Abstract
N-methyl D-aspartate (NMDA) preconditioning is evoked by the administration of a subtoxic dose of NMDA and is protective against neuronal excitotoxicity. This effect may involve a diversity of targets and cell signaling cascades associated to neuroprotection. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinases (MAPKs) such as extracellular regulated protein kinase 1/2 (ERK1/2) and p38MAPK pathways play a major role in neuroprotective mechanisms. However, their involvement in NMDA preconditioning was not yet fully investigated. The present study aimed to evaluate the effect of NMDA preconditioning on PI3K/Akt, ERK1/2, and p38MAPK pathways in the hippocampus of mice and characterize the involvement of PI3K on NMDA preconditioning-evoked prevention of seizures and hippocampal cell damage induced by quinolinic acid (QA). Thus, mice received wortmannin (a PI3K inhibitor) and 15 min later a subconvulsant dose of NMDA (preconditioning) or saline. After 24 h of this treatment, an intracerebroventricular QA infusion was administered. Phosphorylation levels and total content of Akt, glycogen synthase protein kinase-3β (GSK-3β), ERK1/2, and p38MAPK were not altered after 24 h of NMDA preconditioning with or without wortmmanin pretreatment. Moreover, after QA administration, behavioral seizures, hippocampal neuronal degeneration, and Akt activation were evaluated. Inhibition of PI3K pathway was effective in abolishing the protective effect of NMDA preconditioning against QA-induced seizures, but did not modify neuronal protection promoted by preconditioning as evaluated by Fluoro-Jade B staining. The study confirms that PI3K participates in the mechanism of protection induced by NMDA preconditioning against QA-induced seizures. Conversely, NMDA preconditioning-evoked protection against neuronal degeneration is not altered by PI3K signaling pathway inhibition. These results point to differential mechanisms regarding protection against a behavioral and cellular manifestation of neural damage.
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Abbreviations
- Akt:
-
Protein kinase B
- ERK:
-
Extracellular signal–regulated kinases
- GSK-3β:
-
Glycogen synthase kinase-3 beta
- MAPK:
-
Mitogen-activated protein kinases
- NMDA:
-
N-methyl D-aspartate
- NQnc:
-
NMDA-QA non-convulsed group
- NQc:
-
NMDA-QA convulsed group
- OGD:
-
Oxygen/glucose deprivation
- PI3K:
-
Phosphatidylinositol-3 kinase
- p38MAPK :
-
P38 mitogen-activated protein kinases
- QA:
-
Quinolinic Acid
- Wort:
-
Wortmannin
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Acknowledgements
This work was supported by grants from the following Brazilian funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Programa de Apoio aos Núcleos de Excelência (PRONEX–NENASC Project), Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), FINEP (Financiadora de Estudos e Projetos-IBN-Net #01.06.0842-00) and INCT (Instituto Nacional de Ciência e Tecnologia) for Excitotoxicity and Neuroprotection. RBL and CIT are supported by research fellowships from CNPq.
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All experimental procedures involving animals were performed by the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) and were designed to minimize suffering and limit the number of animals used. The experiments were performed after approval of the protocol by the local Institutional Ethics Committee for Animal Research (CEUA/UFSC PP0549).
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Constantino, L.C., Binder, L.B., Vandresen-Filho, S. et al. Role of Phosphatidylinositol-3 Kinase Pathway in NMDA Preconditioning: Different Mechanisms for Seizures and Hippocampal Neuronal Degeneration Induced by Quinolinic Acid. Neurotox Res 34, 452–462 (2018). https://doi.org/10.1007/s12640-018-9903-5
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DOI: https://doi.org/10.1007/s12640-018-9903-5