The expanding impact of methylglyoxal on behavior-related disorders.

Methylglyoxal (MGO) is a reactive dicarbonyl compound formed as a byproduct of glycolysis. MGO is a major cell-permeant precursor of advanced glycation end products (AGEs), since it readily reacts with basic phospholipids and nucleotides, as well as amino acid residues of proteins, such as arginine, cysteine, and lysine. The AGEs production induced by MGO are widely associated with several pathologies, including neurodegenerative diseases. However, the impact of MGO metabolism and AGEs formation in the central nervous system (particularly in neurons, astrocytes and oligodendrocytes) on behavior and psychiatric diseases is not fully understood. Here, we briefly present background information on the biological activity of MGO in the central nervous system. It was gathered the available information on the role of MGO metabolism at the physiological processes, as well as at the neurobiology of psychiatry diseases, especially pain-related experiences, anxiety, depression, and cognition impairment-associated diseases. To clarify the role of MGO on behavior and associated diseases, we reviewed primarily the main findings at preclinical studies focusing on genetic and pharmacological approaches. Since monoamine neurotransmitter systems are implicated as pivotal targets on the pathophysiology and treatment of psychiatry and cognitive-related diseases, we also reviewed how MGO affects these neurotransmission systems and the implications of this phenomenon for nociception and pain; learning and cognition; and mood. In summary, this review highlights the pivotal role of glyoxalase 1 (Glo1) and MGO levels in modulating behavioral phenotypes, as well as related cellular and molecular signaling. Conclusively, this review signals dopamine as a new neurochemical MGO target, as well as highlights how MGO metabolism can modulate the pathophysiology and treatment of pain, psychiatric and cognitive-related diseases.

Vitamin E for the management of major depressive disorder: possible role of the anti-inflammatory and antioxidant systems.

OBJECTIVES: Vitamin E has various functions in humans, including antioxidant, anti-inflammatory, anti-cancer, and anti-atherogenic actions, as well as direct effects on enzymatic activities and modulation of gene transcription. In addition to these functions, vitamin E is also important for the central nervous system, and its role in the prevention and/or treatment of some neurological diseases has been suggested. In particular, the role of vitamin E in the modulation of major depressive disorder (MDD) is an issue that has emerged in recent studies. Many factors have been implicated in the pathophysiology of this disorder, including inflammation, oxidative, and nitrosative stress. METHODS: This narrative review discusses the involvement of inflammation, oxidative, and nitrosative stress in the pathophysiology of MDD and presents clinical and preclinical studies that correlate vitamin E with this psychiatric disorder. RESULTS: We gathered evidence from clinical studies that demonstrated the relationship between low vitamin E status and MDD symptoms. Vitamin E has been reported to exert a beneficial influence on the oxidative and inflammatory status of individuals, factors that may account for the attenuation of depressive symptoms. Preclinical studies have reinforced the antidepressant-like response of vitamin E, and the mechanisms underlying its effect seem to be related to the modulation of oxidative stress and neuroinflammation. CONCLUSION: We suggest that vitamin E has potential to be used as an adjuvant for the management of MDD, but more studies are clearly needed to ascertain the efficacy of vitamin E for alleviating depressive symptoms.

Aerobic exercise ameliorates survival, clinical score, lung inflammation, DNA and protein damage in septic mice.

BACKGROUND AND OBJECTIVE: Sepsis is a potentially deadly organic dysfunction, and one of the main causes of mortality in intensive care units (ICU). Aerobic exercise (AE) is a preventive intervention in the establishment of inflammatory conditions, such as chronic lung diseases, but its effects on sepsis remain unclear. Therefore, this study aimed to evaluate the effects of AE on health condition, mortality, inflammation, and oxidative damage in an experimental model of pneumosepsis induced by Klebsiella pneumoniae (K.p). METHODS: Animals were randomly allocated to Control; Exercise (EXE); Pneumosepsis (PS) or Exercise + Pneumosepsis (EPS) groups. Exercised animals were submitted to treadmill exercise for 2 weeks, 30 min/day, prior to pneumosepsis induced by K.p tracheal instillation. RESULTS: PS produced a striking decrease in the health condition leading to massive death (85%). AE protected mice, as evidenced by better clinical scores and increased survival (70%). AE alleviated sickness behavior in EPS mice as evaluated in the open field test, and inflammation (nitrite + nitrate, TNF-α and IL-1ß levels) in broncoalveolar fluid. Catalase activity, oxidative damage to proteins and DNA was increased by sepsis and prevented by exercise. CONCLUSION: Overall, the beneficial effects of exercise in septic animals encompassed a markedly improved clinical score and decreased mortality, along with lower inflammation markers, less DNA and protein damage, as well as preserved antioxidant enzyme activity. Neural network risk analysis revealed exercise had a considerable effect on the overall health condition of septic mice.

The role of vitamin C in stress-related disorders.

Stress-related disorders, such as depression and anxiety, present marked deficits in behavioral and cognitive functions related to reward. These are highly prevalent disabling conditions with high social and economic costs. Furthermore, a significant percentage of affected individuals cannot benefit from clinical intervention, opening space for new treatments. Although the literature data have reported limited and variable results regarding oxidative stress-related endpoints in stress-related disorders, the possible neuroprotective effect of antioxidant compounds, such as ascorbic acid (vitamin C), emerges as a possible therapy strategy for psychiatric diseases. Here, we briefly present background information on biological activity of ascorbic acid, particularly functions related to the CNS homeostasis. Additionaly, we reviewed the available information on the role of ascorbic acid in stress-related diseases, focusing on supplementation and depletion studies. The vitamin C deficiency is widely associated to stress-related diseases. Although the efficacy of this vitamin in anxiety spectrum disorders is less stablished, several studies showed that ascorbic acid supplementation produces antidepressant effect and improves mood. Interestingly, the modulation of monoaminergic and glutamatergic neurotransmitter systems is postulated as pivotal target for the antidepressant and anxiolytic effects of this vitamin. Given that ascorbic acid supplementation produces fast therapeutic response with low toxicity and high tolerance, it can be considered as a putative candidate for the treatment of mood and anxiety disorders, especially those that are refractory to current treatments. Herein, the literature was reviewed considering the potential use of ascorbic acid as an adjuvant in the treatment of anxiety and depression.

Peroxiredoxin expression and redox status in neutrophils and HL-60 cells.

Peroxiredoxins (Prxs) are thiol peroxidases with a key role in antioxidant defense and redox signaling. They could be important in neutrophils for handling the large amount of oxidants that these cells produce. We investigated the redox state of Prx1 and Prx2 in HL-60 promyelocytic cells differentiated to neutrophil-like cells (dHL-60) and in human neutrophils. HL-60 cell differentiation with dimethyl sulfoxide caused a large decrease in expression of both Prxs, and all-trans retinoic acid also decreased Prx1 expression. Prx1 was mostly reduced in dHL-60 cells. NADPH oxidase activation by phorbol myristate acetate (PMA) or ingestion of Staphylococcus aureus induced rapid oxidation to disulfide-linked dimers, and eventually hyperoxidation. The NADPH oxidase inhibitor, diphenyleneiodonium, prevented Prx1 dimerization in stimulated dHL-60 cells, and decreased the extent of oxidation under resting conditions. In contrast, Prx1 and Prx2 were present in neutrophils from human blood as disulfides, and PMA or S. aureus caused no further oxidation. They remained oxidized on incubation with diphenyleneiodonium in media. Although this suggests that Prx redox cycling could be deficient in neutrophils, thioredoxin expression and thioredoxin reductase activity were similar in neutrophils and dHL-60 cells. Additionally, neutrophil thioredoxin was initially reduced and underwent oxidation after PMA activation. Thus, although the Prxs respond to oxidant generation in dHL-60 cells, in neutrophils they appear "locked" as disulfides. On this basis we propose that neutrophil Prxs are inefficient antioxidants and contribute little to peroxide removal during the oxidative burst, and speculate that they might be involved in other cell processes.

Two epizootic Perkinsus spp. events in commercial oyster farms at Santa Catarina, Brazil.

Perkinsus spp. have been detected in various bivalve species from north-east Brazil. Santa Catarina is a South Brasil state with the highest national oyster production. Considering the pathogenicity of some Perkinsus spp., a study was carried out to survey perkinsosis in two oyster species cultured in this State, the mangrove oyster Crassostrea gasar and the Pacific oyster Crassostrea gigas. Sampling involved eight sites along the state coast, and oyster sampling was collected during the period between January 2013 and December 2014. For the detection of Perkinsus, Ray's fluid thioglycollate medium (RFTM) and histology were used, and for the identification of the species, PCR and DNA sequencing were used. Perkinsus spp. was found by RFTM in C. gigas and C. gasar from São Francisco do Sul. This pathology was also detected in C. gasar from Balneário Barra do Sul both, by RFTM and histology. Perkinsus marinus was identified in C. gigas and C. gasar from São Francisco do Sul and Perkinsus beihaiensis in C. gasar from Balneário Barra do Sul. This is the first report of P. marinus in C. gigas from South America. Results of this preliminary study suggest that both oyster species tolerate the species of Perkinsus identified, without suffering heavy lesions.

Phaseolin ingestion affects vesicular traffic causing oxidative stress in the midgut of Callosobruchus maculatus larvae.

It has been reported that phaseolin, the major storage globulin of the common bean (Phaseolus vulgaris), is toxic to Callosobruchus maculatus larvae, an Old World bruchid beetle that is not capable of infesting this New World edible bean. It has also been demonstrated that vicilin, the major storage globulin found in cowpea (Vigna unguiculata) seeds, is absorbed through receptor-mediated endocytosis in the insect midgut. A putative vicilin receptor has been purified and showed high homology to α-tocopherol transfer protein. However, the ingestion of a variant vicilin purified from C. maculatus resistant seeds inhibits transcytosis, resulting in the accumulation of vicilins in the midgut cells and ultimately antibiosis. In the present work, we studied the cellular up-take of phaseolin in C. maculatus larvae with the aim of discovering if this protein is also capable of inhibiting endocytic traffic in the enterocytes. FITC-labelled vicilin and FITC-labelled phaseolin were incorporated into the diet of the larvae at a physiological concentration of 0.5% w/w. The fate of labelled and non-labelled globulins was monitored by confocal microscopy. Here we demonstrated that phaseolin is also endocytosed by enterocytes causing an accumulation of endocytic vesicles in the midgut when compared to the ingestion of vicilin obtained from a susceptible V. unguiculata cultivar. From the results obtained for HNE, MDA and TBARS, a pro-oxidative scenario was established in the intestinal epithelial cells of the larvae, which may explain the deleterious effect observed in larvae developing inside P. vulgaris seeds.

Intranasal administration of sodium dimethyldithiocarbamate induces motor deficits and dopaminergic dysfunction in mice.

The primary etiology of Parkinson's disease (PD) remains unclear, but likely reflects a combination of genetic and environmental factors. Exposure to some pesticides, including ziram (zinc dimethyldithiocarbamate), is a relevant risk factor for PD. Like some other environmental neurotoxicants, we hypothesized that ziram can enter the central nervous system from the nasal mucosa via the olfactory nerves. To address this issue, we evaluated the effects of 1, 2 or 4 days of intranasal (i.n., 1 mg/nostril/day) infusions of sodium dimethyldithiocarbamate (NaDMDC), a dimethyldithiocarbamate more soluble than ziram, on locomotor activity in the open field, neurological severity score and rotarod performance. We also addressed the effects of four daily i.n. NaDMDC infusions on olfactory bulb (OB) and striatal measures of cell death, reactive oxygen species (ROS), tyrosine hydroxylase, and the levels of dopamine, noradrenaline, serotonin, and their metabolites. A single i.n. administration of NaDMDC did not significantly alter the behavioral measures. Two consecutive days of i.n. NaDMDC administrations led to a transient neurological deficit that spontaneously resolved within a week. However, the i.n. infusions of NaDMDC for 4 consecutive days induced motor and neurological deficits for up to 7 days after the last NaDMDC administration and increased striatal TH immunocontent and dopamine degradation within a day of the last infusion. Pharmacological treatment with the anti-parkinsonian drugs l-DOPA and apomorphine improved the NaDMDC-induced locomotor deficits. NaDMDC increased serotonin levels and noradrenaline metabolism in the OB 24 h after the last NaDMDC infusion, ROS levels in the OB 2 h after the last infusion, and striatum 2 and 24 h after the last infusion. These results demonstrate, for the first time, that i.n. NaDMDC administration induces neurobehavioral and neurochemical impairments in mice. This accords with evidence that dimethyldithio-carbamate exposure increases the risk of PD and highlights the possibility that olfactory system could be a major route for NaDMDC entry to central nervous system.

RA Differentiation Enhances Dopaminergic Features, Changes Redox Parameters, and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells.

Research on Parkinson's disease (PD) and drug development is hampered by the lack of suitable human in vitro models that simply and accurately recreate the disease conditions. To counteract this, many attempts to differentiate cell lines, such as the human SH-SY5Y neuroblastoma, into dopaminergic neurons have been undertaken since they are easier to cultivate when compared with other cellular models. Here, we characterized neuronal features discriminating undifferentiated and retinoic acid (RA)-differentiated SH-SYSY cells and described significant differences between these cell models in 6-hydroxydopamine (6-OHDA) cytotoxicity. In contrast to undifferentiated cells, RA-differentiated SH-SY5Y cells demonstrated low proliferative rate and a pronounced neuronal morphology with high expression of genes related to synapse vesicle cycle, dopamine synthesis/degradation, and of dopamine transporter (DAT). Significant differences between undifferentiated and RA-differentiated SH-SY5Y cells in the overall capacity of antioxidant defenses were found; although RA-differentiated SH-SY5Y cells presented a higher basal antioxidant capacity with high resistance against H2O2 insult, they were twofold more sensitive to 6-OHDA. DAT inhibition by 3α-bis-4-fluorophenyl-methoxytropane and dithiothreitol (a cell-permeable thiol-reducing agent) protected RA-differentiated, but not undifferentiated, SH-SY5Y cells from oxidative damage and cell death caused by 6-OHDA. Here, we demonstrate that undifferentiated and RA-differentiated SH-SY5Y cells are two unique phenotypes and also have dissimilar mechanisms in 6-OHDA cytotoxicity. Hence, our data support the use of RA-differentiated SH-SY5Y cells as an in vitro model of PD. This study may impact our understanding of the pathological mechanisms of PD and the development of new therapies and drugs for the management of the disease.

Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice.

Experimental autoimmune encephalomyelitis (EAE) is the most used animal model of multiple sclerosis (MS) for the development of new therapies. Dopamine receptors can modulate EAE and MS development, thus highlighting the potential use of dopaminergic agonists in the treatment of MS, which has been poorly explored. Herein, we hypothesized that pramipexole (PPX), a dopamine D2/D3 receptor-preferring agonist commonly used to treat Parkinson's disease (PD), would be a suitable therapeutic drug for EAE. Thus, we report the effects and the underlying mechanisms of action of PPX in the prevention of EAE. PPX (0.1 and 1 mg/kg) was administered intraperitoneally (i.p.) from day 0 to 40 post-immunization (p.i.). Our results showed that PPX 1 mg/kg prevented EAE development, abolishing EAE signs by blocking neuroinflammatory response, demyelination, and astroglial activation in spinal cord. Moreover, PPX inhibited the production of inflammatory cytokines, such as IL-17, IL-1ß, and TNF-α in peripheral lymphoid tissue. PPX was also able to restore basal levels of a number of EAE-induced effects in spinal cord and striatum, such as reactive oxygen species, glutathione peroxidase, parkin, and α-synuclein (α-syn). Thus, our findings highlight the usefulness of PPX in preventing EAE-induced motor symptoms, possibly by modulating immune cell responses, such as those found in MS and other T helper cell-mediated inflammatory diseases.

Thiol oxidation of hemolymph proteins in oysters Crassostrea brasiliana as markers of oxidative damage induced by urban sewage exposure.

Urban sewage is a concerning issue worldwide, threatening both wildlife and human health. The present study investigated protein oxidation in mangrove oysters (Crassostrea brasiliana) exposed to seawater from Balneário Camboriú, an important tourist destination in Brazil that is affected by urban sewage. Oysters were exposed for 24 h to seawater collected close to the Camboriú River (CAM1) or 1 km away (CAM2). Seawater from an aquaculture laboratory was used as a reference. Local sewage input was marked by higher levels of coliforms, nitrogen, and phosphorus in seawater, as well as polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), linear alkylbenzenes (LABs), and fecal steroid in sediments at CAM1. Exposure of oysters to CAM1 caused marked bioaccumulation of LABs and decreased PAH and PCB concentrations after exposure to both CAM1 and CAM2. Protein thiol oxidation in gills, digestive gland, and hemolymph was evaluated. Lower levels of reduced protein thiols were detected in hemolymph from CAM1, and actin, segon, and dominin were identified as targets of protein thiol oxidation. Dominin susceptibility to oxidation was confirmed in vitro by exposure to peroxides and hypochlorous acid, and 2 cysteine residues were identified as potential sites of oxidation. Overall, these data indicate that urban sewage contamination in local waters has a toxic potential and that protein thiol oxidation in hemolymph could be a useful biomarker of oxidative stress in bivalves exposed to contaminants. Environ Toxicol Chem 2017;36:1833-1845. © 2016 SETAC.

N-Acetylcysteine does not protect behavioral and biochemical toxicological effect after acute exposure of diphenyl ditelluride.

Diphenyl ditelluride (PhTe)2 is a versatile molecule used in the organic synthesis and it is a potential prototype for the development of novel biologically active molecules. The mechanism(s) involved in (PhTe)2 toxicity is(are) elusive, but thiol oxidation of critical proteins are important targets. Consequently, the possible remedy of its toxicity by thiol-containing compounds is of experimental and clinical interest. The present study aimed to investigate putative mechanisms underlying the toxicity of (PhTe)2 in vivo. We assessed behavioral and oxidative stress parameters in mice, including the modulation of antioxidant enzymatic defense systems. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered before (3 d) and simultaneously with (PhTe)2 (7 d). Mice were separated into six groups receiving daily injections of (1) TFK (2.5 ml/kg, intraperitonealy (i.p.)) plus canola oil (10 ml/kg, subcutaneously (s.c.)), (2) NAC (100 mg/kg, i.p.) plus canola oil s.c., (3) TFK i.p. plus (PhTe)2 (10 µmol/kg, s.c.), (4) TFK i.p. plus (PhTe)2 (50 µmol/kg, s.c.), (5) NAC plus (PhTe)2 (10 µmol/kg, s.c.), and (6) NAC plus (PhTe)2 (50 µmol/kg, s.c.). (PhTe)2 treatment started on the fourth day of treatment with NAC. Results demonstrated that (PhTe)2 induced behavioral alterations and inhibited important selenoenzymes (thioredoxin reductase and glutathione peroxidase). Treatments produced no or minor effects on the activities of antioxidant enzymes catalase and glutathione reductase. Contrary to expected, NAC co-administration did not protect against the deleterious effects of (PhTe)2. Other low-molecular-thiol containing molecules should be investigated to determine whether or not they can be effective against ditellurides.

Gills are an initial target of zinc oxide nanoparticles in oysters Crassostrea gigas, leading to mitochondrial disruption and oxidative stress.

The increasing industrial use of nanomaterials during the last decades poses a potential threat to the environment and in particular to organisms living in the aquatic environment. In the present study, the toxicity of zinc oxide nanoparticles (ZnONP) was investigated in Pacific oysters Crassostrea gigas. The nanoscale of ZnONP, in vehicle or ultrapure water, was confirmed, presenting an average size ranging from 28 to 88 nm. In seawater, aggregation was detected by TEM and DLS analysis, with an increased average size ranging from 1 to 2 µm. Soluble or nanoparticulated zinc presented similar toxicity, displaying a LC50 (96 h) around 30 mg/L. High zinc dissociation from ZnONP, releasing ionic zinc in seawater, is a potential route for zinc assimilation and ZnONP toxicity. To investigate mechanisms of toxicity, oysters were treated with 4 mg/L ZnONP for 6, 24 or 48 h. ZnONP accumulated in gills (24 and 48 h) and digestive glands (48 h). Ultrastructural analysis of gills revealed electron-dense vesicles near the cell membrane and loss of mitochondrial cristae (6 h). Swollen mitochondria and a more conspicuous loss of mitochondrial cristae were observed after 24 h. Mitochondria with disrupted membranes and an increased number of cytosolic vesicles displaying electron-dense material were observed 48 h post exposure. Digestive gland showed similar changes, but these were delayed relative to gills. ZnONP exposure did not greatly affect thiol homeostasis (reduced and oxidized glutathione) or immunological parameters (phagocytosis, hemocyte viability and activation and total hemocyte count). At 24 h post exposure, decreased (-29%) glutathione reductase (GR) activity was observed in gills, but other biochemical responses were observed only after 48 h of exposure: lower GR activity (-28%) and levels of protein thiols (-21%), increased index of lipid peroxidation (+49%) and GPx activity (+26%). In accordance with ultrastructural changes and zinc load, digestive gland showed delayed biochemical responses. Except for a decreased GR activity (-47%) at 48 h post exposure, the biochemical alterations seen in gills were not present in digestive gland. The results indicate that gills are able to incorporate zinc prior (24 h) to digestive gland (48 h), leading to earlier mitochondrial disruption and oxidative stress. Our data suggest that gills are the initial target of ZnONP and that mitochondria are organelles particularly susceptible to ZnONP in C. gigas.

Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice.

The olfactory bulbectomy (OB) animal model of depression is a well-established model that is capable of detecting antidepressant activity following chronic drug therapy, and the surgery results in behavioral and biochemical changes that are reminiscent of various symptoms of depression. In the present study, we investigated the degree to which 14 days of p.o. administration of the classic antidepressant fluoxetine (10mg/kg) were able to reverse OB-induced changes in behavior (namely, hyperactivity in the open-field test and reduced motivational and self-care behaviors in the splash test) and in the activation of hippocampal cell signaling pathways that are thought to be involved in synaptic plasticity. OB caused significant increases in ERK1 and CREB (Ser(133)) phosphorylation and in the expression of BDNF immunocontent, all of which were prevented by fluoxetine administration. Moreover, fluoxetine administration also caused a significant decrease in ERK2 phosphorylation in mice that had undergone OB. Neither Akt nor GSK-3ß phosphorylation was altered in any experimental condition. In conclusion, the present study shows that OB can induce significant behavioral changes that are accompanied by the activation of hippocampal signaling pathways, namely the ERK1/CREB/BDNF pathway, which is involved in the synaptic plasticity. Conversely, fluoxetine prevented these OB-induced behavioral changes and avoided the activation of ERK1/CREB/BDNF in the hippocampus. Taken together, our results extend the data from the existing literature regarding OB-induced behavioral and neurochemical changes, and suggest a possible underlying mechanism that can account for the antidepressant effect of fluoxetine in this model.

Antidepressant-like action of the bark ethanolic extract from Tabebuia avellanedae in the olfactory bulbectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Tabebuia avellanedae Lorentz ex Griseb is a plant employed in tropical America folk medicine for the treatment of several diseases, including depressive disorders. AIM OF THE STUDY: To investigate the ability of Tabebuia avellanedae ethanolic extract (EET) administered chronically to cause an antidepressant-like effect in the tail suspension test (TST), a predictive test of antidepressant activity, and to reverse behavioral (hyperactivity, anhedonic-like behavior and increased immobility time in the TST) and biochemical changes induced by olfactory bulbectomy (OB), a model of depression, in mice. MATERIALS AND METHODS: Mice were submitted to OB to induce depressive-related behaviors, which were evaluated in the open-field test (hyperactivity), splash test (loss of motivational and self-care behavior indicative of an anhedonic-like behavior) and TST (increased immobility time). Phosphorylation levels of Akt, GSK-3ß, ERK1/2 and CREB, as well as BDNF immunocontent, were evaluated in the hippocampus of bulbectomized mice or sham-operated mice treated for 14 days by p.o. route with EET or vehicle. RESULTS: EET (10 and 30mg/kg) given 14 days by p.o route to mice reduced the immobility time in the TST without altering locomotor activity, an indicative of an antidepressant-like effect. EET per se increased both CREB (Ser(133)) and GSK-3ß (Ser(9)) phosphorylation (at doses of 10-30 and 30mg/kg, respectively) in sham-operated mice. OB caused hyperactivity, loss of motivational and self-care behavior, increased immobility time in the TST and an increase in CREB and ERK1 phosphorylation, as well as BDNF immunocontent. EET abolished all these OB-induced alterations except the increment of CREB phosphorylation. Akt (Ser(473)) and ERK2 phosphorylation levels were not altered in any group. CONCLUSIONS: EET ability to abolish the behavioral changes induced by OB was accompanied by modulation of ERK1 and BDNF signaling pathways, being a promising target of EET. Results indicate that this plant could constitute an attractive strategy for the management of depressive disorders, once more validating the traditional use of this plant.

Diphenyl ditelluride targets brain selenoproteins in vivo: inhibition of cerebral thioredoxin reductase and glutathione peroxidase in mice after acute exposure.

In this study, we investigated the effect of diphenyl ditelluride (PhTe)(2) administration (10 and 50 µmol/kg) on adult mouse behavioral performance as well as several parameters of oxidative stress in the brain and liver. Adult mice were injected with (PhTe)(2) or canola oil subcutaneously (s.c.) daily for 7 days. Results demonstrated that (PhTe)(2) induced prominent signs of toxicity (body weight loss), behavioral alterations and increased in lipid peroxidation in brain. 50 µmol/kg (PhTe)(2) inhibited blood δ-aminolevulinic acid dehydratase (δ-ALA-D), a redox sensitive enzyme. (PhTe)(2) caused an increase in cerebral non-protein thiol (NPSH) and protein thiol (PSH) groups. In the liver, 50 µmol/kg (PhTe)(2) decreased NPSH, but did not alter the content of protein thiol groups. (PhTe)(2) decreased cerebral antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), and thioredoxin reductase (TrxR). In liver, (PhTe)(2) increase SOD and GR and decreased GPx activity. Results obtained herein suggest that the brain was more susceptible to oxidative stress induced by (PhTe)(2) than the liver. Furthermore, we have demonstrated for the first time that TrxR is an in vivo target for (PhTe)(2.) Combined, these results highlight a novel molecular mechanism involved in the toxicity of (PhTe)(2). In particular the inhibition of important selenoenzymes (TrxR and GPx) seems to be involved in the neurotoxicity associated with (PhTe)(2) exposure in adult mice.

Structure-activity relationship of flavonoids derived from medicinal plants in preventing methylmercury-induced mitochondrial dysfunction.

In the present study, we investigated the potential protective effects of three flavonoids (myricetin, myricitrin and rutin) derived from medicinal plants against methyl mercury (MeHg)-induced mitochondrial dysfunction in vitro. Incubation of mouse brain mitochondria with MeHg induced a significant decrease in mitochondrial function, which was correlated with decreased glutathione (GSH) levels and increased generation of reactive oxygen species (ROS) and lipid peroxidation. The co-incubation of mouse brain mitochondria with myricetin or myricitrin caused a concentration-dependent decrease of MeHg-induced mitochondrial dysfunction and oxidative stress. The flavonoid rutin was ineffective in counteracting MeHg toxicity. Among the three tested flavonoids, myricetin was the most efficient in protecting against MeHg-induced mitochondrial dysfunction. Moreover, myricetin completely blocked MeHg-induced ROS formation and lipid peroxidation and partially prevented MeHg-induced GSH depletion. The ability of myricetin to attenuate MeHg-induced mitochondrial dysfunction and oxidative stress appears to be related to its higher scavenging capability when compared to myricitrin and rutin. Overall, the results suggest that MeHg-induced mitotoxicity is associated with oxidative stress. The ability of myricetin to prevent MeHg-induced oxidative damage in brain mitochondria renders this flavonoid a promising molecule for further in vivo studies in the search for potential antidotes to counteract MeHg-induced neurotoxicity.

Folic acid administration prevents ouabain-induced hyperlocomotion and alterations in oxidative stress markers in the rat brain.

OBJECTIVE: Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness. Folic acid has been shown to have antidepressant-like effects in preclinical and clinical studies and has also been suggested to play a role in BD. The present work investigates the therapeutic value of folic acid supplementation in a preclinical animal model of mania induced by ouabain. METHODS: Male Wistar rats were treated twice daily for seven days with folic acid (10, 50, and 100 mg/kg, p.o.) or the mood stabilizer lithium chloride (LiCl) (45 mg/kg, p.o.). One day after the last dose was given, the animals received an i.c.v. injection of ouabain (10 microM), a Na(+),K(+)-ATPase-inhibiting compound. Locomotor activity was assessed in the open-field test. Thiobarbituric acid-reactive substance (TBARS) levels, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were measured in the cerebral cortex and hippocampus. RESULTS: Ouabain (10 microM, i.c.v.) significantly increased motor activity in the open-field test, and seven days of pretreatment with folic acid (50 mg/kg, p.o.) or LiCl (45 mg/kg, p.o.) completely prevented this effect. Ouabain treatment elicited lipid peroxidation (increased TBARS levels) and reduced GPx activity in the hippocampus. GR activity was decreased in the cerebral cortex and hippocampus. These effects were prevented by pretreatment with folic acid and LiCl. CONCLUSIONS: Our results show that folic acid, similarly to LiCl, produces a clear antimanic action and prevents the neurochemical alterations indicative of oxidative stress in an animal model of mania.

alpha-Tocopherol administration produces an antidepressant-like effect in predictive animal models of depression.

This study investigated the antidepressant potential of alpha-tocopherol, the most active and abundant form of vitamin E, in the forced swim test (FST) and tail suspension test (TST). The acute oral treatment with alpha-tocopherol at the doses of 30 and 100mg/kg reduced the immobility time in the FST and in the TST. A single i.c.v. administration of alpha-tocopheryl phosphate, a water-soluble analogue of alpha-tocopherol, also reduced the immobility time in the FST (0.1 and 1 nmol/site) and in the TST (0.1 nmol/site). In addition, the long-term treatment (28 days) with alpha-tocopherol (10mg/kg, p.o.) significantly reduced the immobility time in the FST. Moreover, a subeffective dose of alpha-T (10mg/kg, p.o.) potentiated the effect of fluoxetine (10mg/kg, p.o.) in the FST. The long-term treatment with alpha-T was able to increase the glutathione (GSH) antioxidant defense system, while the acute treatment was not. The long-term treatment with alpha-tocopherol (10mg/kg) increased the GSH levels in the hippocampus and in the prefrontal cortex and increased the glutathione peroxidase and glutathione reductase activity in the hippocampus (10mg/kg) and in the prefrontal cortex (10-100mg/kg). The long-term treatment with fluoxetine (10mg/kg, p.o.), a positive control, was also able to increase the GSH levels in the hippocampus, but failed to alter the activity of both enzymes. Besides the specific antidepressant-like effect, long-term, but not the acute treatment with alpha-T, especially in the doses that produced an antidepressant-like effect (10mg/kg), improved the antioxidant defenses in the mouse hippocampus and prefrontal cortex, two structures closely implicated in the pathophysiology of depression.

Expression of tyrosine hydroxylase increases the resistance of human neuroblastoma cells to oxidative insults.

In this study, we demonstrate that human neuroblastoma SH-SY5Y cells transfected with human tyrosine hydroxylase isoform 1 (SH + TH cells) were substantially more resistant to cell death induced by hydrogen peroxide and 6-hydroxydopamine when compared to wild-type SH-SY5Y cells (SH cells). SH + TH cells exhibit increased levels of dopamine (DA) compared to SH cells. Incubation with hydrogen peroxide or 6-hydroxydopamine (10-100microM) for 24 h caused a significant reduction in cell viability and increased apoptosis in both cell types. However, these effects were significantly reduced in the SH + TH cells when compared to the SH cells. The SH + TH cells showed an improved ability to detoxify peroxide, which correlated with an increase in glutathione peroxidase and glutathione reductase activities, while catalase activity was unchanged. Our data suggest that a preconditioning-like mechanism linked to higher DA levels increased the resistance of SH + TH cells against oxidative insults, which is at least in part related to an augmentation in the activity of glutathione-related antioxidant enzymes.