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Glutamate Excitotoxicity Activates the MAPK/ERK Signaling Pathway and Induces the Survival of Rat Hippocampal Neurons In Vivo

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Abstract

Current knowledge concerning the molecular mechanisms of the cellular response to excitotoxic insults in neurodegenerative diseases is insufficient. Although glutamate (Glu) has been widely studied as the main excitatory neurotransmitter and principal excitotoxic agent, the neuroprotective response enacted by neurons is not yet completely understood. Some of the molecular participants have been revealed, but the signaling pathways involved in this protective response are just beginning to be identified. Here, we demonstrate in vivo that, in response to the cell damage and death induced by Glu excitotoxicity, neurons orchestrate a survival response through the extracellular signal-regulated kinase (ERK) signaling pathway by increasing ERK expression in the rat hippocampal (CA1) region, allowing increased neuronal survival. In addition, this protective response is specifically reversed by U0126, an ERK inhibitor, which promotes cell death only when it is administered together with Glu. Our findings demonstrate that the ERK signaling pathway has a neuroprotective role in the response to Glu-induced excitotoxicity in hippocampal neurons. Therefore, the ERK signaling pathway may be activated as a cellular response to excitotoxic injury to prevent damage and neural loss, representing a novel therapeutic target in the treatment of neurodegenerative diseases.

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References

  • Akhtar RS, Ness JM, Roth KA (2004) Bcl-2 family regulation of neuronal development and neurodegeneration. Biochim Biophys Acta 1644:189–203

    Article  CAS  PubMed  Google Scholar 

  • Almeida RD, Manadas BJ, Melo CV et al (2005) Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ 12:1329–1343

    Article  CAS  PubMed  Google Scholar 

  • Anderson CN, Tolkovsky AM (1999) A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci 19:664–673

    CAS  PubMed  Google Scholar 

  • André VM, Cepeda C, Levine MS (2010) Dopamine and glutamate in Huntington’s disease: a balancing act. CNS Neurosci Ther 16:163–178

    Article  PubMed Central  PubMed  Google Scholar 

  • Asomugha CO, Linn DM, Linn CL (2010) ACh receptors link two signaling pathways to neuroprotection against glutamate-induced excitotoxicity in isolated RGCs. J Neurochem 112:214–226

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Babai N, Atlasz T, Tamás A et al (2006) Search for the optimal monosodium glutamate treatment schedule to study the neuroprotective effects of PACAP in the retina. Ann NY Acad Sci 1070:149–155

    Article  CAS  PubMed  Google Scholar 

  • Barnes JW, Tischkau SA, Barnes JA et al (2003) Requirement of mammalian timeless for circadian rhythmicity. Science 302:439–442

    Article  CAS  PubMed  Google Scholar 

  • Beas-Zárate C, Schliebs R, Ortuño-Sahagún D, Morales-Villagrán A, Feria-Velasco A (1994) Effect of systemic monosodium l-glutamate on muscarinic cholinergic receptors in selected rat brain regions during development. Arch Med Res 25:341–346

    PubMed  Google Scholar 

  • Berkeley JL, Decker MJ, Levey AI (2002) The role of muscarinic acetylcholine receptor-mediated activation of extracellular signal-regulated kinase 1/2 in pilocarpine-induced seizures. J Neurochem 82:192–201

    Article  CAS  PubMed  Google Scholar 

  • Boscia F, Esposito CL, Di Crisci A, de Franciscis V, Annunziato L, Cerchia L (2009) GDNF selectively induces microglial activation and neuronal survival in CA1/CA3 hippocampal regions exposed to NMDA insult through Ret/ERK signalling. PLoS One 4:e6486

    Article  PubMed Central  PubMed  Google Scholar 

  • Chen T, Cao L, Dong W et al (2012) Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. Neurochem Res 37:983–990

    Article  CAS  PubMed  Google Scholar 

  • Cortese BM, Phan KL (2005) The role of glutamate in anxiety and related disorders. CNS Spectr 10:820–830

    PubMed  Google Scholar 

  • Dhandapani KM, Wade FM, Wakade C, Mahesh VB, Brann DW (2005) Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFkappaB. J Neurochem 95:9–19

    Article  CAS  PubMed  Google Scholar 

  • Dong M, Wu Y, Fan Y, Xu M, Zhang J (2006) c-fos modulates brain-derived neurotrophic factor mRNA expression in mouse hippocampal CA3 and dentate gyrus neurons. Neurosci Lett 400:177–180

    Article  CAS  PubMed  Google Scholar 

  • Dong X-X, Wang Y, Qin Z-H (2009) Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sinica 30:379–387

    Article  CAS  Google Scholar 

  • Duncia JV, Santella JB 3rd, Higley CA et al (1998) MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett 8:2839–2844

    Article  CAS  PubMed  Google Scholar 

  • Esposito E, Cuzzocrea S (2010) New therapeutic strategy for Parkinson’s and Alzheimer’s disease. Curr Med Chem 17:2764–2774

    Article  CAS  PubMed  Google Scholar 

  • Feng H, Xiang H, Mao YW et al (2004) Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes. Oncogene 23:7310–7321

    Article  CAS  PubMed  Google Scholar 

  • Ferrer I, Blanco R, Carmona M (2001) Differential expression of active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates following quinolinic acid excitotoxicity in the rat. Brain Res Mol Brain Res 94:48–58

    Article  CAS  PubMed  Google Scholar 

  • Ferrer I, Blanco R, Carmona M, Puig B, Domínguez I, Viñals F (2002) Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat. Acta Neuropathol 103:391–407

    Article  CAS  PubMed  Google Scholar 

  • Giovannini MG, Cerbai F, Bellucci A et al (2008) Differential activation of mitogen-activated protein kinase signalling pathways in the hippocampus of CRND8 transgenic mouse, a model of Alzheimer’s disease. Neuroscience 153:618–633

    Article  CAS  PubMed  Google Scholar 

  • Gladding CM, Fitzjohn SM, Molnár E (2009) Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms. Pharmacol Rev 61:395–412

    Article  CAS  PubMed  Google Scholar 

  • Grewer C, Gameiro A, Zhang Z, Tao Z, Braams S, Rauen T (2008) Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life 60:609–619

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hetman M, Kanning K, Cavanaugh JE, Xia Z (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 274:22569–22580

    Article  CAS  PubMed  Google Scholar 

  • Hetman M, Gozdz A (2004) Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. Eur J Biochem 271:2050–2055

    Article  CAS  PubMed  Google Scholar 

  • Jiang X, Zhu D, Okagaki P et al (2003) N-methyl-d-aspartate and TrkB receptor activation in cerebellar granule cells: an in vitro model of preconditioning to stimulate intrinsic survival pathways in neurons. Ann N Y Acad Sci 993:134–145

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Karmarkar SW, Bottum KM, Krager SL, Tischkau SA (2011) ERK/MAPK is essential for endogenous neuroprotection in SCN2.2 cells. PLoS One 6:e23493

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kew JN, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacol (Berl) 179:4–29

    Article  CAS  Google Scholar 

  • Kim EK, Choi E-J (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405

    Article  CAS  PubMed  Google Scholar 

  • Kullmann DM, Lamsa K (2008) Roles of distinct glutamate receptors in induction of anti-Hebbian long-term potentiation. J Physiol 586:1481–1486

    Article  CAS  PubMed  Google Scholar 

  • Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 460:525–542. doi:10.1007/s00424-010-0809-1

    Article  CAS  PubMed  Google Scholar 

  • Lee HG, Zhu X, O’Neill MJ et al (2004) The role of metabotropic glutamate receptors in Alzheimer’s disease. Acta Neurobiol Exp (Wars) 64:89–98

    Google Scholar 

  • Lei K, Davis RJ (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A 100:2432–2437. doi:10.1073/pnas.0438011100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ma Y, Liu W, Wang Y et al (2011) VEGF protects rat cortical neurons from mechanical trauma injury induced apoptosis via the MEK/ERK pathway. Brain Res Bull 86:441–446

    Article  CAS  PubMed  Google Scholar 

  • Maiese K, Chong ZZ, Li F (2005) Driving cellular plasticity and survival through the signal transduction pathways of metabotropic glutamate receptors. Curr Neurovasc Res 2:425–446

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Malik SZ, Motamedi S, Royo NC, LeBold D, Watson DJ (2011) Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain. J Neurotrauma 28:415–430

    Article  PubMed  Google Scholar 

  • Matsuzaki H, Tamatani M, Yamaguchi A et al (2001) Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. FASEB J 15:1218–1220

    CAS  PubMed  Google Scholar 

  • Melo CV, Okumoto S, Gomes JR et al (2013) Spatiotemporal resolution of BDNF neuroprotection against glutamate excitotoxicity in cultured hippocampal neurons. Neuroscience 237:66–86

    Article  CAS  PubMed  Google Scholar 

  • Naoi M, Maruyama W (2010) Monoamine oxidase inhibitors as neuroprotective agents in age-dependent neurodegenerative disorders. Curr Pharm Des 16:2799–2817

    Article  CAS  PubMed  Google Scholar 

  • Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H (2010) BDNF function and intracellular signaling in neurons. Histol Histopathol 25:237–258

    CAS  PubMed  Google Scholar 

  • O’Sullivan AW, Wang JH, Redmond HP (2009) p38 MAP kinase inhibition promotes primary tumour growth via VEGF independent mechanism. World J Surg Oncol 7:89

    Article  PubMed Central  PubMed  Google Scholar 

  • Ortega F, Pérez-Sen R, Delicado EG, Teresa M-PM (2011) ERK1/2 activation is involved in the neuroprotective action of P2Y13 and P2X7 receptors against glutamate excitotoxicity in cerebellar granule neurons. Neuropharmacol 61:1210–1221

    Article  CAS  Google Scholar 

  • Ortuño-Sahagún D, Beas-Zárate C, Adame-Gonzalez G, Feria-Velasco A (1997) Effect of l-glutamate on cholinergic neurotransmission in various brain regions and during the development of rats, when administered perinatally. Neurochem Int 31:683–692

    Article  PubMed  Google Scholar 

  • Ortuño-Sahagún D, Rivera-Cervantes MC, Gudino-Cabrera G et al (2010) Microarray analysis of rat hippocampus exposed to excitotoxicity: reversal Na(+)/Ca(2+) exchanger NCX3 is overexpressed in glial cells. Hippocampus 22:128–140

    Article  PubMed  Google Scholar 

  • Park MA, Zhang G, Mitchell C et al (2008) Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95. Mol Cancer Ther 7:2633–2648

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paschen W (1996) Glutamate excitotoxicity in transient global cerebral ischemia. Acta Neurobiol Exp (Wars) 56:313–322

    CAS  Google Scholar 

  • Peng CH, Chiou SH, Chen SJ et al (2008) Neuroprotection by imipramine against lipopolysaccharide-induced apoptosis in hippocampus-derived neural stem cells mediated by activation of BDNF and the MAPK pathway. Eur Neuropsychopharmacol 18:128–140

    Article  CAS  PubMed  Google Scholar 

  • Petegnief V, Saura J, de Gregorio-Rocasolano N, Paul SM (2001) Neuronal injury-induced expression and release of apolipoprotein E in mixed neuron/glia co-cultures: nuclear factor kappaB inhibitors reduce basal and lesion-induced secretion of apolipoprotein E. Neuroscience 104:223–234

    Article  CAS  PubMed  Google Scholar 

  • Rogers A, Schmuck G, Scholz G, Williams DC (2004) c-fos mRNA expression in rat cortical neurons during glutamate-mediated excitotoxicity. Toxicol Sci 82:562–569

    Article  CAS  PubMed  Google Scholar 

  • Sahota P, Savitz SI (2011) Investigational therapies for ischemic stroke: neuroprotection and neurorecovery. Neurotherapeutics 8:434–451

    Article  CAS  PubMed  Google Scholar 

  • Sánchez A, Tripathy D, Yin X, Luo J, Martínez J, Grammas P (2012) Pigment epithelium-derived factor (PEDF) protects cortical neurons in vitro from oxidant injury by activation of extracellular signal-regulated kinase (ERK) 1/2 and induction of Bcl-2. Neurosci Res 72:1–8

    Article  PubMed Central  PubMed  Google Scholar 

  • Satoh T, Nakatsuka D, Watanabe Y, Nagata I, Kikuchi H, Namura S (2000) Neuroprotection by MAPK/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons. Neurosci Lett 288:163–166

    Article  CAS  PubMed  Google Scholar 

  • Schousboe A, Waagepetersen HS (2005) Role of astrocytes in glutamate homeostasis: implications for excitotoxicity. Neurotox Res 8:221–225

    Article  CAS  PubMed  Google Scholar 

  • Segura Torres JE, Chaparro-Huerta V, Rivera Cervantes MC, Montes-González R, Flores Soto ME, Beas-Zárate C (2006) Neuronal cell death due to glutamate excitotoxicity is mediated by p38 activation in the rat cerebral cortex. Neurosci Lett 403:233–238

    Article  CAS  PubMed  Google Scholar 

  • Son TG, Park HR, Kim SJ et al (2009) Senescence marker protein 30 is up-regulated in kainate-induced hippocampal damage through ERK-mediated astrocytosis. J Neurosci Res 87:2890–2897

    Article  CAS  PubMed  Google Scholar 

  • Thangavelu K, Pan CQ, Karlberg T et al (2012) Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf–Mek–Erk signaling in cancer cell metabolism. Proc Natl Acad Sci U S A 109:7705–7710

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tischkau SA, Gallman EA, Buchanan GF, Gillette MU (2000) Differential cAMP gating of glutamatergic signaling regulates long-term state changes in the suprachiasmatic circadian clock. J Neurosci 20:7830–7837

    CAS  PubMed  Google Scholar 

  • Verheij M, Ruiter GA, Zerp SF et al (1998) The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis. Radiother Oncol 47:225–232

    Article  CAS  PubMed  Google Scholar 

  • Wang CX, Song JH, Song DK, Yong VW, Shuaib A, Hao C (2006) Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2. Cell Death Differ 13:1203–1212

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Zhu G, Yang S et al (2011) Paeonol prevents excitotoxicity in rat pheochromocytoma PC12 cells via downregulation of ERK activation and inhibition of apoptosis. Planta Med 77:1695–1701

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Qin ZH (2010) Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis 15:1382–1402

    Article  CAS  PubMed  Google Scholar 

  • Wu TW, Wang JM, Chen S, Brinton RD (2005) 17Beta-estradiol induced Ca2+ influx via l-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and Bcl-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience 135:59–72

    Article  CAS  PubMed  Google Scholar 

  • Yoon CH, Kim MJ, Park MT et al (2009) Activation of p38 mitogen-activated protein kinase is required for death receptor-independent caspase-8 activation and cell death in response to sphingosine. Mol Cancer Res 7:361–370

    Article  CAS  PubMed  Google Scholar 

  • Zachary I (2005) Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals 14:207–221

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Zhang D, McQuade JS, Behbehani M, Tsien JZ, Xu M (2002) c-fos regulates neuronal excitability and survival. Nat Genet 30:416–420

    Article  CAS  PubMed  Google Scholar 

  • Zhu X, Lee H-G, Raina AK, Perry G, Smith MA (2003) The role of mitogen-activated protein kinase pathways in Alzheimer’s disease. Neurosignals 11:270–281

    Article  Google Scholar 

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Acknowledgments

This work was partially supported by the Network GENIAR from CYTED (the Program for Science and Technology for Development), by Universidad de Guadalajara P3E/2012/137505 to DO-S, and by CONACyT Grant No. 0177594 to CB-Z.

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Authors and Affiliations

  1. Laboratorio de Desarrollo y Regeneración Neural, Instituto de Neurobiología, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Camino Ing. R. Padilla Sánchez, 2100, Las Agujas, Zapopan, 44600, Jalisco, Mexico

    Daniel Ortuño-Sahagún & C. Beas Zárate

  2. Laboratory of Cellular and Molecular Neurobiology, Division of Neuroscience, CIBO, IMSS, Guadalajara, Jalisco, Mexico

    Raúl Montes González, Verónica Chaparro Huerta & C. Beas Zárate

  3. Department of Cellular Biology, Faculty of Biology, University of Barcelona, Nucli Universitari de Pedralbes, 08028, Barcelona, Spain

    Ester Verdaguer

  4. Centro de Investigación Biomédica de Occidente, IMSS, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    Blanca M. Torres-Mendoza

  5. Depto. de Neonatología, Hosp. de Pediatría, CMNO, IMSS, Guadalajara, Jalisco, Mexico

    Lourdes Lemus

  6. Lab. of Neurobiol. Cell. and Molec., Neurobiol. Inst., Dept. of Cell and Molec. Biology, CUCBA, University of Guadalajara, Guadalajara, Jalisco, Mexico

    Martha Catalina Rivera-Cervantes

  7. Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028, Barcelona, Spain

    A. Camins

  8. Laboratory of Regeneration and Neuronal Development, Department of Cell and Molecular Biology, CUCBA, University of Guadalajara, Km. 15.5 Carr. Nogales, Zapopan, Jalisco, Mexico

    C. Beas Zárate

Authors
  1. Daniel Ortuño-Sahagún
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  2. Raúl Montes González
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  3. Ester Verdaguer
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  4. Verónica Chaparro Huerta
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  5. Blanca M. Torres-Mendoza
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  6. Lourdes Lemus
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  7. Martha Catalina Rivera-Cervantes
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  8. A. Camins
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  9. C. Beas Zárate
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Corresponding author

Correspondence to C. Beas Zárate.

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Raúl Montes González and Ester Verdaguer contributed equally to this work.

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Ortuño-Sahagún, D., González, R.M., Verdaguer, E. et al. Glutamate Excitotoxicity Activates the MAPK/ERK Signaling Pathway and Induces the Survival of Rat Hippocampal Neurons In Vivo. J Mol Neurosci 52, 366–377 (2014). https://doi.org/10.1007/s12031-013-0157-7

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