Aging exacerbates cognitive and anxiety alterations induced by an intracerebroventricular injection of amyloid-ß1-42 peptide in mice.

An increasing body of evidence indicates that the activation of indoleamine-2,3-dyoxigenase (IDO), a first and rate-limiting enzyme in the kynurenine (KYN) pathway, is involved in Aß1-42-neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to Aß1-42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of Aß1-42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety-like behaviour in the elevated plus-maze and open field tests after the Aß1-42 administration. Aged mice also responded to Aß1-42 with a higher deficiency of brain-derived neurotrophic factor, glutathione levels and total radical-trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of Aß1-42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin-6, lower levels of interleukin-10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age-associated inflammatory signature and down-regulation of neuroprotectants in the brain render aged mice more vulnerable to Aß1-42-induced memory loss, anxiety symptoms and KYN pathway dysregulation.

Activation of Brain Indoleamine-2,3-dioxygenase Contributes to Depressive-Like Behavior Induced by an Intracerebroventricular Injection of Streptozotocin in Mice.

There is a lack of information concerning the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. The elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In the present study, we reported that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, as measured by the increased duration of immobility in the tail suspension test and decreased sucrose intake in the sucrose preference test. The blockade of IDO activation by the IDO inhibitor 1-methyltryptophan (1-MT) prevents the development of depressive-like behaviors and attenuates STZ-induced up-regulation of proinflammatory cytokines in the hippocampus. 1-MT abrogates kynurenine production and normalizes brain-derived neurotrophic factor (BDNF) and the kynurenine/tryptophan ratio, but does not protect the biomarkers of the serotonin (5-HT) system in the hippocampus of STZ-injected mice. These results implicate IDO as a critical molecular mediator of STZ-induced depressive-like behavior, likely through activation of the kynurenine pathway and subsequent reduction of BDNF levels. Impairment of the 5-HT system may reflect the inflammatory response induced by STZ and also contributes to observed depression symptoms. The present study not only provides evidence that IDO plays a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets for novel therapeutic drugs for depression. In addition, this study provides new insights on the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in preclinical research of depression.

Antioxidant compound (E)-2-benzylidene-4-phenyl-1,3-diselenole protects rats against thioacetamide-induced acute hepatotoxicity.

The aim of this study was to investigate whether (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) protects against hepatotoxicity induced by thioacetamide (TAA). On the first day of treatment, male adult Wistar rats received BPD (10 or 50 mg·kg-1). On the second day, the rats received a single intraperitoneal injection of TAA (400 mg·kg-1). Twenty-four hours after TAA administration, biochemical determinations and liver histological analysis were carried out. BPD (50 mg·kg-1) reduced plasma aspartate and alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities increased by TAA exposure. Treatment with BPD was effective against increased lipid peroxidation levels and attenuated a decrease in hepatic reduced glutathione and ascorbic acid levels as well as an inhibition of glutathione peroxidase activity caused by TAA exposure. The higher dose of BPD protected against the inhibition of hepatic δ-aminolevulinic dehydratase activity induced by TAA. Finally, histopathological examination of the liver showed that BPD markedly ameliorated TAA-induced hepatic injury. In conclusion, BPD protected against hepatotoxicity and oxidative stress caused by TAA exposure in rats.

Selective A2A receptor antagonist SCH 58261 modulates striatal oxidative stress and alleviates toxicity induced by 3-Nitropropionic acid in male Wistar rats.

The aim of the present study was to investigate the effects of SCH58261, a selective adenosine A2A receptor antagonist, on striatal toxicity induced by 3-nitropropionic acid (3-NP) in rats. The experimental protocol consisted of 10 administrations (once a day) of SCH58261 (0.01 or 0.05 mg/kg/day, intraperitoneal, i.p.). From 7th to 10th day, 3-NP (20 mg/kg/day, i.p.) was injected 1 h after SCH58261 administration. Twenty-four hours after the last 3-NP injection, the body weight gain, locomotor activity (open-field test), motor coordination (rotarod test), striatal succinate dehydrogenase (SDH) activity and parameters linked to striatal oxidative status were evaluated in rats. The marked body weight loss resulting from 3-NP injections in rats was partially protected by SCH 58261 at both doses. SCH 58261 at the highest dose was effective against impairments on motor coordination and locomotor activity induced by 3-NP. SCH 58261 was unable to restore the inhibition of SDH activity caused by 3-NP. In addition, the increase in striatal reactive species (RS) levels, depletion of reduced glutathione (GSH) content and stimulation of glutathione reductase (GR) activity provoked by 3-NP injections were alleviated by both doses of SCH 58261. The highest dose of SCH 58261 was also effective in attenuating the increase of protein carbonyl levels as well as the inhibition of glutathione peroxidase (GPx) activity in rats exposed to 3-NP. Our results revealed that reduction of oxidative stress in rat striatum by adenosine A2A receptor antagonism contributes for alleviating 3-NP-induced toxicity.

Organosulfur compound protects against memory decline induced by scopolamine through modulation of oxidative stress and Na+/K+ ATPase activity in mice.

The present study investigated the possible effect of BMMS in protecting against memory impairment in an Alzheimer's disease model induced by scopolamine in mice. Another objective was to evaluate the involvement of oxidative stress and Na+/K+ ATPase activity in cerebral cortex and hippocampus of mice. Male Swiss mice were divided into four groups: groups I and III received canola oil (10 ml/kg, intragastrically (i.g.)), while groups II and IV received BMMS (10 mg/kg, i.g.). Thirty minutes after treatments, groups III and IV received scopolamine (1 mg/kg, intraperitoneal (i.p.)), while groups I and II received saline (5 ml/kg, i.p.). Behavioral tests were performed thirty minutes after scopolamine or saline injection. Cerebral cortex and hippocampus were removed to determine the thiobarbituric acid reactive species (TBARS) levels, non-protein thiols (NPSH) content, catalase (CAT) and Na+/K+ ATPase activities. The results showed that BMMS pretreatment protected against the reduction in alternation and latency time induced by scopolamine in the Y-maze test and step-down inhibitory avoidance, respectively. In the Barnes maze, the latency to find the escape box and the number of holes visited were attenuated by BMMS. Locomotor and exploratory activities were similar in all groups. BMMS pretreatment protected against the increase in the TBARS levels, NPSH content and CAT activity, as well as the inhibition on the Na+/K+ ATPase activity caused by scopolamine in the cerebral cortex. In the hippocampus, no significant difference was observed. In conclusion, the present study revealed that BMMS protected against the impairment of retrieval of short-term and long-term memories caused by scopolamine in mice. Moreover, antioxidant effect and protection on the Na+/K+ ATPase activity are involved in the effect of compound against memory impairment in AD model induced by scopolamine.

Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-ß1-42 peptide in mice.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aß)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aß1-42 peptide (400pmol/mice; 3µl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aß1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aß1-42 induced memory impairment in the object recognition test. Aß1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aß1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aß-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aß-induced neuroinflammation.

Neuropeptide Y administration reverses tricyclic antidepressant treatment-resistant depression induced by ACTH in mice.

Depression is one of the most common mental disorders and a primary cause of disability. To better treat patients suffering this illness, elucidation of the underlying psychopathological and neurobiological mechanisms is urgently needed. Based on the above-mentioned evidence, we sought to investigate the effects of neuropeptide Y (NPY) treatment in tricyclic antidepressant treatment-resistant depression induced by adrenocorticotropic hormone (ACTH) administration. Mice were treated with NPY (5.84, 11.7 or 23.4mmol/µl) intracerebroventricularly (i.c.v.) for one or five days. The levels of serum corticosterone, tryptophan (TRP), kynurenine (KYN), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and indoleamine 2,3-dioxygenase (IDO) activity in the hippocampus were analyzed. The behavioral parameters (depressive-like and locomotor activity) were also verified. This study demonstrated that ACTH administration increased serum corticosterone levels, KYN, 5-HIAA levels, IDO activity (hippocampus), immobility in the forced swimming test (FST) and the latency to feed in the novelty suppressed feeding test (NSFT). In addition, ACTH administration decreased the BDNF and NGF levels in the hippocampus of mice. NPY treatment was effective in preventing these hormonal, neurochemical and behavioral alterations. It is suggested that the main target of NPY is the modulation of corticosterone and neuronal plasticity protein levels, which may be closely linked with pharmacological action in a model of tricyclic antidepressant treatment-resistant depression. Thus, this study demonstrated a protective effect of NPY on the alterations induced by ACTH administration in mice, indicating that it could be useful as a therapy for the treatment of tricyclic antidepressant treatment-resistant depression.

The peroxisome proliferator-activated receptor-γ agonist pioglitazone protects against cisplatin-induced renal damage in mice.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1)). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1) day(-1), per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity.

Depressive-like behaviour induced by an intracerebroventricular injection of streptozotocin in mice: the protective effect of fluoxetine, antitumour necrosis factor-α and thalidomide therapies.

Information on the effect of an intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) on noncognitive behaviour in rodents such as depression states is scarce. Thus, the aim of this study was to examine the depressive-like effect of STZ injected by the i.c.v. route in mice and the potential protective effect of fluoxetine, antitumour necrosis factor-α (anti-TNF-α) and thalidomide. Our results indicated that a single injection of STZ (0.1 mg/site) promoted depressive-like behaviour in the tail suspension and sucrose preference tests without altering either locomotor activity or plasma glucose levels. We also showed that STZ increased TNF-α levels in the hippocampus of mice. Fluoxetine (32 mg/kg, intraperitoneally. 30 min before STZ injection), and the anti-TNF-α antibody (0.1 pg/site, i.c.v.) and thalidomide (3 mg/kg, subcutaneously), coadministered with STZ, prevented these effects. This is the first study to report depressive-like effects of STZ using the i.c.v. route in mice. We concluded that fluoxetine, anti-TNF-α antibody and thalidomide were effective in preventing depressive-like behaviour and the increase in TNF-α levels in the hippocampus of mice induced by an i.c.v. injection of STZ, reinforcing the involvement of TNF-α in the pathophysiology of depression. This model and the mechanisms studied may contribute towards the development of new antidepressant drugs and enhance the options for studying depression.

Hepatoprotective effect of bis(4-methylbenzoyl) diselenide against CCl(4)-induced oxidative damage in mice.

From a pharmacological point of view, organoseleniums are compounds with important and interesting antioxidant and biological activities. The aim of this study was to evaluate the hepatoprotective effect of bis(4-methylbenzoyl) diselenide (BMD) against carbon tetrachloride (CCl4 )-induced oxidative damage in mice. The animals received BMD (25 mg/kg p.o., for 3 days), and after 1 day, CCl4 (1 mg/kg body weight) was administered by intraperitoneal route. One day after the CCl4 exposure, the animals were euthanized for biochemical and histological analysis. Treatment with BMD (25 mg/kg p.o.) protected against aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and lactate dehydrogenase activity increases induced by CCl4 plasma exposure. Treatment with BMD (25 mg/kg) protected against increases in thiobarbituric reactive species and decreasing non-protein thiols and ascorbic acid levels in liver of mice. Catalase and superoxide dismutase activity inhibition in the liver caused by CCl4 were protected by treatment with BMD (25 mg/kg). Glutathione S-transferase activity was inhibited by CCl4 and remained unaltered even after treatment with BMD. Sections of liver from CCl4 -exposed mice presented an intense infiltration of inflammatory cells and loss of the cellular architecture. BMD (25 mg/kg) attenuated CCl4 -induced hepatic histological alterations. The results demonstrated the hepatoprotective effects of BMD in the mouse liver, possibly by modulating the antioxidant status.

Protective effect of diphenyl diselenide on ischemia and reperfusion-induced cerebral injury: involvement of oxidative stress and pro-inflammatory cytokines.

Cerebrovascular diseases, including ischemic stroke, are associated with high mortality worldwide. Oxidative stress and inflammation are important pathophysiological mechanisms involved in post-ischemic cerebral injury. The present study was designed to investigate the potential protective effect of diphenyl diselenide (PhSe)(2), an organoselenium compound with antioxidant and anti-inflammatory properties, against ischemia/reperfusion (I/R) insult in rat brain. The experimental model adopted was that of surgically-induced brain ischemia, performed by means of bilateral common carotid artery occlusion in rats. The effect of a single oral dose of (PhSe)(2) (50 mg/kg), administered 30 min before the onset of ischemia, was investigated by assessing cerebral oxidative stress-related biochemical parameters and pro-inflammatory cytokines in plasma of rats. The results demonstrated an increase in the levels of malondialdehyde (MDA), reactive oxygen species (ROS) and nitrate/nitrite as well as the alteration in the non-enzymatic and enzymatic (catalase and superoxide dismutase) antioxidant defense system induced by I/R insult in rat brain. I/R insult increased the levels of IL-1ß, IL-6, TNF-α and INF-γ in plasma of rats. The administration of (PhSe)(2) restored cerebral levels of MDA, ROS, nitrate/nitrite and antioxidant defenses of rats exposed to I/R insult. (PhSe)(2) markedly reduced pro-inflammatory cytokines in plasma of I/R rats. I/R insult increased the plasma levels of tissue damage markers, such as creatine kinase and α-1-acid glycoprotein. Pretreatment with (PhSe)(2) was effective in reducing the levels of these proteins. In addition, (PhSe)(2) attenuated cerebral histological alterations induced by I/R. This study showed for the first time the in vivo protective effect of (PhSe)(2) against oxidative stress and pro-inflammatory cytokines-induced by I/R insult in rats.

Evidence for the involvement of glutamatergic and neurokinin 1 receptors in the antinociception elicited by tramadol in mice.

This study was designed to evaluate the role of spinal glutamatergic receptors and neurokinin 1-mediated pathway in the antinociception elicited by tramadol in mice. Tramadol (1-50 mg/kg), given intraperitoneally (i.p.), produced significant inhibition of the biting behavior induced by intrathecal injection (i.t.) of glutamate (175 nmol/site), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 135 pmol/site), (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 50 nmol/site) and substance P (SP, 135 ng/site). Tramadol injected by the i.t. route (25-400 nmol/site) also produced inhibition of glutamate-, AMPA-, trans-ACPD- and SP-induced biting response. Pretreatment with tramadol by the i.p. and i.t. routes had no significant effect against the kainate- and N-methyl-D-aspartic acid (NMDA)-mediated biting response in mice.

Hepatoprotective effect of 3-alkynyl selenophene on acute liver injury induced by D-galactosamine and lipopolysaccharide.

The aim of this study was to investigate the hepatoprotective effect of 3-alkynyl selenophene (compound a), a selenophene compound, on acute liver injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) in rats. The animals received compound a (25 and 50 mg/kg; per oral, p.o.) in the first day of treatment. In the second day, the rats received D-GalN (500 mg/kg; intraperitoneal, i.p.) and LPS (50 microg/kg; intraperitoneal, i.p.). Twenty-four hours after D-GalN/LPS administration animals were euthanized to the biochemical and histological analysis. Compound a (25 and 50 mg/kg; p.o.) protected against the increase in aspartate aminotransferase (AST) activity induced by D-GalN/LPS. Compound a at 50 mg/kg protected against the increase in alanine aminotransferase (ALT) activity induced by D-GalN/LPS. The inhibition of delta-aminolevulinic dehydratase (delta-ALA-D) activity and the decrease of ascorbic acid levels caused by D-GalN/LPS were protected by compound a (25 and 50 mg/kg). Glutathione S-transferase (GST) and catalase activities were not altered in all groups. The histological data showed that sections of liver from D-GalN/LPS-treated rats presented massive hemorrhage, the presence of inflammatory cells and necrosis. Compound a attenuated D-GalN/LPS-induced hepatic histopathological alterations. Based on the results, we demonstrated the hepatoprotective effect of compound a on acute liver injury induced by D-GalN/LPS.

Further analysis of the antinociceptive action caused by p-methoxyl-diphenyl diselenide in mice.

The objective of this study was to extend our previous findings by investigating in greater detail the mechanisms that might be involved in the antinociceptive action of p-methoxyl-diphenyl diselenide, (MeOPhSe)(2), in mice. The pretreatment with nitric oxide precursor, l-arginine (600 mg/kg, intraperitoneal, i.p.), reversed antinociception caused by (MeOPhSe)(2) (10 mg/kg, p.o.) or N(G)-nitro-l-arginine (l-NOARG, 75 mg/kg, i.p.) in the glutamate test. Ondansetron (0.5 mg/kg, i.p., a 5-HT(3) receptor antagonist) and SCH23390 (0.05 mg/kg, i.p.., a D(1) receptor antagonist) blocked the antinociceptive effect caused by (MeOPhSe)(2). Conversely, pindolol (1 mg/kg, i.p., a 5-HT(1A)/(1B) receptor/beta adrenoceptor antagonist), WAY 100635 (0.7 mg/kg, i.p., a selective 5-HT(1A) receptor antagonist), ketanserin (0.3 mg/kg, i.p., a selective 5-HT(2A) receptor antagonist), prazosin (0.15 mg/kg, i.p., an alpha(1)-adrenoreceptor antagonist), yohimbine (1.0 mg/kg, i.p., an alpha(2)-adrenoreceptor antagonist), sulpiride (5 mg/kg, i.p., a D(2) receptor antagonist), naloxone (1 mg/kg, i.p., a non-selective opioid receptor antagonist) and caffeine (3 mg/kg, i.p., a non-selective adenosine receptor antagonist) did not change the antinociceptive effect of (MeOPhSe)(2). (MeOPhSe)(2) significantly inhibited nociception induced by intraplantar (i.pl.) injection of bradykinin (10 nmol/paw) and Des-Arg(9)-bradykinin (10 nmol/paw, a B(1) receptor agonist). (MeOPhSe)(2) significantly inhibited phorbol myristate acetate (PMA, 0.03 mug/paw, a protein kinase C (PKC) activator)-induced licking response. These results indicate that (MeOPhSe)(2) produced antinociception in mice through mechanisms that involve an interaction with nitrergic system, 5-HT(3) and D(1) receptors. The antinociceptive effect is related to (MeOPhSe)(2) ability to interact with kinin B(1) and B(2) receptors and PKC pathway mediated mechanisms.

Mechanisms involved in the antinociceptive and anti-inflammatory effects of bis selenide in mice.

OBJECTIVES: The present study examined the mechanisms involved in the antinociceptive effects of bis selenide [(Z)-2,3-bis(4-chlorophenylselanyl)prop-2-en-1-ol]. METHODS: The effects of oral bis selenide were tested against licking behaviour and oedema in mice induced by formalin, serotonin, histamine, glutamate, phorbol 12-myristate 13-acetate (PMA), 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) and prostaglandin E2. The effects of a variety of receptor antagonists on the antinociceptive activity were tested to determine the likely mechanism of action of bis selenide. KEY FINDINGS: Bis selenide caused antinociception on the first and second phases of the formalin test, with mean ID50 values of 34.21 (29.66-39.45) and 15.86 (12.17-20.67) mg/kg and maximal inhibition of 65+/-3% and 90+/-1%, respectively. At 50 mg/kg bis selenide significantly inhibited (31+/-2%) paw oedema induced by intraplantar injection of formalin. At 25 mg/kg given 5 min after the formalin injection, bis selenide caused a significant inhibition (42+/-5%) in the second phase of the formalin test, whereas the prophylactic treatment caused more intense inhibition (64+/-3%). Oral administration of bis selenide reduced licking and paw oedema induced by serotonin, histamine, glutamate, PGE2, PMA and 8-BrcAMP. The antinociceptive effect of bis selenide (25 mg/kg, p.o.) on the formalin test was reversed by i.p. administration of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis), ketanserin (a selective 5-HT2A receptor antagonist), ondansetron (a 5-HT3 receptor antagonist) and ranitidine (a histamine H2-receptor antagonist). CONCLUSIONS: Glutamatergic, prostaglandin E2, serotonergic (5-HT2A and 5-HT3) and histamine H2 receptors are involved in the antinociceptive effects of bis selenide in mice. The interaction of bis selenide with protein kinase C and A signalling pathways was also demonstrated.

Selective blockade of mGlu5 metabotropic glutamate receptors is hepatoprotective against fulminant hepatic failure induced by lipopolysaccharide and D-galactosamine in mice.

This study was designed to investigate the influence of 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP), an antagonist of metabotropic glutamate receptor subtype 5, in lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced fulminant hepatic failure in mice. Mice were given an intraperitoneal injection of 50 microg kg(-1) LPS and 500 mg kg(-1) D-GalN. MPEP (1, 5 and 25 mg kg(-1)) was administered intraperitoneally 1 h before LPS/D-GalN injection. Twenty-four hours after administration of LPS/D-GalN, plasma was collected and used for biochemical assays. Mice were euthanized and histological analysis and toxicological parameters were carried out in the liver. MPEP, at all doses tested, protected against the increase in aspartate and alanine aminotransferase activities induced by LPS/D-GalN exposure. Ascorbic acid levels were not altered in all experimental groups. Glutathione S-transferase activity was increased by administration of LPS/D-GalN and MPEP did not modify the enzyme activity in mice. MPEP, at the doses of 5 and 25 mg kg(-1), was effective in protecting against the decrease in catalase activity caused by LPS/D-GalN administration in mice. The histological data showed that sections of liver from LPS/D-GalN-exposed mice presented extensive injuries. MPEP, at all doses tested, reduced the scores of liver damage and markedly ameliorated the degree of liver damage. The hepatoprotective effect of MPEP on fulminant hepatic failure induced by LPS and D-GalN in mice was demonstrated.

Studies on preventive effects of diphenyl diselenide on acetaminophen-induced hepatotoxicity in rats.

Organoselenium are compounds with important antioxidant activity and with many biological activities interesting from pharmacological point of view. The aim of this study was to evaluate the protective effect of diphenyl diselenide (PhSe)2 on hepatotoxicity caused by administration of acetaminophen (AA) in rats. Rats received (PhSe)2 orally (31mg/kg, dissolved in canola oil) for 2 days. After the second day of treatment, rats received AA orally (2g/kg) in unique dose. Twenty-four hours after the last administration of AA, plasma was used for biochemical assays aspartate (AST) and alanine aminotransferases (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transferase (γ-GT) activities. Glutathione-S-transferase (GST), δ-aminolevulinic dehydratase (δ-ALA-D) and catalase activities as well as ascorbic acid and TBARS levels were determined in the liver of rats. (PhSe)2 protected against the increase in AST, ALT, ALP, LDH and γ-GT activities induced by AA exposure to rats. The histological data showed that sections of liver from AA-exposed rats presented intense cellular necrosis, characterized by the presence of Kupffer cells and other infiltrating cells, mainly around of the centrilobular vein. (PhSe)2 significantly attenuated AA-induced hepatic histopathological alterations. Administration of (PhSe)2 protected against the increase in TBARS levels and the decrease in δ-ALA-D and GST activities as well as ascorbic acid content induced by AA exposure in rats. Catalase activity remained unaltered in all treated groups. The protective effect of (PhSe)2 against hepatotoxicity caused by AA exposure in rats was demonstrated.

Structural modifications into diphenyl diselenide molecule do not cause toxicity in mice.

The aim of the present study was to evaluate toxicological parameters of following compounds: 1a (4,4'-dichloro-diphenyl diselenide [(ClPhSe)(2)]), 1b (3,3'-ditrifluoromethyl-diphenyl diselenide [(F(3)CPhSe)(2)]) and 1c (4,4'-dimethoxyl-diphenyl diselenide [(CH(3)OPhSe)(2)]). Calculated lethal dose (LD(50)) values for mice exposed, by oral route, to a single application of compounds 1a, 1b or 1c were estimated to be >381, 278 and >372mg/kg, respectively. Compounds 1a and 1b significantly reduced body weight gain as well as food and water intake in mice. δ-Aminolevulinate dehydratase (δ-ALA-D) and catalase activities were inhibited in mice which received the highest dose of compounds 1a or 1b. Exposure to compounds 1a, 1b and 1c did not modify lipid peroxidation, vitamin C levels, cerebral Na(+)/K(+)-ATPase activity and the biochemical parameters evaluated. The important point for medicinal chemistry is that the structural modifications are not introducing toxicity for the compounds in mice.

Spinal mechanisms of antinociceptive effect caused by oral administration of bis-selenide in mice.

The present study was designed to investigate further the mechanisms involved in the antinociception caused by bis-selenide in behavioral model of pain in mice. Bis-selenide (5-50 mg/kg), given orally, produced significant inhibition of the antinociceptive behavior induced by intrathecal (i.t.) injection of glutamate (175 nmol/site), kainate (110 pmol/site) and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 50 nmol/site) and the maximal inhibitions observed were 57+/-5, 46+/-7 and 73+/-3%, respectively. Bis-selenide failed to affect the nociception induced by alpha-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA; 135 pmol/site) and N-methyl-d-aspartate (NMDA; 450 pmol/site). This compound also reduced the nociceptive response induced by tumor necrosis factor-alpha (TNF-alpha; 0.1 pg/site), interleukin-1beta (IL-1beta; 1 pg/site), substance P (SP) (135 ng/site, i.t.) and capsaicin (30 ng/site) and the inhibitions observed were 81+/-3%, 88+/-1%, 77+/-3 and 67+/-3, respectively. The oral administration of bis-selenide (25-50 mg/kg) in mice caused a significant increase in the reaction time to thermal stimuli in the hot plate test and the mean ID(50) value (and the 95% confidence limits) was 20.37 (15.00-25.74) mg/kg. The antinociceptive effect caused by bis-selenide (50 mg/kg, p.o.) on the hot plate test in mice was reversed by intrathecal (i.t.) injection of some K(+) channel blockers such as tetraethylammonium (TEA, non-selective voltage-dependent K(+) channel inhibitor) and glibenclamide (ATP-sensitive K(+) channel inhibitor), but not apamin and charybdotoxin (large- and small-conductance Ca(2+)-activated K(+) channel inhibitors, respectively). Together, these results indicate that bis-selenide produces antinociception at spinal sites through the activation of ATP-sensitive and voltage-gated K(+) channels and interaction with kainate and trans-ACDP receptors as well as vanilloid and neuropeptide receptors and pro-inflammatory cytokines.

Neuroprotective effect caused by MPEP, an antagonist of metabotropic glutamate receptor mGluR5, on seizures induced by pilocarpine in 21-day-old rats.

This study was designed to verify the influence of MPEP (2-methyl-6-phenylethynyl pyridine hydrochloride), an antagonist of metabotropic glutamate receptor subtype 5 (mGluR5), in seizures and status epilepticus (SE) induced by pilocarpine in young rats. In order to investigate the protective effect of MPEP on pilocarpine-induced seizures, young male rats (21-day-old) were pretreated by intraperitoneal route (i.p.) with MPEP (1, 5 and 15 mg/kg) before of pilocarpine administration (400 mg/kg, i.p.). The animals were observed for 1 h after injection of pilocarpine (except pilocarpine group) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to the first seizure and number of deaths. Pretreatment with MPEP, at all doses, delayed the onset for the first seizure episode induced by pilocarpine in rats. MPEP abolished the mortality rate caused by administration of pilocarpine in rats. Pretreatment with MPEP (5 and 15 mg/kg) protected against the levels of RS (reactive species), CAT (catalase) and glutathione S-transferase (GST) activities in brain of rats altered by pilocarpine administration. MPEP, at all doses, protected acetylcholinsterase (AChE) activity inhibited by pilocarpine administration in rats. The results suggest that anticonvulsant action of MPEP can be attributed to its mGlu5 receptor antagonism. Therefore, blockade of mGlu5 receptors might represent a novel target for the treatment of seizures in young rats.