Methionine stimulates motor impairment and cerebellar mercury deposition in methylmercury-exposed mice.

Methylmercury (MeHg) is a highly toxic environmental contaminant that produces neurological and developmental impairments in animals and humans. Although its neurotoxic properties have been widely reported, the molecular mechanisms by which MeHg enters the cells and exerts toxicity are not yet completely understood. Taking into account that MeHg is found mostly bound to sulfhydryl-containing molecules such as cysteine in the environment and based on the fact that the MeHg-cysteine complex (MeHg-S-Cys) can be transported via the L-type neutral amino acid carrier transport (LAT) system, the potential beneficial effects of L-methionine (L-Met, a well known LAT substrate) against MeHg (administrated as MeHg-S-Cys)-induced neurotoxicity in mice were investigated. Mice were exposed to MeHg (daily subcutaneous injections of MeHg-S-Cys, 10 mg Hg/kg) and/or L-Met (daily intraperitoneal injections, 250 mg/kg) for 10 consecutive days. After treatments, the measured hallmarks of toxicity were mostly based on behavioral parameters related to motor performance, as well as biochemical parameters related to the cerebellar antioxidant glutathione (GSH) system. MeHg significantly decreased motor activity (open-field test) and impaired motor performance (rota-rod task) compared with controls, as well as producing disturbances in the cerebellar antioxidant GSH system. Interestingly, L-Met administration did not protect against MeHg-induced behavioral and cerebellar changes, but rather increased motor impairments in animals exposed to MeHg. In agreement with this observation, cerebellar levels of mercury (Hg) were higher in animals exposed to MeHg plus L-Met compared to those only exposed to MeHg. However, this event was not observed in kidney and liver. These results are the first to demonstrate that L-Met enhances cerebellar deposition of Hg in mice exposed to MeHg and that this higher deposition may be responsible for the greater motor impairment observed in mice simultaneously exposed to MeHg and L-Met.

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.

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.

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

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

High Cholesterol Diet Exacerbates Blood-Brain Barrier Disruption in LDLr-/- Mice: Impact on Cognitive Function.

BACKGROUND: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr-/-), a mouse model of familial hypercholesterolemia. OBJECTIVE: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr-/-mice. METHODS: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr-/-mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice's prefrontal cortices and hippocampi. RESULTS: A tenfold elevation in plasma cholesterol levels of LDLr-/-mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr-/-mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr-/-mice treated with a hypercholesterolemic diet. The LDLr-/-mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr-/-mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. CONCLUSION: Therefore, LDLr-/-mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.

Probucol Protects Neuronal Cells Against Peroxide-Induced Damage and Directly Activates Glutathione Peroxidase-1.

Experimental evidence has shown that probucol, a hypocholesterolemic agent, is also able to increase glutathione peroxidase (GPx) activity. However, there is a lack of knowledge about the mechanism(s) involved in this event. In this study, in vitro experiments with purified GPx1 from bovine erythrocytes and cultured SH-SY5Y neuroblastoma cells, as well as in silico studies with GPx1, were performed in order to elucidate mechanisms mediating the stimulatory effect of probucol on GPx activity and to investigate the relevance of this event in terms of susceptibility against peroxide-induced cytotoxicity. In vitro experiments with purified GPx1 showed a direct stimulatory effect of probucol on the activity of GPx1, which was related to an increase in Vmax with no changes in KM. Probucol also increased GPx activity in cultured SH-SY5Y neuroblastoma cells, while the levels of GPx1 expression were not changed, corroborating the results found with the purified enzyme. In addition, probucol rendered SH-SY5Y cells more resistant to hydroperoxide-induced cytotoxicity, and this event was abolished in GPx1 knocked-down cells. In silico studies with GPx1 pointed to a potential binding site for probucol at the close vicinity of the GSH pocket. Collectively, the results presented herein indicate that GPx1 plays a central role in the probucol-induced protective effects against peroxide toxicity. This highlights a novel target (GPx1) and a new mechanism of action (direct activation) for an "old drug." The relevance of such results for in vivo conditions deserves further investigation.

Screening of potentially toxic chalcogens in erythrocytes.

Previous literature reports have demonstrated that a number of human diseases, including inflammation and cancer, can be caused by environmental and occupational exposure to toxic compounds, via DNA damage, protein modifications, or lipid peroxidation. The present study was undertaken to screen the toxicity of a variety of chalcogens using erythrocytes as a model of cell injury. The toxicity of these compounds was evaluated via quantification of hemolysis and lipid peroxidation. The present investigation shows that diphenyl ditelluride and phenyl tellurides are toxic to erythrocytes. The organoselenium compounds were not toxic to erythrocytes even when tested at high concentrations and with a hematocrit of 45%. The hemolytic effect of tellurides was not positively correlated with thiobarbituric acid-reactive substance (TBARS) production suggesting that lipid peroxidation is not involved in the hemolysis provoked by organotellurium compounds. The results suggest that chalcogen compounds may be toxic to human erythrocytes, depending on their structure.

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.

Agmatine abolishes restraint stress-induced depressive-like behavior and hippocampal antioxidant imbalance in mice.

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

Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress.

Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and neuroprotective effects. In a previous study, our group demonstrated that this endogenous nucleoside displays antidepressant-like properties in a predictive animal model. Based on the role of oxidative stress in modulating depressive disorders as well as on the association between the neuroprotective and antioxidant properties of guanosine, here we investigated if its antidepressant-like effect is accompanied by a modulation of hippocampal oxidant/antioxidant parameters. Adult Swiss mice were submitted to an acute restraint stress protocol, which is known to cause behavioral changes that are associated with neuronal oxidative damage. Animals submitted to ARS exhibited an increased immobility time in the forced swimming test (FST) and the administration of guanosine (5mg/kg, p.o.) or fluoxetine (10mg/kg, p.o., positive control) before the exposure to stressor prevented this alteration. Moreover, the significantly increased levels of hippocampal malondialdehyde (MDA; an indicator of lipid peroxidation), induced by ARS were not observed in stressed mice treated with guanosine. Although no changes were found in the hippocampal levels of reduced glutathione (GSH), the group submitted to ARS procedure presented enhanced glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) activities and reduced catalase (CAT) activity in the hippocampus. Guanosine was able to prevent the alterations in GPx, GR, CAT activities, and in SOD/CAT activity ratio, but potentiated the increase in SOD activity elicited by ARS. Altogether, the present findings indicate that the observed antidepressant-like effects of guanosine might be related, at least in part, to its capability of modulating antioxidant defenses and mitigating hippocampal oxidative damage induced by ARS.

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

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

Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-ß (Aß(1-40)) administration in mice.

Neuropeptide Y (NPY) is a 36-amino acid peptide widely distributed in the central nervous system (CNS) that has been associated with the modulation of several functions including food intake, learning and memory, mood and neuroprotection. There is great interest in understanding the role of NPY in the deleterious effects induced by the central accumulation of amyloid-ß (Aß) peptides, a pathological hallmark of Alzheimer's disease (AD). Herein, we evaluated the effects of a single intracerebroventricular (i.c.v.) administration of NPY (0.0234 µmol/µL) 15 min prior to the i.c.v. injection of aggregated Aß1-40 peptide (400 pmol/mouse) in behavioral and neurochemical parameters related to oxidative stress in mice. Pretreatment with NPY prevented Aß1-40-induced depressive-like responses and spatial memory impairments evaluated in the tail suspension and object location tasks, respectively. The protective effects of NPY on spatial memory of Aß1-40-treated mice were abolished by the pretreatment with the selective Y2 receptor antagonist BIIE0246. On the other hand, the administration of NPY and Aß1-40 did not alter the performance of the animals in the elevated plus-maze and open field arena, indicating lack of effects on anxiety state and locomotor function. Although Aß1-40 infusion did not change hippocampal and cortical glutathione peroxidase (GPx) activity and glutathione (GSH) levels, Aß1-40-infused animals showed an increased lipid peroxidation in hippocampus and prefrontal cortex that were blunted by NPY administration. These findings indicate that central administration of NPY prevents Aß1-40-induced depressive-like behavior and spatial memory deficits in mice and that this response is mediated, at least in part, by the activation of Y2 receptors and prevention of oxidative stress.

Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake.

Various forms of mercury possess different rates of absorption, metabolism and excretion, and consequently, toxicity. Methylmercury (MeHg) is a highly neurotoxic organic mercurial. Human exposure is mostly due to ingestion of contaminated fish. Ethylmercury (EtHg), another organic mercury compound, has received significant toxicological attention due to its presence in thimerosal-containing vaccines. This study was designed to compare the toxicities induced by MeHg and EtHg, as well as by their complexes with cysteine (MeHg-S-Cys and EtHg-S-Cys) in the C6 rat glioma cell line. MeHg and EtHg caused significant (p<0.0001) decreases in cellular viability when cells were treated during 30min with each mercurial following by a washing period of 24h (EC50 values of 4.83 and 5.05µM, respectively). Significant cytotoxicity (p<0.0001) was also observed when cells were treated under the same conditions with MeHg-S-Cys and EtHg-S-Cys, but the respective EC50 values were significantly increased (11.2 and 9.37µM). l-Methionine, a substrate for the l-type neutral amino acid carrier transport (LAT) system, significantly protected against the toxicities induced by both complexes (MeHg-S-Cys and EtHg-S-Cys). However, no protective effects of l-methionine were observed against MeHg and EtHg toxicities. Corroborating these findings, l-methionine significantly decreased mercurial uptake when cells were exposed to MeHg-S-Cys (p=0.028) and EtHg-S-Cys (p=0.023), but not to MeHg and EtHg. These results indicate that the uptake of MeHg-S-Cys and EtHg-S-Cys into C6 cells is mediated, at least in part, through the LAT system, but MeHg and EtHg enter C6 cells by mechanisms other than LAT system.

An in vivo insight to the toxicological profile of various organotellurides.

In this study we have examined the in vivo toxic effects of various organochalcogens on hepatic, renal, glycemic and lipid profile. Diorganotellurium dichloride phosphonate (C1) at all tested doses did not modify serum alanine aminotransferase (ALT) activity in mice. While, 2-butyltellurium furan (C2) and dinaphthalene ditelluride (C3) at a dose of 0.75 and 0.125 mmol/kg caused an increase in aspartate aminotransferase (AST) and ALT activities. Our data showed that C1 caused an increase in urea content at different doses while treatment with C2 and C3 did not modify urea content. Treatment with C2 caused a significant alteration in serum glucose and fructosamine levels which explains the possible toxicity of these compounds. No significant changes were observed for cholesterol and triglycerides levels. These results suggest that organochalcogen compounds presented liver and renal toxicity and also altered glycemic profile which may leads to various clinical complications.

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

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 at the end of the treatment, while the combination of NAC and TeAsp produced a significant decrease in these parameters. No DNA damage or alterations in cell viability were observed in leukocytes of treated animals. Treatments produced no or minor effects on the activities of antioxidant enzymes catalase, glutathione peroxidase and glutathione reductase, whereas the activity of the thioredoxin reductase was decreased in the brain and increased the liver of the animals in the groups receiving TeAsp or TeAsp plus NAC. In conclusion, the toxicity of TeAsp was potentiated by NAC and oxidative stress appears to play a central role in this process.

Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid ß peptide in mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. The presence of extracellular senile plaques (mainly composed of amyloid-ß (Aß) peptide) is an important molecular hallmark in AD and neuronal damage has been attributed, at least in part, to Aß-mediated toxicity. Although the molecular mechanisms involved in the pathogenesis of AD are not yet completely understood, several lines of evidence indicate that oxidative stress and cholesterol dyshomeostasis play crucial roles in mediating the synaptic loss and cognitive deficits observed in AD patients. This study evaluated the effects of Probucol, a phenolic lipid-lowering agent with anti-inflammatory and antioxidant properties, on biochemical parameters related to oxidative stress and synaptic function (hippocampal glutathione and synaptophysin levels; glutathione peroxidase, glutathione reductase and acetylcholinesterase activities; lipid peroxidation), as well as on behavioral parameters related to the cognitive function (displaced and new object recognition tasks) in Aß-exposed mice. Animals were treated with a single intracerebroventricular (i.c.v.) injection of aggregated Aß(1-40) (400 pmol/site) and, subsequently, received Probucol (10 mg/kg, i.p.) once a day, during the following 2 weeks. At the end of treatments, Aß(1-40)-exposed animals showed a significant impairment on learning-memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels, as well as by an increase in hippocampal acetylcholinesterase activity. Importantly, Probucol treatment blunted the deleterious effects of Aß(1-40) on learning-memory ability and hippocampal biochemistry. Although Aß(1-40) treatment did not change hippocampal glutathione levels and glutathione peroxidase (GPx) and glutathione reductase (GR) activities, Aß(1-40)-exposed animals showed increased hippocampal lipid peroxidation and this event was completely blunted by Probucol treatment. These findings reinforce and extend the notion of the hazardous effects of Aß(1-40) toward hippocampal synaptic homeostasis and cognitive functions. In addition, the present results indicate that Probucol is able to counteract the cognitive and biochemical impairments induced by i.c.v. Aß(1-40) administration in mice. The study is the first to report the protective effects of Probucol (a "non-statin cholesterol-lowering drug") against Aß(1-40)-induced synaptic and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD.

Effects of traumatic brain injury of different severities on emotional, cognitive, and oxidative stress-related parameters in mice.

Cognitive deficits and psychiatric disorders are significant sequelae of traumatic brain injury (TBI). Animal models have been widely employed in TBI research, but few studies have addressed the effects of experimental TBI of different severities on emotional and cognitive parameters. In this study, mice were subjected to weight-drop TBI to induce mild, intermediate, or severe TBI. After neurological assessment, the mice recovered for 10 days, and were then subjected to a battery of behavioral tests, which included open-field, elevated plus-maze, forced swimming, tail suspension, and step-down inhibitory avoidance tests. Oxidative stress-related parameters (nonprotein thiols [NPSH], glutathione peroxidase [GPx], glutathione reductase [GR], and thiobarbituric acid reactive species [TBARS]) were quantified in the cortex and hippocampus at 2 and 24 h and 14 days after TBI, and histopathological analysis was performed 15 days after TBI. Mice subjected to mild TBI showed increased anxiety and depressive-like behaviors, while intermediate and severe TBI induced robust memory deficits. The severe TBI group also displayed increased locomotor activity. Intermediate and severe TBI caused extensive macroscopic and microscopic brain damage, while mild TBI typically had no histological abnormalities. Moreover, a significant increase in TBARS in the ipsilateral cortex and GPx in the ipsilateral hippocampus was observed at 24 h and 14 days, respectively, following intermediate TBI. The current experimental TBI model induced emotional and cognitive changes comparable to sequelae seen in human TBI, and it might therefore represent a useful approach to the study of mechanisms of and new treatments for TBI and related disorders.

Human erythrocyte hemolysis induced by selenium and tellurium compounds increased by GSH or glucose: a possible involvement of reactive oxygen species.

Oxidative stress can induce complex alterations of membrane proteins in red blood cells (RBCs) eventually leading to hemolysis. RBCs represent a good model to investigate the damage induced by oxidizing agents. Literature data have reported that chalcogen compounds can present pro-oxidant properties with potent inhibitory effects on cell growth, causing tissue damage and inhibit a variety of enzymes. In this study, human erythrocytes were incubated in vitro with various chalcogen compounds at 37 degrees C: diphenyl ditelluride (1), dinaphthalen diteluride (2), diphenyl diselenide (3), (S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate (4), (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate (5), selenium dioxide (6) and sodium selenite (7) in order to investigate their potential in vitro toxicity. After 6h of incubation, all the tested compounds increased the hemolysis rate, when compared to control and compound (2) had the most potent hemolytic effect. The addition of reduced glutathione (GSH) or glucose to the incubation medium enhanced hemolysis caused by chalcogen compounds. The thiol oxidase activity of these compounds was evaluated by measuring the rate of cysteine (CYS) and dithiotreitol (DTT) oxidation. DTT and cysteine oxidation was increased by all the compounds tested. The results suggest a relationship between the oxidation of intracellular GSH and subsequent generation of free radicals with the hemolysis by chalcogen compounds.