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N-Methyl-d-aspartate Preconditioning Prevents Quinolinic Acid-Induced Deregulation of Glutamate and Calcium Homeostasis in Mice Hippocampus

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Abstract

The search for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a major factor common to neurodegenerative diseases and in acute events such as cerebral ischemia, traumatic brain injury and epilepsy. We have previously demonstrated that N-methyl-d-aspartate (NMDA) preconditioning in mice showed 50 % of protection against seizures and full protection against damage to neuronal tissue induced by quinolinic acid (QA). In this study, cellular and molecular mechanisms involved on NMDA preconditioning and neuroprotection were investigated in mice treated with NMDA 24 h before QA insult. Calcium uptake and d-aspartate release from hippocampal slices obtained from mice treated with NMDA plus QA and not displaying seizures (protected mice) were similar to control (saline) or NMDA preconditioned mice. Increased calcium uptake and glutamate release is evidenced in unprotected (convulsed) mice as well as QA control, demonstrating that calcium and glutamate are involved in NMDA-induced preconditioning. Increased glutamate release evoked by QA was blocked by MK-801, whereas increased calcium uptake was abolished by voltage-dependent calcium channels inhibitors, but not MK-801. NMDA preconditioning is effective in normalizing the deregulation of glutamate transport and calcium homeostasis evoked by QA due to aberrant NMDA receptors activation that culminates in seizures and hippocampal cells damage.

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Abbreviations

HBSS:

Hank’s balanced salt solution

KRB:

Krebs–Ringer bicarbonate buffer

MK-801:

(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate receptors

QA:

Quinolinic acid

ROS:

Reactive oxygen species

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Acknowledgments

Research supported by grants from the Brazilian funding agencies, CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) – Projects IBN-Net # 01.06.0842-00 and INCT (Instituto Nacional de Ciência e Tecnologia) for Excitotoxicity and Neuroprotection and FAPESC (Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina) – Project NENASC/PRONEX to C.I.T. CAPES, CNPq-Uni e FAPESC-Uni to F.R.M.B.S. C.I.T. is recipient of CNPq productivity fellowship and P.C.S. was recipient of PRODOC/CAPES post-doctoral scholarship.

Conflict of interest

The authors state no conflicts of interest. All authors have materially participated in the research and/or article preparation.

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Authors and Affiliations

  1. Laboratório de Neuroquímica-4, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

    S. Vandresen-Filho, P. C. Severino, L. C. Constantino, W. C. Martins, S. Molz, T. Dal-Cim, D. B. Bertoldo & C. I. Tasca

  2. Laboratório de Hormônios & Transdução de Sinais, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, Florianópolis, SC, 88040-900, Brazil

    F. R. M. B. Silva

  3. Departamento de Ciências Básicas em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso, Boa Esperança, Cuiabá, MT, 78060-900, Brazil

    S. Vandresen-Filho

  4. Curso de Farmácia, Universidade do Contestado, Canoinhas, SC, 89460-000, Brazil

    S. Molz

Authors
  1. S. Vandresen-Filho
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  2. P. C. Severino
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  3. L. C. Constantino
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  4. W. C. Martins
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  5. S. Molz
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  6. T. Dal-Cim
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  7. D. B. Bertoldo
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  8. F. R. M. B. Silva
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  9. C. I. Tasca
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Corresponding author

Correspondence to S. Vandresen-Filho.

Additional information

S. Vandresen-Filho and P.C. Severino have contributed equally to this study.

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Vandresen-Filho, S., Severino, P.C., Constantino, L.C. et al. N-Methyl-d-aspartate Preconditioning Prevents Quinolinic Acid-Induced Deregulation of Glutamate and Calcium Homeostasis in Mice Hippocampus. Neurotox Res 27, 118–128 (2015). https://doi.org/10.1007/s12640-014-9496-6

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  • DOI: https://doi.org/10.1007/s12640-014-9496-6

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