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Quinolinic Acid-induced Seizures Stimulate Glutamate Uptake into Synaptic Vesicles from Rat Brain: Effects Prevented by Guanine-based Purines

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Abstract

Glutamate uptake into synaptic vesicles is a vital step for glutamatergic neurotransmission. Quinolinic acid (QA) is an endogenous glutamate analog that may be involved in the etiology of epilepsy and is related to disturbances on glutamate release and uptake. Guanine-based purines (GBPs) guanosine 5′-monophosphate (GMP and guanosine) have been shown to exert anticonvulsant effects against QA-induced seizures. The aims of this study were to investigate the effects of in vivo administration of several convulsant agents on glutamate uptake into synaptic vesicles and investigate the role of MK-801, guanosine or GMP (anticonvulsants) on glutamate uptake into synaptic vesicles from rats presenting QA-induced seizures. Animals were treated with vehicle (saline 0.9%), QA 239.2 nmoles, kainate 30 mg/kg, picrotoxin 6 mg/kg, PTZ (pentylenetetrazole) 60 mg/kg, caffeine 150 mg/kg or MES (maximal transcorneal electroshock) 80 mA. All convulsant agents induced seizures in 80–100% of animals, but only QA stimulated glutamate uptake into synaptic vesicle. Guanosine or GMP prevented seizures induced by QA (up to 52% of protection), an effect similar to the NMDA antagonist MK-801 (60% of protection). Both GBPs and MK-801 prevented QA-induced glutamate uptake stimulation. This study provided additional evidence on the role of QA and GBPs on glutamatergic system in rat brain, and point to new perspectives on seizures treatment.

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References

  1. Ozawa S, Kamiya H, Tsukuki K (1998) Glutamate receptors in the mammalian central nervous system. Prog Neurobiol 54:581–618

    Article  PubMed  CAS  Google Scholar 

  2. Maragakis NJ, Rothstein JD (2004) Glutamate transporters: animal models to neurologic disease. Neurobiol Dis 15:461–473

    Article  PubMed  CAS  Google Scholar 

  3. Özkan ED, Ueda T (1998) Glutamate transport and storage in synaptic vesicles. Jpn J Pharmacol 77:1–10

    Article  PubMed  Google Scholar 

  4. Bellocchio EE, Reimer RJ, Fremeau RT Jr, Edwards RH (2000) Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289:957–960

    Article  PubMed  CAS  Google Scholar 

  5. Naito S, Ueda T (1985) Characterization of glutamate uptake into synaptic vesicles. J Neurochem 44:99–109

    Article  PubMed  CAS  Google Scholar 

  6. Bradford HF (1995) Glutamate, GABA and epilepsy. Prog Neurobiol 47:477–511

    Article  PubMed  CAS  Google Scholar 

  7. Lewis SM, Lee FS, Todorova M et al (1997) Synaptic vesicle glutamate uptake in epileptic (EL) mice. Neurochem Int 31:581–585

    Article  PubMed  CAS  Google Scholar 

  8. Connick JH, Stone TW (1988) Quinolinic acid effects on amino acid release from the rat cerebral cortex in vitro and in vivo. Br J Pharmacol 93:868–876

    PubMed  CAS  Google Scholar 

  9. Stone TW (2001) Kynurenic acid antagonists and kynurenine pathway inhibitors. Exp Opin Invest Drugs 10:633–645

    Article  CAS  Google Scholar 

  10. Tavares RG, Tasca CI, Santos CE et al (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 40:621–627

    Article  PubMed  CAS  Google Scholar 

  11. Tavares RG, Schmidt AP, Abud J et al (2005) In vivo quinolinic acid increases synaptosomal glutamate release in rats: reversal by guanosine. Neurochem Res 30:439–444

    Article  PubMed  CAS  Google Scholar 

  12. Nakano K, Takahashi S, Mizobuchi M et al (1993) High levels of quinolinic acid in brain of epilepsy-prone E1 mice. Brain Res 619:195–198

    Article  PubMed  CAS  Google Scholar 

  13. Rathbone MP, Middlemiss PJ, Gysbergs JW et al (1999) Trophic effects of purines in neurons and glial cells. Prog Neurobiol 59:663–690

    Article  PubMed  CAS  Google Scholar 

  14. Baron BM, Dudley MW, McCarty DR et al (1989) Guanine nucleotides are competitive inhibitors of N-Methyl-D-Aspartate at its receptor site both in vitro and in vivo. J Pharmacol Exp Ther 250:162–169

    PubMed  CAS  Google Scholar 

  15. Paz MM, Ramos M, Ramirez G et al (1994) Differential effects of guanine nucleotides on kainic acid binding and on adenylate cyclase activity in chick optic tectum. FEBS Lett 355:205–208

    Article  PubMed  CAS  Google Scholar 

  16. Frizzo MES, Lara DR, Dahm KCS et al (2001) Activation of glutamate uptake by guanosine in primary astrocyte cultures. NeuroReport 12:879–881

    Article  PubMed  CAS  Google Scholar 

  17. Frizzo MES, Lara DR, Prokopiuk AS et al (2002) Guanosine enhances glutamate uptake in brain cortical slices at normal and excitotoxic conditions. Cell Mol Neurobiol 22:353–363

    Article  PubMed  CAS  Google Scholar 

  18. Frizzo MES, Soares FA, Dall’Onder LP et al (2003) Extracellular conversion of guanine-based purines to guanosine specifically enhances astrocyte glutamate uptake. Brain Res 972:84–89

    Article  PubMed  CAS  Google Scholar 

  19. Lara DR, Schmidt AP, Frizzo MES et al (2001) Effect of orally administered guanosine on seizures and death induced by glutamatergic agents. Brain Res 912:176–180

    Article  PubMed  CAS  Google Scholar 

  20. Schmidt AP, Lara DR, Maraschin JF et al (2000) Guanosine and GMP prevent seizures induced by quinolinic acid in mice. Brain Res 864:40–43

    Article  PubMed  CAS  Google Scholar 

  21. Schmidt AP, Ávila TT, Souza DO (2005) Intracerebroventricular guanine-based purines protect against seizures induced by quinolinic acid in mice. Neurochem Res 30:69–73

    Article  PubMed  CAS  Google Scholar 

  22. Soares FA, Schmidt AP, Farina M et al (2004) Anticonvulsant effect of GMP depends on its conversion to guanosine. Brain Res 1005:182–186

    Article  PubMed  CAS  Google Scholar 

  23. Vinadé ER, Schmidt AP, Frizzo MES et al (2003) Chronically administered guanosine is anticonvulsant, amnesic and anxiolytic in mice. Brain Res 977:97–102

    Article  PubMed  CAS  Google Scholar 

  24. Vinadé ER, Schmidt AP, Frizzo MES et al (2005) Effects of chronic administered guanosine on behavioral parameters and brain glutamate uptake in rats. J Neurosci Res 79:248–253

    Article  PubMed  CAS  Google Scholar 

  25. Saute JA, da Silveira LE, Soares FA et al (2006) Amnesic effect of GMP depends on its conversion to guanosine. Neurobiol Learn Mem 85:206–212

    Article  PubMed  CAS  Google Scholar 

  26. Vinade ER, Izquierdo I, Lara DR et al (2004) Oral administration of guanosine impairs inhibitory avoidance performance in rats and mice. Neurobiol Learn Mem 81:137–143

    Article  PubMed  CAS  Google Scholar 

  27. Lapin IP (1978) Stimulant and convulsant effects of kynurenines injected into brain ventricles in mice. J Neural Transm 42:37–43

    Article  PubMed  CAS  Google Scholar 

  28. Bonan CD, Walz R, Pereira GS et al (2000) Changes in synaptosomal ectonucleotidase activities in two rat models of temporal lobe epilepsy. Epilepsy Res 39:229–238

    Article  PubMed  CAS  Google Scholar 

  29. Bettler B, Kaupmann K, Mosbacher J et al (2004) Molecular structure and physiological functions of GABA(B) receptors. Physiol Rev 84:835–867

    Article  PubMed  CAS  Google Scholar 

  30. Millan MH, Obrenovitch TP, Sarna GS et al (1991) Changes in rat brain extracellular glutamate concentration during seizures induced by systemic picrotoxin or focal bicuculline injection: an in vivo dialysis study with on-line enzymatic detection. Epilepsy Res 9:86–91

    Article  PubMed  CAS  Google Scholar 

  31. Bruno AN, Oses JP, Bonan CD et al (2002) Increase of nucleotidase activities in rat blood serum after a single convulsive injection of pentylenetetrazol. Neurosci Res 43:283–288

    Article  PubMed  CAS  Google Scholar 

  32. Koryntova H, Kubova H, Tutka P et al (2002) Changes of cortical epileptic afterdischarges under the influence of convulsant drugs. Brain Res Bull 58:49–54

    Article  PubMed  CAS  Google Scholar 

  33. Wlaz P, Potschka H, Loscher W (1998) Frontal versus transcorneal stimulation to induce maximal electroshock seizures or kindling in mice and rats. Epilepsy Res 30:219–229

    Article  PubMed  CAS  Google Scholar 

  34. Fykse EM, Fonnum F (1988) Uptake of gamma-aminobutyric acid by a synaptic vesicle fraction isolated from rat brain. J Neurochem 50:1237–1242

    Article  PubMed  CAS  Google Scholar 

  35. Tavares RG, Tasca CI, Santos CE et al (2000) Quinolinic acid inhibits glutamate uptake into synaptic vesicles from rat brain. NeuroReport 11:249–253

    Article  PubMed  CAS  Google Scholar 

  36. Wolosker H, Souza DO, de Meis L (1996) Regulation of glutamate transport into synaptic vesicles by chloride and proton gradient. J Biol Chem 271:11726–11731

    Article  PubMed  CAS  Google Scholar 

  37. Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  38. Obrenovitch TP, Urenjak J, Zilkha E (1996) Evidence disputing the link between seizure activity and high extracellular glutamate. J Neurochem 66:2446–2454

    Article  PubMed  CAS  Google Scholar 

  39. Slevin JT, Ferrara LP (1985) Lack of effect of entorhinal kindling on L-[3H]glutamic acid presynaptic uptake and postsynaptic binding in hippocampus. Exp Neurol 89:48–58

    Article  PubMed  CAS  Google Scholar 

  40. Yudkoff M, Daikhin Y, Nissim I et al (2003) Metabolism of brain amino acids following pentylenetetrazole treatment. Epilepsy Res 53:151–162

    Article  PubMed  CAS  Google Scholar 

  41. Dalia A, Uretsky NJ, Wallace LJ (1998) Dopaminergic agonists administered into the nucleus accumbens: effects on extracellular glutamate and on locomotor activity. Brain Res 788:111–117

    Article  PubMed  CAS  Google Scholar 

  42. Bole DG, Hirata K, Ueda T (2002) Prolonged depolarization of rat cerebral synaptosomes leads to an increase in vesicular glutamate content. Neurosci Lett 322:17–20

    Article  PubMed  CAS  Google Scholar 

  43. Anand A, Charney DS, Oren DA et al (2000) Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry 57:270–276

    Article  PubMed  CAS  Google Scholar 

  44. Traversa U, Bombi G, Di Iorio P et al (2002) Specific [3H]-guanosine binding sites in rat brain membranes. Br J Pharmacol 135:969–976

    Article  PubMed  CAS  Google Scholar 

  45. Roesler R, Vianna MR, Lara DR et al (2000) Guanosine impairs inhibitory avoidance performance in rats. NeuroReport 11:2537–2540

    Article  PubMed  CAS  Google Scholar 

  46. Moretto MB, Arteni NS, Lavinsky D et al (2005) Hypoxic-ischemic insult decreases glutamate uptake by hippocampal slices from neonatal rats: prevention by guanosine. Exp Neurol 195:400–406

    Article  PubMed  CAS  Google Scholar 

  47. de Oliveira DL, Horn JF, Rodrigues JM et al (2004) Quinolinic acid promotes seizures and decreases glutamate uptake in young rats: reversal by orally administered guanosine. Brain Res 1018:48–54

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by the Brazilian funding agencies CNPq, CAPES and FINEP research grant "Rede Instituto Brasileiro de Neurociência (IBN-Net)" # 01.06.0842-00.

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Authors and Affiliations

  1. Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Avenida Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil

    Rejane G. Tavares, André P. Schmidt & Diogo O. Souza

  2. Department of Biochemistry, CCB, Federal University of Santa Catarina, Florianópolis, SC, Brazil

    Carla I. Tasca

Authors
  1. Rejane G. Tavares
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  2. André P. Schmidt
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  3. Carla I. Tasca
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  4. Diogo O. Souza
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Correspondence to Diogo O. Souza.

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Tavares, R.G., Schmidt, A.P., Tasca, C.I. et al. Quinolinic Acid-induced Seizures Stimulate Glutamate Uptake into Synaptic Vesicles from Rat Brain: Effects Prevented by Guanine-based Purines. Neurochem Res 33, 97–102 (2008). https://doi.org/10.1007/s11064-007-9421-y

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  • DOI: https://doi.org/10.1007/s11064-007-9421-y

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