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Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

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Abstract

The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the up-regulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase -4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy.

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Acknowledgments

This work was supported by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de Salud Carlos III) and by grants from Ministerio de Ciencia (MICINN, MINECO) SAF2009-08233 and SAF2012-34177 and Fundación Ramón Areces to JJL. Grant 2009/SGR00853 from the Generalitat de Catalunya (Autonomous Government of Catalonia) and grants BFU2010-19119/BFI to CA, SAF2011-23631 to AC, and SAF2012-39852-C02-01 to MP from the Spanish Ministerio de Ciencia (MICINN, MINECO) also supported the study. Grant 0177594 from CONACYT (Mexico) was awarded to CBZ.

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda/Diagonal 643, E-08028, Barcelona, Spain

    Miren Ettcheto, Felix Junyent, Luisa de Lemos, Merce Pallas & Antoni Camins

  2. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Miren Ettcheto, Felix Junyent, Luisa de Lemos, Merce Pallas, Jaume Folch, Raquel Gómez-Sintes, José J. Lucas, Carme Auladell & Antoni Camins

  3. Unitat de Bioquímica, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain

    Jaume Folch

  4. Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, CIBO, IMSS, Guadalajara, Mexico

    Carlos Beas-Zarate

  5. Laboratorio de Desarrollo y Regeneración Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    Carlos Beas-Zarate

  6. Center for Molecular Biology “Severo Ochoa” (CBMSO) CSIC/UAM, Madrid, Spain

    Raquel Gómez-Sintes & José J. Lucas

  7. Departament de Biologia Cel•lular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

    Ester Verdaguer & Carme Auladell

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  1. Miren Ettcheto
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  2. Felix Junyent
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  3. Luisa de Lemos
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  4. Merce Pallas
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  11. Antoni Camins
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Correspondence to Antoni Camins.

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Carme Auladell and Antoni Camins are senior co-authors.

Miren Ettcheto and Felix Junyent contributed equally to the manuscript

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Ettcheto, M., Junyent, F., de Lemos, L. et al. Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus. Mol Neurobiol 52, 120–129 (2015). https://doi.org/10.1007/s12035-014-8836-0

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