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Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling

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Abstract

Statins have been shown to promote neuroprotection in a wide range of neurological disorders. However, the mechanisms involved in such effects of statins are not fully understood. Quinolinic acid (QA) is a neurotoxin that induces seizures when infused in vivo and promotes glutamatergic excitotoxicity in the central nervous system. The aim of this study was to evaluate the putative glutamatergic mechanisms and the intracellular signaling pathways involved in the atorvastatin neuroprotective effects against QA toxicity. Atorvastatin (10 mg/kg) treatment for 7 days prevented the QA-induced decrease in glutamate uptake, but had no effect on increased glutamate release induced by QA. Moreover, atorvastatin treatment increased the phosphorylation of ERK1 and prevented the decrease in Akt phosphorylation induced by QA. Neither atorvastatin treatment nor QA infusion altered glutamine synthetase activity or the levels of phosphorylation of p38MAPK or JNK1/2 during the evaluation. Inhibition of MEK/ERK signaling pathway, but not PI3K/Akt signaling, abolished the neuroprotective effect of atorvastatin against QA-induced decrease in glutamate uptake. Our data suggest that atorvastatin protective effects against QA toxicity are related to modulation of glutamate transporters via MAPK/ERK signaling pathway.

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Abbreviations

GLAST:

Glutamate/aspartate transporter

GLT-1:

Glutamate transporter-1

HMG-CoA:

3-Hydroxy-3-methylglutaryl-coenzyme A

i.c.v.:

Intracerebroventricular

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate receptor

QA:

Quinolinic acid, 2,3-pyridine dicarboxylic acid

MAPK:

Mitogen-activated protein kinases pathway

PI3K/Akt:

Phosphatidylinositol-3 kinase/protein kinase B

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Acknowledgments

We thank financial support from CNPq, INCT-EN, FAPESC (NENASC Project—PRONEX—CNPq/FAPESC) and CAPES (REUNI).

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

    S. Vandresen-Filho, W. C. Martins, D. B. Bertoldo, D. K. Rieger, M. Maestri, R. B. Leal & C. I. Tasca

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

    S. Vandresen-Filho

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  1. S. Vandresen-Filho
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Vandresen-Filho, S., Martins, W.C., Bertoldo, D.B. et al. Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling. Neurochem Res 41, 2017–2028 (2016). https://doi.org/10.1007/s11064-016-1913-1

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