Neurochemical Research

, Volume 30, Issue 1, pp 69–73 | Cite as

Intracerebroventricular Guanine-Based Purines Protect Against Seizures Induced by Quinolinic Acid in Mice

  • André P. Schmidt
  • Thiago T. Ávila
  • Diogo O. Souza


Acute and chronic administration of the nucleoside guanosine have been shown to prevent quinolinic acid (QA) and α-dendrotoxin-induced seizures, as well as to impair memory and anxiety in rats and mice. In this study, we investigated the effect of i.c.v. administration of guanine-based purines (GTP, GDP, GMP, and guanosine) against seizures induced by the NMDA agonist and glutamate releaser quinolinic acid in mice. We also aimed to study the effects of the poorly hydrolysable analogs of GTP (GppNHp and GTPγS) and GDP (GDPβS) in this seizure model. QA produced seizures in 100% of mice, an effect partially prevented by guanine-based purines. In contrast to GTP (480 nmol), GDP (320–640 nmol), GMP (320–480 nmol) and guanosine (300–400 nmol), the poorly hydrolysable analogs of GTP and GDP did not affect QA-induced seizures. Thus, the protective effects of guanine nucleotides seem to be due to their conversion to guanosine. Altogether, these findings suggest a potential role of guanine-based purines for treating diseases involving glutamatergic excitotoxicity.


Excitotoxicity guanosine guanine-based purines seizures 


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  1. Ozawa, S., Kamiya, H., Tsuzuki, K. 1998Glutamate receptors in the mammalian central nervous systemProg. Neurobiol.54581618CrossRefGoogle Scholar
  2. Castellano, C., Cestari, V., Ciamei, A. 2001NMDA receptors and learning and memory processesCurr. Drug Targets2273283Google Scholar
  3. Lipton, S. A., Rosemberg, P. A. 1994Excitatory amino acids as a final common pathway for neurologic disordersNew Engl. J. Med.330613622CrossRefGoogle Scholar
  4. Heyes, M. P., Wyler, A. R., Devinsky, O., Yergey, J. A., Markey, S. P., Nadi, N. S. 1990Quinolinic acid concentrations in brain and cerebrospinal fluid of patients with intractable complex partial seizuresEpilepsia31172177Google Scholar
  5. Nakano, K., Takahashi, S., Mizobuchi, M., Kuroda, T., Masuda, K., Kitoh, J. 1993High levels of quinolinic acid in brain of epilepsy-prone E1 miceBrain Res.619195198CrossRefGoogle Scholar
  6. Meldrum, B. S. 1994The role of glutamate in epilepsy and other CNS disordersNeurology44S14s23PubMedGoogle Scholar
  7. Schmidt, A. P., Lara, D. R., Maraschin, J. F., Perla, A. S., Souza, D. O. 2000Guanosine and GMP prevent seizures induced by quinolinic acid in miceBrain Res.8644043CrossRefGoogle Scholar
  8. Ralevic, V., Burnstock, G. 1998Receptors for purines and pyrimidinesPharmacol. Rev.50413492Google Scholar
  9. Brundege, J. M., Dunwiddie, T. V. 1997Role of adenosine as a modulator of synaptic activity in the central nervous systemAdv. Pharmacol.39353391Google Scholar
  10. Ciccarelli, R., Ballerini, P., Sabatino, G., Rathbone, M. P., D’Onofrio, M., Caciagli, F., Di Iorio, P. 2001Involvement of astrocytes in purine-mediated reparative processes in the brainInt. J. Dev. Neurosci.19395414CrossRefGoogle Scholar
  11. Baron, B. M., Dudley, M. W., McCarty, D. R., Miller, F. P., Reynolds, I. J., Schmidt, C. J. 1989Guanine nucleotides are competitive inhibitors of N-Methyl-D-Aspartate at its receptor site both in vitro and in vivoJ. Pharmacol. Exp. Ther.250162169Google Scholar
  12. Burgos, J. S., Barat, A., Souza, D. O., Ramírez, G. 1998Guanine nucleotides protect against kainate toxicity in an ex vivo chick retinal preparationFEBS Lett.430176180CrossRefGoogle Scholar
  13. Paz, M. M., Ramos, M., Ramirez, G., Souza, D. 1994Differential effects of guanine nucleotides on kainic acid binding and on adenylate cyclase activity in chick optic tectumFEBS Lett.355205208CrossRefGoogle Scholar
  14. Regner, A., Ramírez, G., Belló-Klein, A., Souza, D. O. 1998Effects of guanine nucleotides on glutamate-induced chemiluminescence in rat hippocampal slices submitted to hypoxiaNeurochem. Res.23519524CrossRefGoogle Scholar
  15. Frizzo, M. E. S., Lara, D. R., Dahm, K. C. S., Prokopiuk, A. S., Swanson, R., Souza, D. O. 2001Activation of glutamate uptake by guanosine in primary astrocyte culturesNeuroReport12879881CrossRefGoogle Scholar
  16. Frizzo, M. E. S., Lara, D. R., Prokopiuk, A. S., Vargas, C. R., Salbego, C. G., Wajner, M., Souza, D. O. 2002Guanosine enhances glutamate uptake in brain cortical slices at normal and excitotoxic conditionsCell. Mol. Neurobiol.22353363CrossRefGoogle Scholar
  17. Frizzo, M. E. S., Soares, F. A., Dall’Onder, L. P., Lara, D. R., Swanson, R. A., Souza, D. O. 2003Extracellular conversion of guanine-based purines to guanosine specifically enhances astrocyte glutamate uptakeBrain Res.9728489CrossRefGoogle Scholar
  18. Paas, Y., Devillers-Thiery, A., Changeux, J. P., Medevielle, F., Teichberg, V. I. 1996Identification of an extracellular motif involved in the binding of guanine nucleotides by a glutamate receptorEMBO J.1515481556Google Scholar
  19. Souza, D. O., Frizzo, M. E. S., Lara, D. R. 2000Glutamate uptake enhanced by guanosine in vitro: possible neuroprotective mechanism against hypoxia/hypoglycemia injury.Drug Dev. Res.50115Google Scholar
  20. Caciagli, F., Di Iorio, P., Giuliani, P., Middlemiss, M. P., Rathbone, M. P. 2000The neuroprotective activity of guanosine involves the production of trophic factors and the outflow of purines from astrocytes.Drug Dev. Res.5032Google Scholar
  21. Lara, D. R., Schmidt, A. P., Frizzo, M. E. S., Burgos, J. S., Ramirez, G., Souza, D. O. 2001Effect of orally administered guanosine on seizures and death induced by glutamatergic agentsBrain Res.912176180CrossRefGoogle Scholar
  22. Soares, F. A., Schmidt, A. P., Farina, M., Frizzo, M. E., Tavares, R. G., Portela, L. V., Lara, D. R., Souza, D. O. 2004Anticonvulsant effect of GMP depends on its conversion to guanosineBrain Res.1005182186CrossRefGoogle Scholar
  23. Vinadé, E. R., Schmidt, A. P., Frizzo, M. E. S., Izquierdo, I., Elizabetsky, E., Souza, D. O. 2003Chronically administered guanosine is anticonvulsant, amnesic and anxiolytic in miceBrain Res.97797102CrossRefGoogle Scholar
  24. Haley, T. J., McCormick, W. G. 1957Pharmacologic effects of intracerebral injection of drugs in conscious mouseBr. J. Pharmacol.121215Google Scholar
  25. Hallak, M., Irtenkauf, S. M., Janusz, C. A., Cotton, D. B. 1993Stimulation and inhibition of N-methyl-D-aspartate receptors in rats: developing a seizure modelAm. J. Obstet. Gynecol.169695700Google Scholar
  26. Rubin, M. A., Jurach, A., Costa, E. M., Lima, T. T., Jimenez-Bernal, R. E., Begnini, J., Souza, D. O., Mello, C. F. 1996GMP reverses the facilitatory effect of glutamate on inhibitory avoidance task in ratsNeuroReport720782080Google Scholar
  27. Malcon, C., Achaval, M., Komlos, F., Partata, W., Sauressig, M., Ramírez, G., Souza, D. O. 1997GMP protects against quinolinic acid-induced loss of NADPH-diaphorase-positive cells in the rat striatumNeurosci. Lett.225145148CrossRefGoogle Scholar
  28. Roesler, R., Vianna, M. R., Lara, D. R., Izquierdo, I., Schmidt, A. P., Souza, D. O. 2000Guanosine impairs inhibitory avoidance performance in ratsNeuroReport1125372540Google Scholar
  29. Vinade, E. R., Izquierdo, I., Lara, D. R., Schmidt, A. P., Souza, D. O. 2004Oral administration of guanosine impairs inhibitory avoidance performance in rats and miceNeurobiol. Learn. Mem.81137143CrossRefGoogle Scholar
  30. Oliveira, I. J., Molz, S., Souza, D. O., Tasca, C. I. 2002Neuroprotective effect of GMP in hippocampal slices submitted to an in vitro model of ischemiaCell. Mol. Neurobiol.22335344CrossRefGoogle Scholar
  31. Rotta, L. N., Schmidt, A. P., Melo e Souza, T., Nogueira, C. W., Souza, K.B., Izquierdo, I. A., Perry, M. L., Souza, D. O. 2003Effects of undernutrition on glutamatergic parameters in rat brainNeurochem. Res.2811811186CrossRefGoogle Scholar
  32. Tasca, C. I., Santos, T. G., Tavares, R. G., Battastini, A. M., Rocha, J. B., Souza, D. O. 2004Guanine derivatives modulate L-glutamate uptake into rat brain synaptic vesiclesNeurochem. Int.44423431CrossRefGoogle Scholar
  33. Ciccarelli, R., Di Iorio, P., Giuliani, P., D’Alimonte, I., Ballerini, P., Caciagli, F., Rathbone, M. P. 1999Rat cultured astrocytes release guanine-based purines in basal conditions and after hypoxia/hypoglycemiaGlia259398Google Scholar
  34. Traversa, U., Bombi, G., Di Iorio, P., Ciccarelli, R., Werstiuk, E. S., Rathbone, M. P. 2002Specific (3H)-guanosine binding sites in rat brain membranesBr. J. Pharmacol.135969Google Scholar
  35. Tasca, C. I., Cardoso, L. F., Martini, L. H., Souza, D. O. 1998Guanine nucleotides inhibit cAMP accumulation induced by metabotropic glutamate receptor activationNeurochem. Res.23183188CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • André P. Schmidt
    • 1
    • 2
  • Thiago T. Ávila
    • 1
  • Diogo O. Souza
    • 1
  1. 1.Department of BiochemistryICBS, Federal University of Rio Grande do SulPorto AlegreBrazil
  2. 2.André P. SchmidtPorto AlegreBrazil

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