Abstract
Perinatal cerebral hypoxia–ischemia (HI) is an important cause of mortality and neurological disabilities such as cerebral palsy, epilepsy, and mental retardation. The potential for neuroprotection in HI can be achieved mainly during the recovery period. In previous work, we demonstrated that guanosine (Guo) prevented the decrease of glutamate uptake by hippocampal slices of neonatal rats exposed to a hypoxic-ischemic (HI) insult in vivo when administrated before and after insult. In the present study, we compared the effect of Guo administration only after HI using various protocols. When compared with the control, a decrease of [3H] glutamate uptake was avoided only when three doses of Guo were administered immediately, 24 h and 48 h after insult, or at 3 h, 24 h, and 48 h after injury or at 6 h, 24 h, and 48 h after HI. These findings indicate that early Guo administration (until 6 h) after HI, in three doses may enhance glutamate uptake into brain slices after hypoxia/ischemia, probably resulting in decreased excitotoxicity.


References
Badr Zahr, L. K., & Purdy, I. (2006). Brain injury in the infant: the old, the new, and the uncertain. The Journal of Perinatal & Neonatal Nursing, 20, 163–175.
Ciccarelli, R., Di Iorio, P., Bruno, V., Battaglia, G., D’Alimonte, I., D’Onofrio, M., et al. (1999). Activation of A (1) adenosine or mGlu3 metabotropic glutamate receptors enhances the release of nerve growth factor and S-100beta protein from cultured astrocytes. Glia, 27, 275–281. doi:10.1002/(SICI)1098-1136(199909)27:3<275::AID-GLIA9>3.0.CO;2-0.
Danbolt, N. C. (2001). Glutamate uptake. Progress in Neurobiology, 65, 1–105. doi:10.1016/S0301-0082(00)00067-8.
de Oliveira, D. L., Horn, J. F., Rodrigues, J. M., Frizzo, M. E., Moriguchi, E., Souza, D. O., et al. (2004). Quinolinic acid promotes seizures and decreases glutamate uptake in young rats: reversal by orally administered guanosine. Brain Research, 1018, 48–54. doi:10.1016/j.brainres.2004.05.033.
Dong, W. Q., Schurr, A., Reid, K. H., Shields, C. B., & West, C. A. (1988). The rat hippocampal slice preparation as an in vitro model of ischemia. Stroke, 19, 498–502.
Frizzo, M. E., Antunes Soares, F. A., Dall’Onder, L. P., Lara, D. R., Swanson, R. A., & Souza, D. O. (2003). Extracellular conversion of guanine-based purines to guanosine specifically enhances astrocyte glutamate uptake. Brain Research, 972, 84–89. doi:10.1016/S0006-8993(03)02506-X.
Frizzo, M. E., Lara, D. R., Dahm, K. C., Prokopiuk, A. S., Swanson, R. A., & Souza, D. O. (2001). Activation of glutamate uptake by guanosine in primary astrocyte cultures. Neuroreport, 12, 879–881. doi:10.1097/00001756-200103260-00051.
Frizzo M. E., Lara D. R., Prokopiuk Ade S., Vargas C. R., Salbego C. G., Wajner M., & Souza D. O. (2002). Guanosine enhances glutamate uptake in brain cortical slices at normal and excitotoxic conditions. Cell Mol Neurobiol, 22, 353–363.
Gluckman, P. D., Pinal, C. S., & Gunn, A. J. (2001). Hypoxic-ischemic brain injury in the newborn: pathophysiology and potential strategies for intervention. Seminars in Neonatology, 6, 109–120. Review. doi:10.1053/siny.2001.0042.
Johnston, M. V., Nakajima, W., & Hagberg, H. (2002). Mechanisms of hypoxic neurodegeneration in the developing brain. The Neuroscientist, 8, 212–220. Review.
Moretto, M. B., Arteni, N. S., Lavinsky, D., Netto, C. A., Rocha, J. B., Souza, D. O., et al. (2005). Hypoxic-ischemic insult decreases glutamate uptake by hippocampal slices from neonatal rats: prevention by guanosine. Experimental Neurology, 195, 400–406. doi:10.1016/j.expneurol.2005.06.005.
Moretto, M. B., de Mattos-Dutra, A., Arteni, N., Meirelles, R., de Freitas, M. S., Netto, C. A., et al. (1999). Effects of neonatal cerebral hypoxia-ischemia on the in vitro phosphorylation of synapsin 1 in rat synaptosomes. Neurochemical Research, 24, 1263–1269. doi:10.1023/A:1020925107130.
Northington, F. J. (2006). Brief update on animal models of hypoxic-ischemic encephalopathy and neonatal stroke. ILAR Journal, 47(1), 32–38.
Peterson, G. L. (1977). A simplification of the protein assay method of Lowry et al. which is more generally applicable. Analytical Biochemistry, 83, 346–356. doi:10.1016/0003-2697(77)90043-4.
Schmidt, A. P., Lara, D. R., de Faria Maraschin, J., da Silveira Perla, A., & Onofre Souza, D. (2000). Guanosine and GMP prevent seizures induced by quinolinic acid in mice. Brain Research, 864, 40–43. doi:10.1016/S0006-8993(00)02106-5.
Tavares, R. G., Schmidt, A. P., Abud, J., Tasca, C. I., & Souza, D. O. (2005). In vivo quinolinic acid increases synaptosomal glutamate release in rats: reversal by guanosine. Neurochemical Research, 30, 439–444. doi:10.1007/s11064-005-2678-0.
Thomazi, A. P., Boff, B., Pires, T. D., Godinho, G., Battú, C. E., Gottfried, C., et al. (2008). Profile of glutamate uptake and cellular viability in hippocampal slices exposed to oxygen and glucose deprivation: developmental aspects and protection by guanosine. Brain Research, 1188, 233–240. doi:10.1016/j.brainres.2007.10.037.
Uemura, Y., Miller, J. M., Matson, W. R., & Beal, M. F. (1991). Neurochemical analysis of focal ischemia in rats. Stroke, 22, 1548–1553.
Vannucci, S. J., & Hagberg, H. (2004). Hypoxia-ischemia in the immature brain. The Journal of Experimental Biology, 207, 3149–3154. Review. doi:10.1242/jeb.01064.
Volpe, J. J. (2001). Perinatal brain injury: from pathogenesis to neuroprotection. Mental Retardation and Developmental Disabilities Research Reviews, 7, 56–64. Review. doi:10.1002/1098-2779(200102)7:1<56::AID-MRDD1008>3.0.CO;2-A.
Acknowledgments
This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Coordenação de Aperfeiçoamento de Pessoal de Nível superior (CAPES).
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Moretto, M.B., Boff, B., Lavinsky, D. et al. Importance of Schedule of Administration in the Therapeutic Efficacy of Guanosine: Early Intervention After Injury Enhances Glutamate Uptake in Model of Hypoxia-ischemia. J Mol Neurosci 38, 216–219 (2009). https://doi.org/10.1007/s12031-008-9154-7
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DOI: https://doi.org/10.1007/s12031-008-9154-7