Diphenyl diselenide and diphenyl ditelluride affect the rat glutamatergic system in vitro and in vivo

Brain Research 906 (2001) 157–163 www.elsevier.com / locate / bres

Research report

Diphenyl diselenide and diphenyl ditelluride affect the rat glutamatergic system in vitro and in vivo a,b , b b Cristina Wayne Nogueira *, Liane Nanci Rotta , Marcos Luiz Perry , b ˜ Batista Teixeira da Rocha a Diogo Onofre Souza , Joao a

Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, 97105 -900 Santa Maria, RS, Brazil b ´ , Universidade Federal do Rio Grande do Sul, 90035 -003 Porto Alegre, RS, Brazil Departamento de Bioquımica Accepted 23 January 2001

Abstract The aim of this study was to investigate the possible involvement of the glutamatergic system in the toxicity of organochalcogens, since this is an important neurotransmitter system for signal transduction and neural function. The results indicated that 100 mM diphenyl diselenide (PhSe) 2 and diphenyl ditelluride (PhTe) 2 inhibit by 50 and 70% (P , 0.05), respectively, [ 3 H]glutamate binding in vitro. Acute administration of 25 mmol / kg (PhSe) 2 or 3 mmol / kg (PhTe) 2 caused a significant reduction in [ 3 H]glutamate (30%, P , 0.05) or [ 3 H]MK-801 binding (30%, P , 0.05) to rat synaptic membranes. These results suggest that (PhSe) 2 and (PhTe) 2 affect, in a rather complex way, the glutamatergic system after acute in vivo exposure in rats. In vitro, total [ 3 H]GMP-PNP binding was inhibited about 40% at 100 mM (PhSe) 2 and (PhTe) 2 . Acute exposure in vivo to (PhSe) 2 decreased the stable [ 3 H]GMP-PNP binding to 25% and (PhTe) 2 to 68% of the control value (P , 0.05, for both compounds). Simultaneously, the unstable binding of [ 3 H]GMP-PNP was decreased about 30 and 50% (P , 0.05, for both compounds) after exposure to (PhSe) 2 and (PhTe) 2 , respectively. GMP-PNP stimulated adenylate cyclase (AC) activity significantly in control animals. (PhSe) 2 - and (PhTe) 2 -treated animals increased the basal activity of this enzyme, but GMP-PNP stimulation was totally abolished. These results suggest that the toxic effects of organochalcogens could result from action at different levels of neural signal transduction pathways, possibly involving other neurotransmitters besides the glutamatergic system.  2001 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Neurotoxicity Keywords: Diphenyl diselenide; Diphenyl ditelluride; Organochalcogen; Neurotoxicity; Glutamatergic system; Adenylate cyclase and GMP-PNP binding protein

1. Introduction Most excitatory pathways in the central nervous system employ glutamate as a neurotransmitter. The glutamatergic receptors may be ionotropic or metabotropic, and excitatory transmission is mediated by combinations of these receptors [26]. Ionotropic receptors are cation-specific ion channels, whereas metabotropic receptors are coupled to

*Corresponding author. Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil. Fax: 155-55-220-8031. E-mail address: [email protected] (C.W. Nogueira).

GTP-binding proteins (G-proteins), modulating second messenger systems [15]. Adenylate cyclase (AC) is a membrane bound enzyme which produces intracellular cAMP, a second messenger that mediates the intracellular response to the activation of various G-protein-coupled receptors [15,24], modulating phosphorylation of cellular proteins, affecting synaptic transmission and neural function [32,38,47]. However, besides its essential role in normal brain function, over-stimulation of the glutamatergic system is involved in many acute and chronic brain injuries [26], a process known as excitotoxicity. Guanine nucleotides can antagonize glutamatergic transmission by acting at extracellular sites located at the membrane surface. These

0006-8993 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0006-8993( 01 )02165-5

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extracellular sites are distinct from the classical intracellular adenylate cyclase-coupled G-protein site that binds guanosine triphosphate (GTP) [27,34,39,41], and guanine nucleotide binding to the extracellular site seems to confer neuroprotection against glutamate excitotoxicity. Selenium is an essential element with physiological antioxidant properties, appearing as a selenocysteine [6], a structural component of several enzymes involved in peroxide decomposition, including glutathione peroxidase [14,33] and phospholipid hydroperoxide glutathione peroxidase [46]. Tellurium has a similar electronic configuration to selenium and, consequently, it shares some chemical properties with selenium. In contrast to selenium, no biological function has been described for tellurium [43], which is probably related to its superior reactivity when compared to selenium [9]. In spite of the fact that inorganic tellurium compounds are highly toxic to the CNS of rodents [11,16,44] and inorganic selenium compounds can generate reactive oxygen species by reacting with thiols [19], organic forms of selenium and tellurium have been suggested as possible antioxidant agents because they exhibit glutathione peroxidase-like activity and oxidize –SH during the reduction of H 2 O 2 [25,48]. In addition, these organochalcogens also retard the lipoperoxidation induced by a variety of oxidants [12]. Moreover, ebselen, an organic selenium compound, is being used in pre-clinical studies due to its neuroprotective properties [36]. Inorganic and organic tellurium compounds are highly toxic to the CNS of rodents [11,16,22,43,44]. Similarly, exposure to high doses of diphenyl diselenide causes central effects in mice, indicating that the brain is a potential target for the toxic effect of organochalcogens [17,22]. The rationale for studying the effect of organochalcogens resides in the fact that these are important intermediates and reagents in organic synthesis [7], which increases the risk of human exposure to these chemicals in the workplace. The goal of this study was to investigate the possible involvement of the glutamatergic system in the neurotoxicity of organochalcogens, since this neurotransmitter system is important for signal transduction and neural function. The possible interaction between G-protein signalling and the neurotoxic effects of organochalcogens was also examined.

were of analytical grade and obtained from standard commercial suppliers. Diphenyl diselenide (PhSe) 2 and diphenyl ditelluride (PhTe) 2 were synthesized by the method described previously [7].

2.2. Animals Adult male Wistar rats from our own breeding colony were used. They were maintained at 258C, on a 12 h light / 12 h dark cycle, with free access to food and water. The animals were used according to the guidelines of the Committee on Care and Use of Experimental Animal Resources, School of Veterinary Medicine and Animal ˜ Paulo, Brazil. Science of the University of Sao

2.3. Brain membrane preparation All binding assays were performed using brain synaptic membranes prepared as described [18] and stored at 2708C for up to 2 months according to Ref. [13]. On the day of the binding assay, the membranes were rapidly thawed in a water bath (378C), homogenized with three volumes of assay buffer, pH 7.4, and centrifuged three times at 27,0003g for 15 min. The final pellet was resuspended in the same buffer in order to yield a protein concentration of 1–2 mg / ml and was used for the binding assay.

2.4. [ 3 H] MK-801 binding assay Unless otherwise indicated, 4 nM [ 3 H]MK-801 (total volume 1 ml) was used and incubations were started by the addition of 100–200 mg of membrane protein to a medium containing 5 mM Tris / HCl, pH 7.4. After 60 min incubation at 378C, binding was terminated by filtration under pressure through pre-wetted Whatman GF / B filters. Assay tubes were rinsed three times with 3 ml of ice-cold Tris assay buffer. Nonspecific binding typically amounted to 10–20% of total binding.

2.5. [ 3 H] Glutamate binding assay

2. Materials and methods

2.1. Materials [ 3 H]MK-801 (1000 Ci / mmol) was purchased from DuPont-NEN, and [ 3 H]glutamic acid (49 Ci / mmol) and [ 3 H]GMP-PNP (19.2 Ci / mmol) were purchased from Amersham International, UK, USA. All other chemicals

Membranes were incubated in 0.5 ml reaction mixture containing 50 mM Tris / acetate, pH 7.4, and 40 nM [ 3 H]glutamate. Incubation was carried out at 308C for 30 min and the reaction was stopped by centrifugation at 27,0003g for 15 min. The pellet and the wall of the tube were quickly and carefully washed with ice-cold Milli-Q water. SDS (0.1%) and scintillation liquid were added to the dry pellet and incorporated radioactivity was determined.

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2.6. Total [ 3 H] GMP-PNP binding assay

2.9. Protein quantification

Previous studies from our group [29,31,35,40] and others [5,23,27] indicate that extracellular guanine derivatives may modulate neural cell activity by acting outside of cells, besides their classic intracellular effects via G-proteins [15,24]. These studies point to the physiological and physiopathological relevance of these sites and determined various differences between them. In this study, based on previous protocols [29,31,35,40] we investigated the effects of (PhSe) 2 and (PhTe) 2 on the GMP-PNP (a GTP analog) binding in both intracellular (stable to washing procedure) and extracellular (unstable to washing procedure) binding sites. In all binding experiments, nonspecific binding was determined by adding 1000 times nonradioactive ligands to the medium in a parallel assay. Specific binding was considered to be the difference between total and nonspecific binding.

Protein concentration was measured as previously described [21], using bovine serum albumin as the standard.

2.7. Exposure In vivo experiments were performed by treating male adult rats with one intraperitoneal (i.p.) injection of 25 mmol / kg diphenyl diselenide (PhSe) 2 or 3 mmol / kg dyphenyl ditelluride (PhTe) 2 (experimental groups) or vehicle (ethanol) (control group, 1 ml / kg). Diphenyl diselenide at 25 mmol / kg was the highest dose that did not cause body weight losses and did not affect survival of rats. Diphenyl ditelluride at 10 mmol / kg caused the death of 100% of the (PhTe) 2 -treated rats on the first day of experimentation, so we worked with 3 mmol / kg, which still caused the death of 30% of (PhTe) 2 -treated animals. Animals were killed 48 h after the injection and brain synaptic membranes were prepared as described above. Binding assays and adenylate cyclase activity were performed using these brain synaptic membranes.

2.8. Adenylate cyclase activity Enzymatic activity was determined by measuring the amount of cAMP formed during the incubation of membrane preparations (20–40 mg of protein) in a medium (100 ml) containing 20 mM Tris / HCl buffer, pH 7.4, 10 mM MgCl 2 and 0.1 g% bovine serum albumin, as described [1]. Incubations were carried out at 308C and were started by adding ATP (final concentration 1 mM) after 15 min of preincubation of the membrane preparation in the reaction medium. The reaction was stopped after 1 min by boiling the tubes for 5 min. The tubes were centrifuged at 15,8003g for 15 min and the supernatants were used to measure the cAMP content. The cAMP content was measured by radiobinding assay as described previously [42], using [ 3 H]cAMP and protein kinase A from bovine heart as the binding protein.

2.10. Statistical analysis Data were analyzed by one-way analysis of variance (ANOVA) followed by Duncan’s multiple range test and Student’s t-test, when necessary.

3. Results Diphenyl diselenide and diphenyl ditelluride caused a concentration-dependent inhibition of [ 3 H]glutamate binding. However, the effect of diphenyl ditelluride was significantly greater than that of diphenyl diselenide (Fig. 1a), and was significant only at 1000 mM. In a similar way to that observed in vitro, acute administration of (PhSe) 2 or (PhTe) 2 caused a significant reduction of [ 3 H]glutamate binding to brain synaptic membranes (Fig. 2a); however, the maximal inhibitory effect attained with either compound was about 30%. Diphenyl diselenide and diphenyl ditelluride inhibited [ 3 H]MK-801 binding to brain synaptic membranes in vitro. As observed for [ 3 H]glutamate binding, (PhTe) 2 tended to have a more pronounced inhibitory effect, but this was observed only at low concentrations of the organochalcogens (Fig. 1b). Similarly as observed for [ 3 H]glutamate binding, acute treatment with these compounds caused a significant inhibition of about 30% in [ 3 H]MK-801 binding to rat synaptic membranes (Fig. 2b). Taking into account that the toxicity of selenium could be related to the oxidation of thiols of biological importance [4,28,45] and that neuronal effects of diphenyl diselenide and diphenyl ditelluride may occur through a change in the thiol–disulfide balance of glutamatergic receptors, the effect of dithiothreitol (DTT) on [ 3 H]glutamate binding was examined. At 1 mM, DTT, a reducing agent that protects sulphydryl molecules from oxidants, did not reverse the inhibitory action of (PhSe) 2 and (PhTe) 2 on [ 3 H]glutamate binding in vitro (Fig. 3). Total [ 3 H]GMP-PNP binding was inhibited about 40% at 100 mM (PhSe) 2 and (PhTe) 2 in vitro (Fig. 4). Similar results were observed in animals that received acute diphenyl diselenide and diphenyl ditelluride treatment (Table 1). However, the inhibitory effect observed after in vivo administration was slightly greater than that obtained in vitro with 100 mM (PhSe) 2 or (PhTe) 2. In fact, acute exposure to (PhSe) 2 and (PhTe) 2 caused a reduction in total [ 3 H]GMP-PNP binding that corresponded to 50 and 60%, respectively. Table 1 shows that exposure to (PhSe) 2 and (PhTe) 2 in vivo decreased [ 3 H]GMP-PNP stable binding. The stable binding of [ 3 H]GMP-PNP was more

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Fig. 1. Effect of diphenyl diselenide and diphenyl ditelluride in vitro on [ 3 H]glutamate (a) and [ 3 H]MK-801 binding (b). (a) An aliquot of synaptic membrane preparation was incubated with 40 nM [ 3 H]glutamate at 308C for 30 min in the presence of four different concentrations of diphenyl diselenide (s) or diphenyl ditelluride (j). Control binding (pmol / mg of protein) was 3.560.8. (b) An aliquot of synaptic membrane preparation was incubated with 4 nM [ 3 H]MK-801 at 378C for 60 min in the presence of four different concentrations of diphenyl diselenide (s) and diphenyl ditelluride (j). Control binding (pmol / mg of protein) was 1.360.3. Data are mean6S.E.M. for five and seven separate determinations performed in triplicate for [ 3 H]glutamate and [ 3 H]MK-801 binding, respectively. (*) Significantly different from control at P , 0.05.

Fig. 2. Effect of diphenyl diselenide and diphenyl ditelluride in vivo on [ 3 H]glutamate (a) and [ 3 H]MK-801 binding (b). (a) An aliquot of synaptic membrane preparation from control animals, 3 mmol / kg diphenyl ditelluride and 25 mmol / kg diphenyl diselenide treated animals was incubated with 40 nM [ 3 H]glutamate at 308C for 30 min. (b) An aliquot of synaptic membrane preparation from control animals, 3 mmol / kg diphenyl ditelluride and 25 mmol / kg diphenyl diselenide treated animals was incubated with 4 nM [ 3 H]MK-801 at 378C for 60 min. Control binding (pmol / mg of protein) was similar to that in in vitro assays. Data are mean6S.E.M. for 11 separate determinations performed in triplicate for [ 3 H]glutamate and [ 3 H]MK-801 binding. (*) Significantly different from control at P , 0.05.

4. Discussion

affected by (PhSe) 2 than (PhTe) 2 . In fact, diphenyl diselenide reduced the stable binding of [ 3 H]GMP-PNP to 26% of the control value, while diphenyl ditelluride inhibited [ 3 H]GMP-PNP binding to 68% of the control value (Table 1). The unstable binding of [ 3 H]GMP-PNP was decreased about 30 and 50%, respectively, after exposure to (PhSe) 2 and (PhTe) 2 in vivo. Fig. 5 shows that GMP-PNP significantly stimulated the adenylate cyclase activity in control animals. Treatment of rats with (PhSe) 2 and (PhTe) 2 increased the basal activity of this enzyme; however, GMP-PNP caused a marked reduction of the stimulation caused by (PhSe) 2 and (PhTe) 2 treatment.

The present results show that diphenyl diselenide and diphenyl ditelluride inhibit the [ 3 H]glutamate, [ 3 H]MK801 and unstable [ 3 H]GMP-PNP binding to rat brain synaptic membrane preparations after both in vitro and in vivo exposure. These parameters are important indicators of glutamatergic system functionality. Observations suggest that organotellurides are more reactive than the structurally related organoselenium compounds, essentially due to their higher electronegativity in relation to carbon, associated with a larger atomic volume [9]. Results from experiments in vivo are in agreement with these observations. The dose of diphenyl diselenide used was about eight times higher than that of diphenyl ditelluride and these doses caused similar reductions in

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Fig. 3. Effect of dithiothreitol (DTT) on [ 3 H]glutamate binding in vitro. An aliquot of synaptic membrane preparation was incubated with 40 nM [ 3 H]glutamate at 308C for 30 min in the presence of 100 mM diphenyl diselenide or diphenyl ditelluride and 1 mM DTT, added simultaneously to the medium assay. Data are mean6S.E.M. for four separate determinations performed in triplicate. (*) Significantly different from control at P , 0.05.

Fig. 4. Effect of diphenyl diselenide and diphenyl ditelluride on total binding of [ 3 H]GMP-PNP, in vitro. An aliquot of synaptic membrane preparation was incubated with 800 nM [ 3 H]GMP-PNP at 308C for 60 min in the presence of four different concentrations of diphenyl diselenide (s) and diphenyl ditelluride (j). Data are mean6S.E.M. for three separate determinations performed in triplicate. (*) Significantly different from control at P , 0.05.

Table 1 Effect of a single dose of diphenyl diselenide and diphenyl ditelluride on [ 3 H]GMP-PNP binding to brain synaptic membrane preparations a Binding

Control

(PhSe) 2

(PhTe) 2

Total Unstable Stable

23.063.2 14.062.1 10.061.7

12.063.4* 9.76 2.1 2.660.4*

14.662.4* 7.061.5* 6.860.4*

a

Data are mean6S.E.M. for five separate determinations performed in triplicate for [ 3 H]GMP-PNP binding (pmol / mg protein). *Significantly different from respective control (animals treated with vehicle) (P , 0.05). For details, see the Materials and methods section.

Fig. 5. Effect of diphenyl diselenide and diphenyl ditelluride on adenylate cyclase activity, in vivo. An aliquot of synaptic membrane preparation from control animals, 3 mmol / kg diphenyl ditelluride and 25 mmol / kg diphenyl diselenide treated animals was incubated at 308C. Incubations were started by adding ATP (final concentration 1 mM) to the reaction medium after 15 min of preincubation of the membrane preparation. Data are mean6S.E.M. for six separate determinations performed in triplicate. (*) Significantly different from control at P , 0.05.

[ 3 H]MK-801, [ 3 H]glutamate and [ 3 H]GMP-PNP binding, suggesting that (PhTe) 2 is more toxic than (PhSe) 2 when the dose injected is considered. However, in vitro the reactivity towards biological systems does not always follow this rule, since only [ 3 H]glutamate binding was more sensitive to diphenyl ditelluride than to diphenyl diselenide. [ 3 H]MK-801 and total [ 3 H]GMP-PNP binding were similarly affected by both compounds. Thus, the in vitro toxicological properties of organochalcogens varies depending on the parameters evaluated. The mechanism(s) underlining the neurotoxicology of organochalcogens is still poorly known, but tenta-

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tively involves the oxidation of essential thiols in target proteins [17,22]. The absence of a protective role of DTT against the inhibitory effects of (PhSe) 2 and (PhTe) 2 on [ 3 H]glutamate binding to synaptic plasma membranes suggests that the toxicological properties of these organochalcogens are not related to the oxidation of –SH groups on glutamate receptors. Alternatively, (PhSe) 2 and (PhTe) 2 could oxidize cysteinyl residues located in a hydrophobic site of the receptor not accessible to the more hydrophilic DTT. Inhibition of endogenous agonist binding to the NMDA receptor may be an important factor in the neurotoxic effects of these compounds. This receptor is apparently involved in both physiological processes such as learning and plasticity [8,26] and pathological situations [20,26,30]. An inhibitory effect on [ 3 H]glutamate and [ 3 H]MK-801 binding may indicate that the toxicological properties of organochalcogens may be related, at least in part, to the inhibition of physiological excitatory neurotransmitter systems. Recent evidence has shown that fine tuning of glutamatergic system functioning is essential for proper brain functioning. In fact, an unbalanced increase or decrease in glutamatergic systems is highly neurotoxic [26]. These results suggest that organochalcogens affect, in a rather complex way, the glutamatergic system after in vivo acute exposure in rats. The two organochalcogens tested inhibited the binding of ligands to glutamatergic receptors and the binding of [ 3 H]GMP-PNP, presumably to G-proteins that may be linked to these receptors. Adenylate cyclase activity can be modulated by the activation of a number of neurotransmitter receptors, for example GABAergic, cholinergic, adrenergic or glutamatergic, which either stimulate or inhibit the enzyme via activation of the heterotrimeric G-proteins G s or G i , respectively [24]. Considering that the binding of GTP modulates many effectors, such as adenylate cyclase, it is possible to correlate the effects on binding of guanine derivatives on G-proteins and changes in adenylate cyclase activity after exposure to (PhSe) 2 and (PhTe) 2 . Experimental results in vivo demonstrated that diphenyl diselenide and diphenyl ditelluride drastically reduced the [ 3 H]GMP-PNP binding to G-proteins and the response of adenylate cyclase activity to GMP-PNP; additionally, diphenyl diselenide and diphenyl ditelluride also increased the basal adenylate cyclase activity, indicating a direct effect on adenylate cyclase. A significant amount of data has implicated cAMP in several physiological (spatial memory and synaptic plasticity) [49] as well as pathological processes (drug tolerance, dependence and neurodegenerative diseases) [2,3,10,37]. These results suggest that the toxic effects of organochalcogens could result from action at different levels of neural signal transduction pathways, possibly involving other neurotransmitters besides the glutamatergic system.

Acknowledgements Supported by CNPq (PRONEX grant 41960904-366\96 to D. Souza).

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