Preferences help
enabled [disable] Abstract
Number of results
2009 | 56 | 1 | 125-134
Article title

Diphenyl diselenide and diphenyl ditelluride increase the latency for 4-aminopyridine-induced chemical seizure and prevent death in mice

Title variants
Languages of publication
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 4-aminopyridine 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 Ca2+ 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.
Physical description
  • Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Brasil
  • Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Brasil
  • Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Brasil
  • Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Brasil
  • Aarts MM, Tymianski M (2003) Novel treatment of excitotoxicity: targeted disruption of intracellular signaling from glutamate receptors. Biochem Pharmacol 66: 877-886.
  • Albeck A, Weitman H, Sredni B, Albeck M (1998) Tellurium compounds: selective inhibition of cysteine proteases and model reaction with thiols. Inorg Chem 37: 1704-1712.
  • Alexander GM, Godwin DW (2006) Metabotropic glutamate receptors as a strategic target for the treatment of epilepsy. Epilepsy Res 71: 1-22.
  • Andersson CM, Brattsand R, Hallberg A, Engman L, Persson J, Moldeus P, Cotgreave I (1994) Diaryl tellurides as inhibitors of lipid peroxidation in biological and chemical systems. Free Radic Res 20: 401-410.
  • Andersson CM, Hallberg A, Brattsand R, Cotgreave IA, Engman L, Persson J (1993) Glutathione peroxidase-like activity of diaryl tellurides. Bioorg Med Chem Lett 3: 2553-2558.
  • Arriba SG, Krügel U, Regenthal R, Vissiennon Z, Verdaguer E, Lewerenz A, García-Jordá E, Pallas M, Camins A, Münch G, Nieber K, Allgaier C (2006) Carbonyl stress and NMDA receptor activation contribute to methylglyoxal neurotoxicity. Free Radic Biol Med 40: 779-790.
  • Ashrafi MR, Shabanian R, Abbaskhanian A, Nasirian A, Ghofrani M, Mohammadi M, Zamani GR, Kayhanidoost Z, Ebrahimi S, Pourpak Z (2007a) Selenium and intractable epilepsy: is there any correlation? Pediatr Neurol 36: 25-29.
  • Ashrafi MR, Shams S, Nouri M, Mohseni M, Shabanian R, Yekaninejad MS, Chegini N, Khodadad A, Safaralizadeh R (2007b) A Probable causative factor for an old problem: selenium and glutathione peroxidase appear to play important roles in epilepsy pathogenesis. Epilepsia 48: 1750-1755.
  • Beck MA, Nelson HK, Shi Q, Dael PV, Schiffrin EJ, Blum S, Barclay D, Levander OA (2001) Selenium deficiency increases the pathology of an influenza virus infection. FASEB J 15: 1481-1483.
  • Behne D, Hilmert H, Scheid S, Gessner H, Elger W (1988) Evidence for specific selenium target tissues and new biologically important selenoproteins. Biochim Biophys Acta 966: 12-21.
  • Behne D, Kyriakopoulos A (2001) Mammalian selenium-containing proteins. Annu Rev Nutr 21: 453-473.
  • Behne D, Weiler H, Kyriakopoulos A (1996) Effects of selenium deficiency on testicular morphology and function in rats. J Reprod Fertil 106: 291-297.
  • Bradford HF (1995) Glutamate, GABA and epilepsy. Prog Neurobiol 47: 477-511.
  • Brown MR, Cohen HJ, Lyons JM, Curtis TW, Thunberg B, Cochran WJ, Klish WJ (1986) Proximal muscle weakness and selenium deficiency associated with long term parenteral nutrition. Am J Clin Nutr 43: 549-554.
  • Burger M, Fachinetto R, Calegari L, Paixão MW, Braga AL, Rocha JBT (2004) Effects of age on reserpine-induced orofacial dyskinesia and possible protection of diphenyl diselenide. Brain Res Bull 64: 339-345.
  • Burger M, Fachinetto R, Wagner C, Perottoni J, Pereira RP, Zeni G, Rocha JBT (2006) Effects of diphenyl-diselenide on orofacial dyskinesia model in rats. Brain Res Bull 70: 165-170.
  • Cho J, Lee H (2004) Wogonin inhibits excitotoxic and oxidative neuronal damage in primary cultured rat cortical cells. Eur J Pharmacol 485: 105-110.
  • Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623-634.
  • Clemens JA, Penetta JA (1995) Free radicals in central nervous systems diseases. In: Immunopharmacology of free radical species. Blake D, Winyard PG, eds, pp 73-83. Academic Press, San Diego.
  • Commandeur JN, Rooseboom M, Vermeulen NP (2001) Chemistry and biological activity of novel selenium-containing compounds. Adv Exp Med Biol 500: 105-112.
  • Cowan LD (2002) The epidemiology of the epilepsies in children. Ment Retard Dev Disabil Res Rev 8: 171-181.
  • Davis FA, Stefoski D, Schauf CL (1990) Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol 27: 186-192.
  • Engman L, Persson J, Vessman K, Ekstrom M, Berglund M, Andersson CM (1995) Organotellurium compounds as efficient retards of lipid peroxidation in methanol. Free Rad Biol Med 19: 441-452.
  • Engman L, Stern D, Cotgreave IA, Andersson CM (1992) Thiol peroxidase activity of diaryl ditellurides as determined by a HNMR method. J Am Chem Soc 114: 9737-9743.
  • Engman L, Stern D, Pelcman M, Andersson CM (1994) Thiol peroxidase activity of diorganyl tellurides. M J Org Chem 59: 1973-1979.
  • Fantuzzi G, Reed DA, Dinarello CA (1999) IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor. J Clin Invest 104: 761-767.
  • Fragoso-Veloz J, Massieu L, Alvarado R, Tapia R (1990) Seizures and wet-dog shakes induced by 4-aminopyridine, and their potentiation by nifedipine. Eur J Pharmacol 178: 275-284.
  • Fragoso-Veloz J, Tapia R (1992) NMDA receptor antagonists protect against seizures and wet-dog shakes induced by 4-aminopyridine. Eur J Pharmacol 221: 275-280.
  • Ganther HE (2001) Selenium metabolism and mechanisms of cancer prevention. Adv Exp Med Biol 492: 119-130.
  • Halter JA, Blight AR, Donovan WH, Calvillo O (2000) Intrathecal administration of 4-aminopyridine in chronic spinal injured patients. Spinal Cord 38: 728-732.
  • Hauser WA, Hesdorffer DC (1990) Epilepsy: frequency, causes and consequences, pp 1-51. Demos, New York.
  • Hayes KC, Potter PJ, Wolfe DL, Hsieh JTC, Delaney GA, Blight AR (1994) 4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. J Neurotrauma 11: 433-446.
  • Jensen JM, Shi R (2003) Effects of 4-aminopyridine on stretched mammalian spinal cord: the role of potassium channels in axonal conduction. J Neurophysiol 90: 2334-2340.
  • Kamikawa H, Hori T, Nakane H, Aou S, Tashiro N (1998) IL-1β increases norepinephrine level in rat frontal cortex: involvement of prostanoids, NO, and glutamate. Am J Physiol 275: R803-R810.
  • Kaneko K, Itoh K, Berliner LJ, Miyasaka K, Fujii DH (2002) Consequences of nitric oxide generation in epileptic-seizure rodent models as studied by in vivo EPR. Magn Reson Med 48: 1051-1056.
  • Klotz L, Sies H (2003) Defenses against peroxynitrite: selenocompounds and flavonoids. Toxicol Lett 140: 125-132.
  • Klotz LO, Kroncke KD, Buchczyk DP, Sies H (2003) Role of copper, zinc, selenium and tellurium in the cellular defense against oxidative and nitrosative stress. J Nutr 133: 1448S-1451S.
  • Kyriakopoulos A, Behne D (2002) Selenium-containing proteins in mammals and other forms of life. Rev Physiol Biochem Pharmacol 145: 1-46.
  • Liang LP, Beaudoin ME, Fritz MJ, Fulton R, Patel M (2007) Kainate-induced seizures, oxidative stress and neuronal loss in aging rats. Neuroscience 147: 1114-1118.
  • Liang LP, Ho YS, Patel M (2000) Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 101: 563-570.
  • Lothman EW, Bertram EH, Stringer JL (1991) Functional anatomy of hippocampal seizures. Prog Neurobiol 37: 1-82.
  • Lundh H, Nilsson O, Rosen I (1979) Effects of 4-aminopyridine in myasthenia gravis. J Neurol Neurosurg Psychiatry 42: 171-175.
  • Maciel EN, Flores EM, Rocha JBT, Folmer V (2003) Comparative deposition of diphenyl diselenide in liver, kidney, and brain of mice. Bull Environ Contam Toxicol 70: 470-476.
  • Maggio R, Fumagalli F, Donati E, Barbier P, Racagni G, Corsini GU, Riva M (1995) Inhibition of nitric oxide synthase dramatically potentates seizures induced by kainic acid and pilocarpine in rats. Brain Res 679: 184-187.
  • McBride JM, Smith DT, Byrn SR, Borgens RB, Shi R (2006) Dose responses of three 4-aminopyridine derivatives on axonal conduction in spinal cord trauma. Eur J Pharm Sci 27: 237-242.
  • McEvoy KM, Windebank AJ, Daube NJR, Low PA (1989) 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 321: 1567-1571.
  • Mcnamara JO (1994) Cellular and molecular basis of epilepsy. J Neurosci 14: 3413-3425.
  • Mcnamara JO (1999) Emerging insights into the genesis of epilepsy. Nature 399: A15-A22.
  • Meldrum B (1995) Neurotransmission in epilepsy. Epilepsy 36: S30-S35.
  • Meotti FC, Borges VC, Zeni G, Rocha JBT, Nogueira CW (2003) Potential renal and hepatic toxicity of diphenyl diselenide, diphenyl ditelluride and ebselen for rats and mice. Toxicol Lett 143: 9-16.
  • Meotti FC, Stangherlin EC, Zeni G, Nogueira CW, Rocha JBT (2004) Protective role of aryl and alkyl diselenides on lipid peroxidation. Environ Res 94: 276-282.
  • Minami M, Kuraishi Y, Satoh M (1991) Effects of kainic acid on messenger RNA levels of IL-1β, IL-6, TNFα, and Lif in the rat brain. Biochem Biophys Res Commun 176: 593-598.
  • Molgó J, Lemeignan M, Peradejordi F, Lechat P (1985) Effects presynaptiques des aminopyridines a la juntion neuromusculaire de vertébrés. J Pharmacol 16: 109-144.
  • Montiel T, Camacho A, Estrada-Sánchez AM, Massieu L (2005) Differential effects of the substrate inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC) and the non-substrate inhibitor dl-threo-β-benzyloxyaspartate (dl-TBOA) of glutamate transporters on neuronal damage and extracellular amino acid levels in rat brain in vivo. Neuroscience 133: 667-678.
  • Morales-Villagrán A, Tapia R (1996) Preferential stimulation of glutamate release by 4-aminopyridine in rat striatum in vivo. Neurochem Int 28: 35-40.
  • Morales-Villagrán A, Ureña-Guerrero M, Tapia R (1996) Protection by NMDA receptor antagonists against seizures induced by intracerebral administration of 4-aminopyridine. Eur J Pharmacol 305: 87-93.
  • Moretto MB, Rossato JI, Nogueira CW, Zeni G, Rocha JBT (2003) Voltage-dependent ebselen and diorganochalcogenides inhibition of 45Ca2+influx into brain synaptosomes. J Biochem Mol Toxicol 17: 154-160.
  • Mueller-Burke D, Koehler RC, Martin LJ (2008) Rapid NMDA receptor phosphorylation and oxidative stress precede striatal neurodegeneration after hypoxic ischemia in newborn piglets and are attenuated with hypothermia. Int J Dev Neurosci 26: 67-76.
  • Neve J (1996) Selenium as a risk factor for cardiovascular diseases. J Cardiovasc Risk 3: 42-47.
  • Nogueira CW, Meotti FC, Curte E, Pilissão C, Zeni G, Rocha JBT (2003a) Investigations into the potential neurotoxicity induced by diselenides in mice and rats. Toxicology 183: 29-37.
  • Nogueira CW, Quinhones EB, Jung EAC, Zeni G, Rocha JBT (2003b) Evidence for anti-inflammatory and antinociceptive activity of diphenyl diselenide. Inflamm Res 52: 56-63.
  • Nogueira CW, Rotta LN, Perry ML, Souza DO, Rocha JBT (2001) Diphenyl diselenide and diphenyl ditelluride affect the rat glutamatergic system in vitro and in vivo. Brain Res 906: 157-163.
  • Nogueira CW, Zeni G, Rocha JBT (2004) Organoselenium and organotellurium compounds: toxicology and pharmacology. Chem Rev 104: 6255-6285.
  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95: 351-358.
  • Oztas B, Kilic S, Dural E, Ispir T (2001) Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures. J Neurosci Res 66: 674-678.
  • Paulmier C (1986) Selenoorganic functional groups. Selenium reagents and intermediates in organic synthesis, pp 25-51. Pergamon Press, Oxford.
  • Peña F, Tapia R (1999) Relationships among seizures, extracellular amino acid changes, and neurodegeneration induced by 4-aminopyridine in rat hippocampus: a microdialysis and electroencephalographic study. J Neurochem 72: 2006-2014.
  • Persike DS, Cunha RLOR, Juliano L, Silva IR, Rosim FE, Vignoli T, Dona F, Cavalheiro EA, Fernandes MJS (2008) Protective effect of the organotelluroxetane RF-07 in pilocarpine-induced status epilepticus. Neurobiol Dis 31: 120-126.
  • Petragnani N (1994) Tellurium in Organic Synthesis, pp 9-88. Academic Press, London.
  • Posser T, Franco JL, Santos DA, Rigon AP, Farina M, Dafré AL, Rocha JBT, Leal RB (2008) Diphenyl diselenide confers neuroprotection against hydrogen peroxide toxicity in hippocampal slices. Brain Res 1199: 138-147.
  • Prigol M, Wilhelm EA, Schneider CC, Rocha JBT, Nogueira CW, Zeni G (2007) Involvement of oxidative stress in seizures induced by diphenyl diselenide in rat pups. Brain Res 1147: 226-232.
  • Ramaekers VT, Calomme M, Vanden Berghe D, Makropoulos W (1994) Selenium deficiency triggering intractable seizures. Neuropediatrics 25: 217-223.
  • Ravizza T, Lucas SM, Balosso S, Bernardino L, Ku G, Noé F, Malva J, Randle JC, Allan S, Vezzani A (2006) Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47: 1160-1168.
  • Rayman MP (2000) The importance of selenium to human health. Lancet 356: 233-241.
  • Rogawski MA, Barker JL (1983) Effects of 4-aminopyridine on calcium action potentials and calcium current under voltage clamp in spinal neurons. Brain Res 280: 180-185.
  • Rosa RM, Flores DG, Appelt HR, Braga AL, Henriques JA, Roesler R (2003) Facilitation of long-term object recognition memory by pre-training administration of diphenyl diselenide in mice. Neurosci Lett 341: 217-220.
  • Rossato JI, Ketzer LA, Centurião FB, Silva SJN, Lüdtke DS, Zeni G, Braga AL, Rubin MA, Rocha JBT (2002a) Antioxidant properties of new chalcogenides against lipid peroxidation in rat brain. Neurochem Res 27: 297-303.
  • Rossato JI, Zeni G, Mello CF, Rubin MA, Rocha JBT (2002b) Ebselen blocks the quinolinic acid-induced production of thiobarbituric acid reactive species but does not prevent the behavioural alterations produced by intra-striatal quinolinic acid administration in the rat. Neurosci Lett 318: 137-140.
  • Rubin JJ, Willmore LJ (1980) Prevention of iron-induced epileptiform discharges in rats by treatment with antiperoxidants. Exp Neurol 67: 472-480.
  • Said SJ, Pakbaz H, Berisha HI, Raza S (2000) NMDA receptor activation: critical role in oxidant tissue injury. Free Rad Biol Med 28: 1300-1302.
  • Santos LFL, Freitas RLM, Xavier SML, Saldanha GB, Freitas RM (2008) Neuroprotective actions of vitamin C related to decreased lipid peroxidation and increased catalase activity in adult rats after pilocarpine-induced seizures. Pharmacol Biochem Behav 89: 1-5.
  • Savaskan NE, Bräuer AU, Kühbacher M, Eyüpoglu IY, Kyriakopoulos A, Ninnemann O, Behne D, Nitsch R (2002) Selenium deficiency increases susceptibility to glutamate-induced excitotoxicity. FASEB J 17: 112-114.
  • Savegnago L, Pinto LG, Jesse CR, Alves D, Rocha JBT, Nogueira CW, Zeni G (2007) Antinociceptive properties of diphenyl diselenide: Evidences for the mechanism of action. Eur J Pharmacol 555: 129-138.
  • Schafer EWJ, Brunton RB, Cunningham DJ (1973) A summary of the acute toxicity of 4-aminopyridine to birds and mammals. Toxicol Appl Pharmacol 26: 532-538.
  • Schomburg L, Schweizer U, Holtmann B, Flohe L, Sendtner M, Kohrle J (2003) Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem J 370: 397-402.
  • Sellin LC (1981) The action of batulinum toxin at the neuromuscular junction. Med Biol 59: 11-20.
  • Spallholz JE, Boylan LM, Larsen HS (1990) Advances in understanding selenium's role in the immune system. Ann NY Acad Sci 587: 123-139.
  • Spyker DA, Lynch C, Shabanowitz J, Sinn JA (1980) Poisoning with 4-aminopyridine: report of three cases. Clin Toxicol 16: 487-497.
  • Stafstrom CE, Moshe SL, Swann JW, Nehlig A, Jacobs MP, Schwartzkroin PA (2006) Models of pediatric epilepsies: strategies and opportunities. Epilepsia 47: 1407-1414.
  • Tapia R, Medina-Ceja L, Pena F (1999) On the relationship between extracellular glutamate, hyperexcitation and neurodegeneration, in vivo. Neurochem Int 34: 23-31.
  • Thesleff S (1980) Aminopyridines and synaptic transmission. Neuroscience 5: 1413-1419.
  • Tinggi U (2003) Essentiality and toxicity of selenium and its status in Australia: a review. Toxicol Lett 137: 103-110.
  • Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoniet MG (1999) Interleukin-1β immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci 19: 5054-5065.
  • Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MG, Sperk G, Andell-Jonsson S, Lundkvist J, Iverfeldt K, Bartfaiet T (2000) Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci USA 97: 11534-11539.
  • Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M (2003) Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23: 8692-8700.
  • Weber GF, Maertens P, Meng XZ, Pippenger CE (1991) Glutathione peroxidase deficiency and childhood seizures. Lancet 337: 1443-1444.
  • Widy-Tyszkiewicz E, Piechal A, Gajkowska B, Smialek M (2002) Tellurium-induced cognitive deficits in rats are related to neuropathological changes in the central nervous system. Toxicol Lett 131: 203-214.
  • Willmore IJ, Rubin JJ (1981) Antiperoxidant pretreatment and iron-induced epileptiform discharges in the rat: EEG and histopathologic studies. Neurology 31: 63-69.
  • Wong JYF, Ross SA, McColl C, Massalas JS, Powney E, Finkelstein DI, Clark M, Horne MK, Berkovic SF, Drago J (2002) Proconvulsant-induced seizures in α4 nicotinic acetylcholine receptor subunit knockout mice. Neuropharmacology 43: 55-64.
  • Xin Y, Xiao-Guang S, Hong S, Yong-Nan L, Jun Y, Yan-Chun D, Yuan-Gui H (2008) Activation of cerebral peroxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus. Brain Res 1200: 146-158.
  • Yamaguchi S, Rogawski MA (1992) Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice. Epilepsy Res 11: 9-16.
  • Ye ZC, Sontheimer H (1996) Cytokine modulation of glial glutamate-uptake: a possible involvement of nitric oxide. Neuroreport 7: 2181-2185.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.