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Quinolinate-induced Rat Striatal Excitotoxicity Impairs Endoplasmic Reticulum Ca2+-ATPase Function

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Abstract

Excessive activation of NMDA glutamate receptors and the resulting loss of intracellular Ca2+ homeostasis may be lethal (excitotoxic) to neurons. Such excitotoxicity can be induced in vivo by intrastriatal infusion of quinolinate, as this substance selectively activates NMDA receptors. The aim of the present research was to investigate whether the in vivo treatment of striatal tissue with quinolinate would lead to an early impairment of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity or mitochondrial Ca2+ sequestration, two intracellular mechanisms involved in Ca2+ homeostasis and signaling. Sodium quinolinate was infused intrastriatally into adult rats, and 6 h later the brains were removed and the corpora striata dissected. At this time point, striatal sections stained with Fluoro-Jade, a cellular marker of cell death, showed initial signs of neuronal degeneration. In addition, SERCA activity decreased 39% in relation to the activity observed in the control striata. A corresponding decrease of the same magnitude in 45Ca2+ uptake by striatal microsomes was also found in the treated striata. Western blot analysis did not indicate any decrease in SERCA levels in striatal tissue after quinolinate infusion. Mitochondrial Ca2+ sequestration was still preserved in quinolinate-treated striatal tissue when the assay was carried out in the presence of physiological concentrations of ATP and Mg2+. These results suggest that impairment of the SERCA function may be an early event in excitotoxicity.

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Acknowledgements

The authors would like to thank Edilene S. Siqueira and Elisangela J. Silva for technical assistance and Professor Helena M. Scofano for providing the laboratory facilities for many of the experiments described here. This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Fundo de Apoio ao Ensino, Pesquisa e Extensão (FAEPEX-UNICAMP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). A.M.A.P. Fernandes was supported by FAPESP and CNPq fellowships.

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  1. Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), CP 6111, Campinas, SP, 13083-887, Brazil

    Anna M. A. P. Fernandes & Roger F. Castilho

  2. Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil

    Ana M. Landeira-Fernandez, Patrícia Souza-Santos & Paulo C. Carvalho-Alves

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  1. Anna M. A. P. Fernandes
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Correspondence to Anna M. A. P. Fernandes.

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Fernandes, A.M.A.P., Landeira-Fernandez, A.M., Souza-Santos, P. et al. Quinolinate-induced Rat Striatal Excitotoxicity Impairs Endoplasmic Reticulum Ca2+-ATPase Function. Neurochem Res 33, 1749–1758 (2008). https://doi.org/10.1007/s11064-008-9619-7

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