Skip to main content
NCBI home page
Cellular and Molecular Neurobiology logoLink to Cellular and Molecular Neurobiology
. 2002 Jun;22(3):353–363. doi: 10.1023/A:1020728203682

Guanosine Enhances Glutamate Uptake in Brain Cortical Slices at Normal and Excitotoxic Conditions

Marcos Emílio dos Santos Frizzo 1,2, Diogo Rizzato Lara 3, Alexandre de Souza Prokopiuk 1, Carmen Regla Vargas 4, Christianne Gazzana Salbego 1, Moacir Wajner 1, Diogo Onofre Souza 1
PMCID: PMC11533736  PMID: 12469876

Abstract

1. The effect of guanosine on L-[2,3-3H]glutamate uptake was investigated in brain cortical slices under normal or oxygen–glucose deprivation (OGD) conditions.

2. In slices exposed to physiological conditions, guanosine (1–100 μM) stimulated glutamate uptake (up to 100%) in a concentration-dependent manner when a high (100 μM) but not a low (1 μM) concentration of glutamate was used.

3. In slices submitted to OGD, guanosine 1 and 100 μM also increased 100 μM glutamate uptake (38 and 70%, respectively).

4. The increasing of glutamate and taurine released to the incubation medium in cortical slices submitted to OGD were significantly attenuated by the presence of guanosine in the incubation medium.

5. Guanosine prevented the increase in propidium iodide incorporation into cortical slices induced by OGD, indicating a protective role against ischemic injury.

6. These results support the hypothesis of a protective role for guanosine during brain ischemia, possibly by activating glutamate uptake into neural cells.

Keywords: hypoxia, hypoglycemia, excitotoxicity, neuroprotection, taurine, glutamate

REFERENCES

  1. Anderson, C. M., and Swanson, R. A. (2000). Astrocyte glutamate transport: Review of properties, regulation, and physiological functions. Glia32:1–14. [PubMed] [Google Scholar]
  2. Asai, S., Zhao, H., Yamashita, A., Jike, T., Kunimatsu, T., Nagata, T., Kohno, T., and Ishikawa, K. (1999). Nicergoline enhances glutamate re-uptake and protects against brain damage in rat global brain ischemia. Eur. J. Pharmacol.383:267–274. [DOI] [PubMed] [Google Scholar]
  3. Boldyrev, A. A., Johnson, P., Wei, Y., Tan, Y., and Carpenter, D. O. (1999). Carnosine and taurine protect rat cerebellar granular cells from free radical damage. Neurosci. Lett.263:169–172. [DOI] [PubMed] [Google Scholar]
  4. Ciccarelli, R., Di Iorio, P., Giuliani, P., D'Alimonte, I., Ballerini, P., Caciagli, F., and Rathbone, M. (1999). Rat cultured astrocytes release guanine-based purines in basal conditions and after hypoxia/ hypoglycemia. Glia25:93–98. [PubMed] [Google Scholar]
  5. Danbolt, N. C. (2001). Glutamate uptake. Prog. Neurobiol.65:1–105. [DOI] [PubMed] [Google Scholar]
  6. Dirnagl, U., Iadecola, C., and Moskowitz, M. A. (1999). Pathobiology of ischemic stroke: An integrated view. Trends Neurosci.22:391–397. [DOI] [PubMed] [Google Scholar]
  7. Dobolyi, ´ A., Reichart, A., Szikra, T., Nyitrai, G., K´ ekesi, K. A., and Juh´ asz, G. (2000). Sustained depolarization induces changes in the extracellular concentrations of purine and pyrimidine nucleosides in the rat thalamus. Neurochem. Int.37:71–79. [DOI] [PubMed] [Google Scholar]
  8. Duan, S., Anderson, C. M., Stein, B. A., and Swanson, R. A. (1999). Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J. Neurosci.19:10193–10200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Frizzo, M. E. S., Lara, D. R., Dahm, K. C., Prokopiuk, A. S., Swanson, R. A., and Souza, D. O. (2001). Activation of glutamate uptake by guanosine in primary astrocyte cultures. Neuroreport12:879–881. [DOI] [PubMed] [Google Scholar]
  10. Gegelashvili, G., Civenni, G., Racagni, G., Danbolt, N. C., Schousboe, I., and Schousboe, A. (1996). Glutamate receptor agonists up-regulate glutamate transporter GLAST in astrocytes. Neuroreport8:261–265. [DOI] [PubMed] [Google Scholar]
  11. Greene, J. G., and Greenamyre, J. T. (1996). Bioenergetics and glutamate excitotoxicity. Prog. Neurobiol.48:613–634. [DOI] [PubMed] [Google Scholar]
  12. Izquierdo, I., Medina, J. H., Vianna, M.R., Izquierdo, L. A., and Barros, D.M. (1999). Separate mechanisms for short-and long-term memory. Behav. Brain Res.103:1–11. [DOI] [PubMed] [Google Scholar]
  13. Joseph, M. H., and Marsden, C. A. (1986). Amino acids and small peptides. In Lim, C. K. (ed.), HPLC of Small Peptides, IRL Press, Oxford, pp. 13–27. [Google Scholar]
  14. Jurkowitz, M. S., Litsky, M. L., and Browning, M. J. (1998). Adenosine, inosine, and guanosine protect glial cells during glucose deprivation and mitocondrial inhibition: Correlation between protection and ATP preservation. J. Neurochem.71:535–548. [DOI] [PubMed] [Google Scholar]
  15. Lara, D. R., Schmidt, A. P., Frizzo, M. E. S., Burgos, J. S., Ramirez, G., and Souza, D. O. (2001). Effect of orally administered guanosine on seizures and death induced by glutamatergic agents. Brain Res.912:176–180. [DOI] [PubMed] [Google Scholar]
  16. Lee, J. M., Zipfel, G. J., and Choi, D.W. (1999). The changing landscape of ischaemic brain injury mechanisms. Nature399:A7–A14. [DOI] [PubMed] [Google Scholar]
  17. Masliah, E., Raber, J., Alford, M., Mallory, M., Mattson, M. P., Yang, D., Wong, D., and Mucke, L. (1998). Amyloid protein precursor stimulates excitatory amino acid transport. Implications for roles in neuroprotection and pathogenesis. J. Biol. Chem.273:12548–12554. [DOI] [PubMed] [Google Scholar]
  18. Meldrum, B. S. (2000). Glutamate as a neurotransmitter in the brain: Review of physiology and pathology. J. Nutr.130:1007S–1015S. [DOI] [PubMed] [Google Scholar]
  19. Monahan, J. B., Hood, W. F., Michel, J., and Compton, R. P. (1988). Effects of guanine nucleotides on N-methyl-D-aspartate receptor-ligand interactions. Mol. Pharmacol.34:111–116. [PubMed] [Google Scholar]
  20. Munir, M., Correale, D. M., and Robinson, M. B. (2000). Substrate-induced up-regulation of Na(C)-dependent glutamate transport activity. Neurochem. Int.37:147–162. [DOI] [PubMed] [Google Scholar]
  21. Nicholls, D. G., and Budd, S. L. (1998). Mitochondria and neuronal glutamate excitotoxicity. Biochem. Biophys. Acta1366:97–112. [DOI] [PubMed] [Google Scholar]
  22. Nieoullon, A., Kerkerian, L., and Dusticier, N. (1983). Presynaptic dopaminergic control of high affinity glutamate uptake in the striatum. Neurosci. Lett.43:191–196. [DOI] [PubMed] [Google Scholar]
  23. Nishizawa, Y. (2001). Glutamate release and neuronal damage in ischemia. Life Sci.69:369–381. vOzawa, S., Kamiya, H., and Tsuzuki, K. (1998). Glutamate receptors in the mammalian central nervous system. Prog. Neurobiol.54:581–618. [DOI] [PubMed] [Google Scholar]
  24. Peterson, G. L. (1977). Review of the Folin phenol protein quantitation method of Lowry, Rosebrough, Farr and Randall. Anal. Biochem.83:346–356. [DOI] [PubMed] [Google Scholar]
  25. Phillis, J. W., Ren, J., and O'Regan, M. H. (2000). Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with DL-threo-beta-benzyloxyaspartate. Brain Res.880:224. [DOI] [PubMed] [Google Scholar]
  26. Rathbone, M. P., Middlemiss, P. J., Gysbers, J. W., Andrew, C., Herman, M. A. R., Reed, J. K., Ciccarelli, R., Di Iorio, P., and Caciagli, F. (1999). Tropic effects of purines in neurons and glial cells. Prog. Neurobiol.59:663–690. [DOI] [PubMed] [Google Scholar]
  27. Sanchez-Carbente, M. R., and Massieu, L. (1999). Transient inhibition of glutamate uptake in vivo induces neurodegeneration when energy metabolism is impaired. J. Neurochem.72:129–138. [DOI] [PubMed] [Google Scholar]
  28. Saransaari, P., and Oja, S. S. (2000). Taurine and neural cell damage. Amino Acids 19:509–526. [DOI] [PubMed] [Google Scholar]
  29. Schmidt, A. P., Lara, D. R., Maraschin, J. F., Perla, A. S., and Souza, D. O. (2000). Guanosine and GMP prevent seizures induced by quinolinic acid in mice. Brain Res.864:40–43. [DOI] [PubMed] [Google Scholar]
  30. Segovia, G., Porras, A., Del Arco, A., and Mora, F. (2001). Glutamatergic neurotransmission in aging: A critical perspective. Mech. Ageing Dev.122:1–29. [DOI] [PubMed] [Google Scholar]
  31. Shimada, F., Shiga, Y., Morikawa, M., Kawazura, H., Morikawa, O., Matsuoka, T., Nishizaki, T., and Saito, N. (1999). The neuroprotective agent MS-153 stimulates glutamate uptake. Eur. J. Pharmacol.386:263–270. [DOI] [PubMed] [Google Scholar]
  32. Souza, D. O., and Ramirez, G. (1991). Effects of guanine nucleotides on kainic acid binding and on adenylate cyclase in chick optic tectum and cerebellum. J. Mol. Neurosci.3:39–45. [DOI] [PubMed] [Google Scholar]
  33. Stover, J. F., and Unterberg, A. W. (2000). Increased cerebrospinal fluid glutamate and taurine concentrations are associated with traumatic brain edema formation in rats. Brain Res.875:51–55. [DOI] [PubMed] [Google Scholar]
  34. Tang, X. C., Rao, M. R., Hu, G., and Wang, H. (2000). Alterations of amino acid levels from striatum, hippocampus, and cerebral cortex induced by global cerebral ischemia in gerbil. Acta Pharmacol. Sin.21:819–823. [PubMed] [Google Scholar]
  35. Traversa, U., Bombi, G., Di Iorio, P., Ciccarelli, R., Werstiuk, E. S., and Rathbone, M. (2002). Specific [3H]-guanosine binding sites in rat brain membranes. Br. J. Pharmacol.135:969–976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Uemura, Y., Miller, J. M., Matson, W. R., and Beal, M. F. (1991). Neurochemical analysis of focal ischemia in rats. Stroke22:1548–1553. [DOI] [PubMed] [Google Scholar]

Articles from Cellular and Molecular Neurobiology are provided here courtesy of Springer

RESOURCES