Direito

In this work was investigated the effect of pre-treatment with (PhSe) 2 and (PhTe) 2 on chemical seizure and 4-aminopyridine-induced lethality in mice. Additionally, lipid peroxidation levels of whole brain after treatment with 4-aminopyridine and effect of pre-treatment with (PhSe) 2 and (PhTe) 2 on these levels were investigated. Mice were pre-treated with (PhSe) 2 or (PhTe) 2 (50, 100, or 150 µmol/kg) 30 min before 4-aminopyridine (12 mg/kg) administration. The treatment with 4aminopyridine caused a significant incidence of seizures (clonic, tonic) and death. Pre-treatment with (PhSe) 2 and (PhTe) 2 significantly increased the latency for clonic and tonic seizures, and prevented 4-aminopyridine-induced death. Significantly, the pre-treatment with (PhSe) 2 or (PhTe) 2 increased the latency for clonic seizures in a dose-dependent manner. Additionally, a significant increase was observed in the brain lipid peroxidation level after treatment with 4-aminopyridine, which was significantly inhibited by pre-treatment with 150 µmol/kg (PhSe) 2 or (PhTe) 2 . These results demonstrate that (PhSe) 2 and (PhTe) 2 counteract the harmful effects of 4-aminopyridine. It is possible that this effect results from modulation of the redox state of N-methyl-d-aspartate receptors and/or of Ca 2+ channel activity with subsequent alteration in neurotransmitter release. Importantly, this study provides evidence for anticonvulsant and antioxidant properties of (PhSe) 2 and (PhTe) 2 , which indicates a neuroprotective activity of these compounds.

An in vitro evaluation on the antioxidant effect of diphenyl diselenide (PhSe) 2 , an organochalcogenide, against sodium nitroprusside (SNP)-induced lipid peroxidation (LPO) was conduced. Human platelets and erythrocyte membranes (ghosts), as well as rat brain homogenates (S 1 ), were pre-incubated with different concentrations of SNP (0-10 M). All SNP concentrations tested significantly increased LPO in human platelets and S 1 . Platelets were more sensitive to SNP-induced peroxidative damage when compared to S 1 . SNP 10 M decreased glutathione peroxidase (GPx) activity and did not affect glutathione reductase (GR) and catalase (CAT) activities in human platelets. However, ghosts were insensitive to SNP-induced LPO and no changes on GPx, GR and CAT activities were observed. Diphenyl diselenide significantly protected human platelets against SNP-induced LPO and recovered GPx inactivation. This effect was more evident at (PhSe) 2 concentrations above 2 M. The presented results indicate that (PhSe) 2 exerts protective effects on SNP-induced oxidative damage in human blood components and in rat brain. These phenomena seem to be related to its thiol peroxidase-like activity and to a possible direct interaction with SNP and derivatives. Based on our results and on literature, diphenyl diselenide can be pointed as a promising antioxidant molecule.

Reserpine-induced orofacial dyskinesia is an alleged animal model of tardive dyskinesia whose pathophysiology has been related to striatal oxidative stress. In the present investigation, the authors examined whether ebselen, an antioxidant organochalcogen with glutathione peroxidase-like activity, changes the behavioral and neurochemical effect of acute reserpine administration. Reserpine injection for 3 days every other day caused a significant increase on the tongue protrusion frequency and ebselen (30 mg/kg ip for 4 days, starting 1 day before reserpine) reversed partially the effect of reserpine ( P < .05). Reserpine-and reserpine + ebselen-treated groups displayed an increase in vacuous chewing frequency when compared to control and ebselen-treated groups ( P < .05) Reserpine increased the duration of facial twitching and ebselen reversed partially the effect of reserpine ( P < .01). Reserpine increased significantly the thiobarbituric acid-reactive species (TBARS) levels, and ebselen reversed the effect of reserpine on TBARS production in rat striatum. The results of the present study clearly indicated that ebselen has a protective role against reserpine-induced orofacial dyskinesia and reversed the increase in TBARS production caused by reserpine administration. Consequently, the use of ebselen as a therapeutic agent for the treatment of tardive dyskinesia should be considered. D

The aim of this study was to investigate the effect of Krebs cycle intermediates on basal and quinolinic acid (QA)- or iron-induced TBARS production in brain membranes. Oxaloacetate, citrate, succinate and malate reduced significantly the basal and QA-induced TBARS production. The potency for basal TBARS inhibition was in the order (IC50 is given in parenthesis as mM) citrate (0.37) > oxaloacetate (1.33) = succinate (1.91) >> malate (12.74). α-Ketoglutarate caused an increase in TBARS production without modifying the QA-induced TBARS production. Cyanide (CN−) did not modify the basal or QA-induced TBARS production; however, CN− abolished the antioxidant effects of succinate. QA-induced TBARS production was enhanced by iron ions, and abolished by desferrioxamine (DFO). The intermediates used in this study, except for α-ketoglutarate, prevented iron-induced TBARS production. Oxaloacetate, citrate, α-ketoglutarate and malate, but no succinate and QA, exhibited significantly iron-chelating properties. Only α-ketoglutarate and oxaloacetate protected against hydrogen peroxide-induced deoxyribose degradation, while succinate and malate showed a modest effect against Fe2+/H2O2-induced deoxyribose degradation. Using heat-treated preparations citrate, malate and oxaloacetate protected against basal or QA-induced TBARS production, whereas α-ketoglutarate induced TBARS production. Succinate did not offer protection against basal or QA-induced TBARS production. These results suggest that oxaloacetate, malate, succinate, and citrate are effective antioxidants against basal and iron or QA-induced TBARS production, while α-ketoglutarate stimulates TBARS production. The mechanism through which Krebs cycle intermediates offer protection against TBARS production is distinct depending on the intermediate used. Thus, under pathological conditions such as ischemia, where citrate concentrations vary it can assume an important role as a modulator of oxidative stress associated with such situations.

The effect of post-treatment with diphenyl diselenide on liver damage induced by 2-nitropropane (2-NP) was examined in male rats. Rats were pre-treated with a single dose of 2-NP (100 mg/kg body weight dissolved in canola oil). Afterward, the animals were post-treated with a dose of diphenyl diselenide (10, 50 or 100 mol/kg). The parameters that indicate tissue damage such as liver histopathology, plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), ␥-glutamyl transferase (GGT), urea and creatinine were determined. Since the liver damage induced by 2-NP is related to oxidative damage, lipid peroxidation, superoxide dismutase (SOD), catalase (CAT) and ascorbic acid level were also evaluated. Diphenyl diselenide (50 and 100 mol/kg) effectively restored the increase of ALT and AST activities and urea level when compared to the 2-NP group. At the higher dose, diphenyl diselenide decreased GGT activity. Treatment with diphenyl diselenide, at all doses, effectively ameliorated the increase of hepatic and renal lipid peroxidation when compared to 2-NP group. 2-NP reduced CAT activity and neither alter SOD activity nor ascorbic acid level. This study points out the involvement of CAT activity in 2-NP-induced acute liver damage and suggests that the post-treatment with diphenyl diselenide was effective in restoring the hepatic damage induced by 2-NP.

Cadmium is an environmental toxic metal implicated in human diseases. In the present study, the effect of diphenyl diselenide, (PhSe) 2 , on sub-chronic exposure with cadmium chloride (CdCl 2 ) was investigated in rats. Male adult Swiss albino rats received CdCl 2 (10 mol/kg, orally) and (PhSe) 2 (5 mol/kg, orally) for a period of 30 days. A number of parameters were examined as indicators of toxicity, including hepatic and renal damage, glucose and glycogen levels and markers of oxidative stress. Cadmium content, liver histology, ␦-aminolevulinate dehydratase (␦-ALA-D) activity, metallothionein (MT) levels were also evaluated. Cadmium content determined in the tissue of rats exposed to CdCl 2 provides evidence that the liver is the major cadmium target where (PhSe) 2 acts. The concentration of cadmium in liver was about three fold higher than that in kidney, and (PhSe) 2 reduced about six fold the levels of this metal in liver of rats exposed. Rats exposed to CdCl 2 showed histological alterations abolished by (PhSe) 2 administration. (PhSe) 2 administration ameliorated plasma malondialdehyde (MDA) levels, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT) activities increased by CdCl 2 exposure. Urea and bilirubin levels increased by CdCl 2 exposure were also reduced by (PhSe) 2 . In conclusion, this study demonstrated that co-treatment with (PhSe) 2 ameliorated hepatotoxicity and cellular damage in rat liver after sub-chronic exposure with CdCl 2 . The proposed mechanisms by which (PhSe) 2 acts in this experimental protocol are its antioxidant properties and its capacity to form a complex with cadmium.

In this study, we described the local peripheral antinociceptive activity produced by diphenyl diselenide in the formalin test as compared to ebselen, an amply studied organoselenium compound. A second objective was to evaluate, the possible mechanisms underlying the antinociceptive effect caused by diphenyl diselenide. Administration of diphenyl diselenide or ebselen produced a significant antinociceptive local effect on the late phase (15-30 min) of the formalin test. As well, diphenyl diselenide and ebselen injected in the contra lateral paw produced a significant decrease in licking time on the late phase (15-30 min). The mechanisms underlying the analgesic action of diphenyl diselenide seem to be unlike the activation of opioid, dopaminergic D2, muscarinic cholinergic receptors or the interaction with ␣ 1 and ␣ 2 adrenoceptors. Furthermore, the effect of a 5-HT 3 receptor antagonist in abolishing the antinociception induced by diphenyl diselenide suggests the involvement of serotonergic pathways.

The present study examined the acute toxicity and antinociceptive effects of diphenyl diselenide (PhSe) 2 , given orally (p.o.), in chemical and thermical models of pain in mice. Diphenyl diselenide (7.8-312 mg/kg, p.o.) did not cause mortality. This compound did not change plasma AST (aspartate aminotransferase) and ALT (alanine aminotransferase) activities as well as urea and creatinine levels in mice after 72 h of exposure. Diphenyl diselenide (1-100 mg/kg, p.o.) inhibited acetic acid-, capsaicin-, glutamate-, bradykinin(BK)-and phorbol myristate acetate (PMA)induced pain. Diphenyl diselenide also reduced glutamate-, bradykinin-, PMA-induced paw oedema formation. Moreover, diphenyl diselenide caused a significant increase in tail-immersion response latency time. Diphenyl diselenide co-injected subplantarly in association with glutamateinduced a significant reduction of the licking and in the paw oedema formation induced by glutamate. The local pre-treatment of mice with Larginine, intraplantarly, restored antinociception caused by diphenyl diselenide or N G -nitro-L-arginine methyl ester (L-NAME) when analyzed against glutamate-induced nociception. The pre-treatment of mice with dithiothreitol (DTT) intraplantarly restored local antinociception caused by diphenyl diselenide or 5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) when analyzed against glutamate-induced nociception. These results indicate that diphenyl diselenide produced antinociception in several models of pain through mechanisms that involve an interaction with not only nitrergic system but also via interaction with redox modulatory sites of glutamate receptors.

The effect of diphenyl diselenide, (PhSe) 2 , administration on 2-nitropropane (2-NP)-induced hepatic damage was examined in male rats. Rats were pre-treated with a single dose of diphenyl diselenide (10, 50 or 100 mol/kg). Afterward, they received only one dose of 2-NP (100 mg/kg body weight dissolved in olive oil). The parameters that indicate tissue damage such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), ␥-glutamyl transferase (GGT), alpha-fetoprotein (AFP), creatinine and urea were determined. Since toxicity induced by 2-NP is related to oxidative stress, lipid peroxidation was also evaluated. Diphenyl diselenide (100 mol/kg) significantly reduced plasma ALT, ␥-GGT, AFP levels when compared to 2-NP group. Treatment with diphenyl diselenide, at all doses, effectively protects the increase of lipid peroxidation when compared to 2-NP group. Histological examination revealed that 2-NP treatment causes a moderate swelling and degenerative alterations on hepatocytes and diphenyl diselenide (100 mol/kg) protects against these alterations. Diphenyl diselenide (50 and 100 mol/kg) significantly decreased the urea level. This study evidences the protective effect of diphenyl diselenide by 2-NP-induced acute hepatic damage.

The concept that selenium-containing molecules may be better antioxidants than classical antioxidants, has led to the design of synthetic organoselenium compounds. In the present investigation subchronic deleterious effects of cadmium-intoxication in mice and a possible protective effect of diphenyl diselenide (PhSe) 2 (5 mol/kg) were studied. Male adult Swiss albino mice (25-35 g) received CdCl 2 (10 mol/kg, subcutaneously), five times/week, for 4 weeks. A number of toxicological parameters in blood, liver, kidney, spleen and brain of mice were examined including ␦-aminolevulinic acid dehydratase (␦-ALA-D) activity, lipid peroxidation and ascorbic acid content, the parameters that indicate tissue damage such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and lactate dehydrogenase (LDH) were also determined. The results demonstrated that cadmium caused inhibition of ␦-ALA-D activity in liver (24%), kidney (33%) and spleen (73%) and (PhSe) 2 therapy was effective in restoring enzyme activity in all tissues. A reduction in ascorbic acid content was observed in kidney (11%) and spleen (10.7%) of cadmium-treated mice and (PhSe) 2 was only effective in improving this reduction in kidney. An increase of lipid peroxidation induced by cadmium was noted in liver (29%) and brain (28%) tissues and (PhSe) 2 therapy was effective in restoring TBARS levels in both tissues. We also observed an increase on plasma LDH (1.99-times), AST (1.93-times) and ALT (4.24-times) activities. (PhSe) 2 therapy was effective in restoring AST activity at control level. (PhSe) 2 did not present toxic effects when plasma parameters were evaluated. The results suggest that the administration of an antioxidant (PhSe) 2 , during cadmium intoxication may provide beneficial effects by reducing oxidative stress in tissues.

The antisecretory and antiulcer effects of diphenyl diselenide were studied in vivo and in vitro. Diphenyl diselenide, administered intraperitoneally prevented the development of gastric lesions induced by ethanol and indomethacin. There was no difference in plasma uric acid concentrations in diphenyl diselenide-treated rats with gastric lesions induced by 70% ethanol. There were no changes in TBARS levels in diphenyl diselenidetreated rats with gastric lesions induced by indomethacin and ethanol. Diphenyl diselenide (5, 10 and 50 mg/kg) inhibited gastric acid secretion in pylorus-ligated rats. In vitro results demonstrated that diphenyl diselenide inhibited lipid peroxidation induced by Fe 2+ /ascorbate/H 2 O 2 and reduced K + -dependent ATPase activity. The mechanisms by which pre-administered diselenide protects the damaged area in the gastric mucosa are not clear but it appears that the antiulcer activity of diphenyl diselenide is the result of antisecretory activity, via inhibition of gastric K + -ATPase activity.

Reactive oxygen species have been demonstrated to be associated with a variety of diseases including neurodegenerative disorders. Flavonoid compounds have been investigated for their protective action against oxidative mechanisms in different in vivo and in vitro models, which seems to be linked to their antioxidant properties. In the present study, we examine the protective mechanism of quercitrin, a glycoside form of quercetin, against the production of TBARS induced by different agents. TBARS production was stimulated by the incubation of rat brain homogenate with Fe 2+ , Fe 2+ plus EDTA, quinolinic acid (QA), sodium nitroprusside (SNP) and potassium ferricyanide ([Fe(CN) 6 ] 3− ). Quercitrin was able to prevent the formation of TBARS induced by pro-oxidant agents tested; however, it was more effective against potassium ferricyanide ([Fe(CN) 6 ] 3− , IC 50 = 2.5), than quinolinic acid (QA, IC 50 = 6 μg/ml) and sodium nitroprusside (SNP, IC 50 = 5.88 μg/ml) than Fe 2+ (Fe 2+ , IC 50 = 14.81 μg/ml), Fe 2+ plus EDTA (Fe 2+ plus EDTA, IC 50 = 48.15 μg/ml). The effect of quercitrin on the Fenton reaction was also investigated (deoxyribose degradation). Quercitrin caused a significant decrease in deoxyribose degradation that was not dependent on the concentration. Taken together, the data presented here indicate that quercitrin exhibits a scavenger and antioxidant role, and these effects probably are mediated via different mechanisms, which may involve the negative modulation of the Fenton reaction and NMDA receptor.

In this work was investigated the effect of pre-treatment with (PhSe) 2 and (PhTe) 2 on chemical seizure and 4-aminopyridine-induced lethality in mice. Additionally, lipid peroxidation levels of whole brain after treatment with 4-aminopyridine and effect of pre-treatment with (PhSe) 2 and (PhTe) 2 on these levels were investigated. Mice were pre-treated with (PhSe) 2 or (PhTe) 2 (50, 100, or 150 µmol/kg) 30 min before 4-aminopyridine (12 mg/kg) administration. The treatment with 4aminopyridine caused a significant incidence of seizures (clonic, tonic) and death. Pre-treatment with (PhSe) 2 and (PhTe) 2 significantly increased the latency for clonic and tonic seizures, and prevented 4-aminopyridine-induced death. Significantly, the pre-treatment with (PhSe) 2 or (PhTe) 2 increased the latency for clonic seizures in a dose-dependent manner. Additionally, a significant increase was observed in the brain lipid peroxidation level after treatment with 4-aminopyridine, which was significantly inhibited by pre-treatment with 150 µmol/kg (PhSe) 2 or (PhTe) 2 . These results demonstrate that (PhSe) 2 and (PhTe) 2 counteract the harmful effects of 4-aminopyridine. It is possible that this effect results from modulation of the redox state of N-methyl-d-aspartate receptors and/or of Ca 2+ channel activity with subsequent alteration in neurotransmitter release. Importantly, this study provides evidence for anticonvulsant and antioxidant properties of (PhSe) 2 and (PhTe) 2 , which indicates a neuroprotective activity of these compounds.

An in vitro evaluation on the antioxidant effect of diphenyl diselenide (PhSe) 2 , an organochalcogenide, against sodium nitroprusside (SNP)-induced lipid peroxidation (LPO) was conduced. Human platelets and erythrocyte membranes (ghosts), as well as rat brain homogenates (S 1 ), were pre-incubated with different concentrations of SNP (0-10 M). All SNP concentrations tested significantly increased LPO in human platelets and S 1 . Platelets were more sensitive to SNP-induced peroxidative damage when compared to S 1 . SNP 10 M decreased glutathione peroxidase (GPx) activity and did not affect glutathione reductase (GR) and catalase (CAT) activities in human platelets. However, ghosts were insensitive to SNP-induced LPO and no changes on GPx, GR and CAT activities were observed. Diphenyl diselenide significantly protected human platelets against SNP-induced LPO and recovered GPx inactivation. This effect was more evident at (PhSe) 2 concentrations above 2 M. The presented results indicate that (PhSe) 2 exerts protective effects on SNP-induced oxidative damage in human blood components and in rat brain. These phenomena seem to be related to its thiol peroxidase-like activity and to a possible direct interaction with SNP and derivatives. Based on our results and on literature, diphenyl diselenide can be pointed as a promising antioxidant molecule.

Reserpine-induced orofacial dyskinesia is an alleged animal model of tardive dyskinesia whose pathophysiology has been related to striatal oxidative stress. In the present investigation, the authors examined whether ebselen, an antioxidant organochalcogen with glutathione peroxidase-like activity, changes the behavioral and neurochemical effect of acute reserpine administration. Reserpine injection for 3 days every other day caused a significant increase on the tongue protrusion frequency and ebselen (30 mg/kg ip for 4 days, starting 1 day before reserpine) reversed partially the effect of reserpine ( P < .05). Reserpine-and reserpine + ebselen-treated groups displayed an increase in vacuous chewing frequency when compared to control and ebselen-treated groups ( P < .05) Reserpine increased the duration of facial twitching and ebselen reversed partially the effect of reserpine ( P < .01). Reserpine increased significantly the thiobarbituric acid-reactive species (TBARS) levels, and ebselen reversed the effect of reserpine on TBARS production in rat striatum. The results of the present study clearly indicated that ebselen has a protective role against reserpine-induced orofacial dyskinesia and reversed the increase in TBARS production caused by reserpine administration. Consequently, the use of ebselen as a therapeutic agent for the treatment of tardive dyskinesia should be considered. D

The aim of this study was to investigate the effect of Krebs cycle intermediates on basal and quinolinic acid (QA)- or iron-induced TBARS production in brain membranes. Oxaloacetate, citrate, succinate and malate reduced significantly the basal and QA-induced TBARS production. The potency for basal TBARS inhibition was in the order (IC50 is given in parenthesis as mM) citrate (0.37) > oxaloacetate (1.33) = succinate (1.91) >> malate (12.74). α-Ketoglutarate caused an increase in TBARS production without modifying the QA-induced TBARS production. Cyanide (CN−) did not modify the basal or QA-induced TBARS production; however, CN− abolished the antioxidant effects of succinate. QA-induced TBARS production was enhanced by iron ions, and abolished by desferrioxamine (DFO). The intermediates used in this study, except for α-ketoglutarate, prevented iron-induced TBARS production. Oxaloacetate, citrate, α-ketoglutarate and malate, but no succinate and QA, exhibited significantly iron-chelating properties. Only α-ketoglutarate and oxaloacetate protected against hydrogen peroxide-induced deoxyribose degradation, while succinate and malate showed a modest effect against Fe2+/H2O2-induced deoxyribose degradation. Using heat-treated preparations citrate, malate and oxaloacetate protected against basal or QA-induced TBARS production, whereas α-ketoglutarate induced TBARS production. Succinate did not offer protection against basal or QA-induced TBARS production. These results suggest that oxaloacetate, malate, succinate, and citrate are effective antioxidants against basal and iron or QA-induced TBARS production, while α-ketoglutarate stimulates TBARS production. The mechanism through which Krebs cycle intermediates offer protection against TBARS production is distinct depending on the intermediate used. Thus, under pathological conditions such as ischemia, where citrate concentrations vary it can assume an important role as a modulator of oxidative stress associated with such situations.