µg mL −1 E. tirucalli extract.

Research paper thumbnail of Sub-acute administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate induces toxicity and oxidative stress in mice: unexpected effects of N-acetylcysteine

SpringerPlus, 2013

The organic tellurium compound (S)-dimethyl 2-(3-(phenyltellanyl) propanamide) succinate (TeAsp) ... more The organic tellurium compound (S)-dimethyl 2-(3-(phenyltellanyl) propanamide) succinate (TeAsp) exhibits thiol-peroxidase activity that could potentially offer protection against oxidative stress. However, data from the literature show that tellurium is a toxic agent to rodents. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered in parallel with TeAsp during 10 days. Mice were separated into four groups receiving daily injections of (A) vehicle (PBS 2.5 ml/kg, i.p. and DMSO 1 ml/kg, s.c.), (B) NAC (100 mg/kg, i.p. and DMSO s.c.), (C) PBS i.p. and TeAsp (92.5 μmol/kg, s.c), or (D) NAC plus TeAsp. TeAsp treatment started on the fourth day. Vehicle or NAC-treated animals showed an increase in body weight whereas TeAsp caused a significant reduction. Contrary to expected, NAC co-administration potentiated the toxic effect of TeAsp, causing a decrease in body weight. Vehicle, NAC or TeAsp did not affect the exploratory and motor activity in the open-field test a...

Research paper thumbnail of Intrahippocampal infusion of ebselen impairs retention of an inhibitory avoidance task in rats

European Journal of Pharmacology, 2002

Ebselen is a seleno-compound used in the treatment of neurological disorders involving the glutam... more Ebselen is a seleno-compound used in the treatment of neurological disorders involving the glutamatergic system. Although ebselen is currently used in clinical trials, the physiological effects of this seleno-compound are poorly known. In this study, we investigated the effects of intrahippocampal infusion of ebselen (0.1-3 nmol) in rats submitted to an inhibitory avoidance task. Ebselen (1-3 nmol) infused after the training session impaired retention of inhibitory avoidance, tested 90 min or 24 h after the training session. Moreover, ebselen also impaired the retention when infused 30 min prior to training or 10 min prior to test sessions. In summary, ebselen impaired memory consolidation, acquisition and retrieval. This amnesic effect of ebselen could be related to oxidant activity at N-methyl-D-aspartate (NMDA) receptors. Our results indicate that more studies must be performed to investigate the mechanisms of this amnesic effect and whether ebselen has a cognition-impairing effect when administered chronically.

Research paper thumbnail of Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

Brain Research, 2007

The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and e... more The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F 2 -isoprostanes (F 2 -IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 μ M MeHg for 1 or 6 hours. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (ΔΨm), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that ΔΨ m is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 μ M. MeHg pretreatment (1, 5 and 10 μ M) for 30 min also inhibited the net uptake of glutamine ( 3 H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 μ M) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 μ M) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to cellular dysfunction and cell death.

Research paper thumbnail of Organotellurium and organoselenium compounds attenuate Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress

Free Radical Biology and Medicine, 2012

Organochalcogens have been widely studied given their antioxidant activity, which confers neuropr... more Organochalcogens have been widely studied given their antioxidant activity, which confers neuroprotection, antiulcer, and antidiabetic properties. Given the complexity of mammalian models, understanding the cellular and molecular effects of organochalcogens has been hampered. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging, and in vivo live analysis of toxicity. We previously showed that manganese (Mn)-exposed worms exhibit oxidative-stress-induced neurodegeneration and life-span reduction. Here we use Mn-exposed worms as a model for an oxidatively challenged organism to investigate the underlying mechanisms of organochalcogen antioxidant properties. First, we recapitulate in C. elegans the effects of organochalcogens formerly observed in mice, including their antioxidant activity. This is followed by studies on the ability of these compounds to afford protection against Mn-induced toxicity. Diethyl-2-phenyl-2-tellurophenyl vinyl phosphonate (DPTVP) was the most efficacious compound, fully reversing the Mn-induced reduction in survival and life span. Ebselen was also effective, reversing the Mn-induced reduction in survival and life span, but to a lesser extent compared with DPTVP. DPTVP also lowered Mn-induced increases in oxidant levels, indicating that the increased survival associated with exposure to this compound is secondary to a decrease in oxidative stress. Furthermore, DPTVP induced nuclear translocation of the transcriptional factor DAF-16/FOXO, which regulates stress responsiveness and aging in worms. Our findings establish that the organochalcogens DPTVP and ebselen act as antiaging agents in a model of Mn-induced toxicity and aging by regulating DAF-16/ FOXO signaling and attenuating oxidative stress.

Research paper thumbnail of Trichilia  catigua  (Catuaba)  bark  extract  exerts  neuroprotection  against oxidative  stress  induced  by  different  neurotoxic  agents  in  rat hippocampal  slices

Plant extracts have been reported to prevent various diseases associated with oxidative stress. T... more Plant extracts have been reported to prevent various diseases associated with oxidative stress. Trichilia catigua, a traditional Brazilian herbal medicine, exhibits beneficial behavioral effects in experimental models of neuropathologies and protects rat hippocampal slices from oxidative stress induced by ischemia-reperfusion injury. In the present study, we investigated the protective effects of T. catigua against hydrogen peroxide (H 2 O 2 )-, sodium nitroprusside (SNP)-, and 3-nitropropionic acid (3-NPA)induced neurotoxicity in rat hippocampal slices. Exposure of rat hippocampal slices to H 2 O 2 , SNP or 3-NPA (150-500 M) for 1 h caused significant decrease in cellular viability (evaluated by MTT reduction), increased reactive oxygen/nitrogen species in the incubation medium as well as lipid peroxidation in slices homogenates. Pre-treatment of slices with T. catigua (10-100 g/mL) for 30 min significantly attenuated the toxic effects of pro-oxidants. Phytochemical profile of T. catigua determined by high performance liquid chromatography (HPLC-DAD) indicated the presence of phenolic and flavonoid compounds. These antioxidant compounds can be involved in T. catigua neuroprotective effects. Consequently, T. catigua antioxidative properties may be useful in the prevention of cellular damage triggered by oxidative stress found in acute and chronic neuropathological situations.

Research paper thumbnail of Acute Brain Damage Induced by Acetaminophen in Mice: Effect of Diphenyl Diselenide on Oxidative Stress and Mitochondrial Dysfunction

Neurotoxicity Research, 2012

Organoselenium compounds exhibit antioxidant activity, as well as a variety of biological activit... more Organoselenium compounds exhibit antioxidant activity, as well as a variety of biological activities, with potential pharmacological and therapeutic applications. The aim of this study was to investigate the effect of diphenyl diselenide (PhSe)(2) in reversing oxidative brain damage and mitochondrial dysfunction caused by administration of acetaminophen (APAP) in mice. Mice received a toxic dose of APAP, followed by a dose of (PhSe)(2) 1 h later. Four hours after the administration of APAP, plasma was withdrawn from the mice and used for biochemical assays of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatotoxicity. Brain homogenate was examined to determine oxidative stress. Isolated brain mitochondria were examined to quantify mitochondrial transmembrane's electrical potential and mitochondrial swelling and to estimate reactive oxygen species (ROS) production. APAP administration caused an increase in plasma ALT and AST activities. APAP administration also caused a significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and dichlorofluorescein oxidation in brain homogenate. Similarly, mitochondrial swelling and ROS production increased after APAP administration. APAP treatment also caused a decrease in Na(+), K(+)- ATPase activity and in mitochondrial membrane potential. These alterations observed in the brain of APAP-treated mice were restored by (PhSe)(2). Glutathione levels were decreased by APAP, but (PhSe)(2) did not reverse this change. Treatment with (PhSe)(2) after APAP administration can reverse the neurotoxicity caused by a single toxic dose of APAP. The neuroprotective effect of (PhSe)(2) is likely associated with its antioxidant properties.

Research paper thumbnail of The antioxidant properties of different phthalocyanines

Toxicology in Vitro, 2012

Oxidative stress is involved in the etiology of several chronic diseases, including cardiovascula... more Oxidative stress is involved in the etiology of several chronic diseases, including cardiovascular disease, diabetes, cancer, and neurodegenerative disorders. From this perspective, we have evaluated the possible antioxidant capacities of five different phthalocyanines (PCs), consisting of four metallophthalocyanines (MPCs) and one simple phthalocyanine (PC) in order to explore, for the first time, the potential antioxidant activities of these compounds. Our results show that all PCs tested in this study have significant antioxidant activity in lipid peroxidation assay, providing protection from sodium nitroprusside -induced oxidative damage to supernatant from the homogenized liver, brain, e rim of mice. Compared to the non-induced control, the PCs were generally more efficient in reducing malondialdehyde levels in all assays on lipid peroxidation induced by sodium nitroprusside; the order of approximate decrease in efficiency was as follows: manganese-PC (better efficiency)>copper-PC>iron-PC>zinc-PC>PC (worst efficiency). Furthermore, the copper-PC and manganese-PC compounds exerted a significant protective effect in deoxyribose degradation assays, when employing Fe(2+), Fe(2+)+H(2)O(2), and H(2)O(2) solutions. In conclusion, all PCs tested here were shown to be promising compounds for future in vivo investigations, because of their potential antioxidant activities in vitro.

Research paper thumbnail of Cooperation of Non-Effective Concentration of Glutamatergic System Modulators and Antioxidant Against Oxidative Stress Induced by Quinolinic Acid

Neurochemical Research, 2012

Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been... more Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been hypothesized as key mechanisms contributing to quinolinic acid (QA)-induced toxicity. Thus, here we investigate if the use of diphenyl diselenide (PhSe) 2 , guanosine (GUO) and MK-801, alone or in combination, could protect rat brain slices from QA-induced toxicity. QA (1 mM) increased ROS formation, thiobarbituric acid reactive substances (TBARS) and decreased cell viability after 2 h of exposure. (PhSe) 2 (1 lM) protected against this ROS formation in the cortex and the striatum and also prevented decreases in cell viability induced by QA. (PhSe) 2 (5 lM) prevented ROS formation in the hippocampus. GUO (10 and 100 lM) blocked the increase in ROS formation caused by QA and MK-801 (20 and 100 lM) abolished the pro-oxidant effect of QA. When the noneffective concentrations were used in combination produced a decrease in ROS formation, mainly (PhSe) 2 ? GUO and (PhSe) 2 ? GUO ? MK-801. These results demonstrate that this combination could be effective to avoid toxic effects caused by high concentrations of QA. Furthermore, the data obtained in the ROS formation and cellular viability assays suggest different pathways in amelioration of QA toxicity present in the neurodegenerative process.

Research paper thumbnail of Neuroprotective Effect of Diphenyl Diselenide in a Experimental Stroke Model: Maintenance of Redox System in Mitochondria of Brain Regions

Neurotoxicity Research, 2014

Acute stroke is a major risk for morbidity and mortality in aging population. Mitochondrion has b... more Acute stroke is a major risk for morbidity and mortality in aging population. Mitochondrion has been the focus of a wide stroke-related research. This study investigated if treatment or pre-treatment with diphenyl diselenide (PhSe)2 can prevent mitochondrial damage in cerebral structures of rats induced by an ischemia and reperfusion (I/R) model. Adult male Wistar rats were assigned into five experimental groups: sham operation, ischemia/reperfusion, pre-treated + I/R, treated + I/R, and Sham + (PhSe)2. Neurological score showed the damage caused by I/R, which was partially prevented by (PhSe)2. Moreover, mitochondria of hippocampus and cortex were impaired by I/R through an increase of reactive oxygen species production, mitochondrial membrane potential (ΔΨm) and electrons flow alteration, activity of complex I deregulation as well as mitochondrial swelling. However, the ischemic damage did not induce an increase in pro-apoptotic proteins expression, but demonstrated an enhanced expression of Hsp70. The mitochondrial redox state was also altered (GSH/GSSG ratio, MnSOD, and GPx activities). Our results revealed that all treatments with (PhSe)2 significantly reduced the mitochondrial damage induced by I/R. These findings suggest that neuroprotective properties of (PhSe)2 may be attributed to the maintenance of mitochondrial redox balance.

Research paper thumbnail of Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosophila melanogaster

Free radical biology & medicine, 2014

Corrigendum to "Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosoph... more Corrigendum to "Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosophila melanogaster" [Free Radic. Biol. Med. 71 (2014) 99-108]

Research paper thumbnail of The combination of organoselenium compounds and guanosine prevents glutamate-induced oxidative stress in different regions of rat brains

This study was designed to investigate the protective effects of the combination of guanosine and... more This study was designed to investigate the protective effects of the combination of guanosine and 2 organoselenium compounds (ebselen and diphenyl diselenide) against glutamateinduced oxidative stress in different regions of rat brains. Glutamate caused an increase in reactive oxygen species (ROS) generation and a decrease in [ 3 H]-glutamate uptake in striatal, cortical, and hippocampal slices. Guanosine, ebselen, and diphenyl diselenide prevented glutamate-induced ROS production in striatal, cortical and hippocampal slices. The combination of guanosine with organoselenium compounds was more effective against glutamateinduced ROS production than the individual compounds alone. Guanosine prevented [ 3 H]glutamate uptake inhibition in striatal, cortical, and hippocampal slices. Thus, protection against the harmful effects of glutamate is possibly due to the combination of the antioxidant properties of organoselenium compounds and the stimulatory effect of guanosine on glutamate uptake. In conclusion, the combination of antioxidants and glutamatergic system modulators could be considered a potential therapy against the prooxidant effects of glutamate.

Research paper thumbnail of African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca(2+)-induced mitochondrial swelling

Asian Pacific journal of tropical biomedicine, 2013

To evaluate the antioxidant and radical scavenging activities of Solanum anguivi fruit (SAG) and ... more To evaluate the antioxidant and radical scavenging activities of Solanum anguivi fruit (SAG) and its possible effect on mitochondrial permeability transition pore as well as mitochondrial membrane potential (ΔΨm) isolated from rat liver. Antioxidant activity of SAG was assayed by using 2,2-diphenyl-1-picrylhydrazyl (DPPH), reducing power, iron chelation and ability to inhibit lipid peroxidation in both liver and brain homogenate of rats. Also, the effect of SAG on mitochondrial membrane potential and mitochondrial swelling were determined. Identification and quantification of bioactive polyphenolics was done by HPLC-DAD. SAG exhibited potent and concentration dependent free radical-scavenging activity (IC50/DPPH=275.03±7.8 μg/mL). Reductive and iron chelation abilities also increase with increase in SAG concentration. SAG also inhibited peroxidation of cerebral and hepatic lipids subjected to iron oxidative assault. SAG protected against Ca(2+) (110 μmol/L)-induced mitochondrial swe...

Research paper thumbnail of Antioxidant effect of organic purple grape juice on exhaustive exercise

Applied Physiology, Nutrition, and Metabolism, 2013

This study aimed to assess the potential protective effect of organic purple grape juice (PGJ) on... more This study aimed to assess the potential protective effect of organic purple grape juice (PGJ) on oxidative stress produced by an exhaustive exercise bout in rats. To test this hypothesis, rats were acutely treated with organic PGJ (Vitis labrusca) and subsequently submitted to an exhaustive exercise bout. Parameters of oxidative stress, such as thiobarbituric acid reactive species (TBARS) levels, 2',7',-dichlorofluorescein diacetate (DCFH-DA) oxidation, and nonprotein sulfhydryl levels (NP-SH) in the brain, skeletal muscle, and blood, were evaluated. Enzyme activity of Na(+),K(+)-ATPase, Ca(2+)-ATPase, and δ-aminolevulinate dehydratase (δ-ALA-D) in the brain, skeletal muscle, and blood were also assayed. Statistical analysis showed that the exhaustive exercise bout increased TBARS levels and DCFH-DA oxidation, and decreased NP-SH levels in rat tissue. Ca(2+)-ATPase activity was increased in groups exposed to both exercise and PGJ treatment. The results indicate that organic PGJ intake was able to protect against the oxidative damage caused by an exhaustive exercise bout in different rat tissues.