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Activation of NF-κB p65/c-Rel dimer is associated with neuroprotection elicited by mGlu5 receptor agonists against MPP+ toxicity in SK-N-SH cells

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Nuclear factor-κB (NF-κB) is a transcriptional regulator of neuron survival eliciting diverse effects according to the specific composition of its active dimer. While p50/p65 mediates neurodegenerative events, c-Rel-containing dimers promote cell survival. Stimulation of metabotropic glutamate receptors type 5 (mGlu5) reduces neuron vulnerability to amyloid-β through activation of anti-apoptotic, c-Rel-dependent transcription of Bcl-XL pathway. We here evaluated the protective activity of mGlu5 agonists in dopaminergic SK-N-SH cells exposed to 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causing parkinsonism in experimental animals. MPP+ produced a concentration-dependent cell loss. Activation of mGlu5 receptors by CHPG (1 mM) and 3HPG (50 μM) abolished the toxic effect produced by 3 μM MPP+. The neuroprotection was associated with activation of NF-κB p65/c-Rel dimer and reduction of p50/p65. These effects were prevented by the mGlu5 receptor antagonist MPEP (5 μM). It is suggested that mGlu5 receptor agonists through activation of a c-Rel-dependent anti-apoptotic pathway can rescue dopaminergic cell from mitochondrial toxicity.

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Abbreviations

MPP+ :

1-Methyl-4-phenylpyridinium ion

CHPG:

(R,S)-2-Chloro-5-hydroxyphenylglycine

3HPG:

(S)-3-Hydroxy-phenyl-glycine

mGlu receptor:

Metabotropic glutamate receptor

MPEP:

2-Methyl-6-phenylethynyl-pyridine

NF-κB:

Nuclear factor-κB

References

  • Allen JW, Knoblach SM, Faden AI (2000) Activation of group I metabotropic glutamate receptors reduces neuronal apoptosis but increases necrotic cell death in vitro. Cell Death Differ 7:470–476

    Article  PubMed  CAS  Google Scholar 

  • Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D (2003) Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 17:2106–2118

    Article  PubMed  Google Scholar 

  • Arora PK, Riachi NJ, Fiedler GC, Singh MP, Abdallah F, Harik SI, Sayre LM (1990) Structure-neurotoxicity trends of analogues of 1-methyl-4-phenylpyridinium (MPP+), the cytotoxic metabolite of the dopaminergic neurotoxin MPTP. Life Sci 46:379–390

    Article  PubMed  CAS  Google Scholar 

  • Bao WL, Williams AJ, Faden AI, Tortella FC (2001) Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia. Brain Res 922:173–179

    Article  PubMed  CAS  Google Scholar 

  • Battaglia G, Fornai F, Busceti CL, Aloisi G, Cerrito F, De Blasi A, Melchiorri D, Nicoletti F (2002) Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity. J Neurosci 22:2135–2141

    PubMed  CAS  Google Scholar 

  • Battaglia G, Busceti CL, Molinaro G, Biagioni F, Storto M, Fornai F, Nicoletti F, Bruno V (2004) Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. J Neurosci 24:828–835

    Article  PubMed  CAS  Google Scholar 

  • Biedler JL, Roffler-Tarlov S, Schachner M, Freedman LS (1978) Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res 38:3751–3757

    PubMed  CAS  Google Scholar 

  • Bruno V, Battaglia G, Copani A, Cespedes VM, Galindo MF, Cena V, Sanchez-Prieto J, Gasparini F, Kuhn R, Flor PJ, Nicoletti F (2001) An activity-dependent switch from facilitation to inhibition in the control of excitotoxicity by group I metabotropic glutamate receptors. Eur J Neurosci 13:1469–1478

    Article  PubMed  CAS  Google Scholar 

  • Buck KJ, Amara SG (1994) Chimeric dopamine-norepinephrine transporters delineate structural domains influencing selectivity for catecholamines and 1-methyl-4-phenylpyridinium. Proc Natl Acad Sci USA 91:12584–12588

    Article  PubMed  CAS  Google Scholar 

  • Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80:4546–4550

    Article  PubMed  CAS  Google Scholar 

  • Ciccarone V, Spengler BA, Meyers MB, Biedler JL, Ross RA (1989) Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages. Cancer Res 49:219–225

    PubMed  CAS  Google Scholar 

  • Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88:494–501

    Article  PubMed  CAS  Google Scholar 

  • Fall CP, Bennett JP Jr (1999) Characterization and time course of MPP+-induced apoptosis in human SH-SY5Y neuroblastoma cells. J Neurosci Res 55:620–628

    Article  PubMed  CAS  Google Scholar 

  • Farooqui SM (1994) Induction of adenylate cyclase sensitive dopamine D2-receptors in retinoic acid induced differentiated human neuroblastoma SHSY-5Y cells. Life Sci 55:1887–1893

    Article  PubMed  CAS  Google Scholar 

  • Ghribi O, Herman MM, Pramoonjago P, Savory J (2003) MPP+ induces the endoplasmic reticulum stress response in rabbit brain involving activation of the ATF-6 and NF-kappaB signaling pathways. J Neuropathol Exp Neurol 62:1144–1153

    PubMed  CAS  Google Scholar 

  • Gosh S, May, Kopp EB (1998) NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Ann Rev Immunol 16:225–260

    Article  Google Scholar 

  • Herrero I, Miras-Portugal MT, Sanchez-Prieto J (1998) Functional switch from facilitation to inhibition in the control of glutamate release by metabotropic glutamate receptors. J Biol Chem 273:1951–1958

    Article  PubMed  CAS  Google Scholar 

  • Inta I, Paxian S, Maegele I, Zhang W, Pizzi M, Spano PF, Sarnico I, Muhammad S, Herrmann O, Inta D, Baumann B, Liou HC, Schmid RM, Schwaninger M (2006) Bim and Noxa are candidates to mediate the deleterious effect of the NF-kappa B subunit RelA in cerebral ischemia. J Neurosci 26:12896–12903

    Article  PubMed  CAS  Google Scholar 

  • Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Disord 13(Suppl 1):24–34

    PubMed  Google Scholar 

  • Keeney PM, Xie J, Capaldi RA, Bennett JP Jr (2006) Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci 26(19):5256–5264

    Article  PubMed  CAS  Google Scholar 

  • Kitamura Y, Shimohama S, Akaike A, Taniguchi T (2000) The parkinsonian models: invertebrates to mammals. Japanese J Pharmacol 84:237–243

    Article  CAS  Google Scholar 

  • Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980

    Article  PubMed  CAS  Google Scholar 

  • Lea PM 4th, Faden AI (2003) Modulation of metabotropic glutamate receptors as potential treatment for acute and chronic neurodegenerative disorders. Drug News Perspect 16:513–522

    Article  PubMed  CAS  Google Scholar 

  • Lipton KP, Singer IP (1993) Advances in our understanding of the mechanisms toxicity of MPTP and related compounds. J Neurochem 61:1191–1206

    Article  Google Scholar 

  • Liu J, Wang CY, O’Brien JS (2001) Prosaptide D5, a retro-inverso 11-mer peptidomimetic, rescued dopaminergic neurons in a model of Parkinson’s disease. FASEB J 15:1080–1082

    Article  PubMed  CAS  Google Scholar 

  • Montoliu C, Llansola M, Cucarella C, Grisolia S, Felipo V (1997) Activation of the metabotropic glutamate receptor mGluR5 prevents glutamate toxicity in primary cultures of cerebellar neurons. J Pharmacol Exp Ther 281:643–647

    PubMed  CAS  Google Scholar 

  • Moratalla R, Quinn B, DeLanney LE, Irwin I, Langston JW, Graybiel AM (1992) Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 89:3859–3863

    Article  PubMed  CAS  Google Scholar 

  • Movsesyan VA, O’Leary DM, Fan L, Bao W, Mullins PG, Knoblach SM, Faden AI (2001) mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 296:41–47

    PubMed  CAS  Google Scholar 

  • Noda Y, Sumino T, Fujisawa Y, Miyata N, Kaiya T, Kohda K (2004) 1-Amino-4-phenyl-1, 2, 3, 6-tetrahydropyridine and 1-amino-4-phenylpyridinium salt, the 1-amino analogues of neurotoxins, MPTP and MPP+, induce apoptosis in PC12 cells: detection of apoptotic cells by comet assay and flow cytometric analysis. In Vivo 18:561–569

    PubMed  CAS  Google Scholar 

  • Pizzi M, Spano P (2006) Distinct roles of diverse nuclear factor-kappaB complexes in neuropathological mechanisms. Eur J Pharmacol 545:22–28

    Article  PubMed  CAS  Google Scholar 

  • Pizzi M, Boroni F, Bianchetti A, Moraitis C, Sarnico I, Benarese M, Goffi F, Valerio A, Spano P (2002a) Expression of functional NR1/NR2B-type NMDA receptors in neuronally differentiated SK-N-SH human cell line. Eur J Neurosci 16:2342–2350

    Article  PubMed  Google Scholar 

  • Pizzi M, Goffi F, Boroni F, Benarese M, Perkins SE, Liou HC, Spano P (2002b) Opposing roles for NF-kappa B/Rel factors p65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1beta. J Biol Chem 277:20717–20723

    Article  PubMed  CAS  Google Scholar 

  • Pizzi M, Sarnico I, Boroni F, Benarese M, Steimberg N, Mazzoleni G, Dietz GPH, Bähr M, Liou HC, Spano PF (2005) NF-kappaB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid beta-peptide toxicity. Cell Death Differ 12:761–772

    Article  PubMed  CAS  Google Scholar 

  • Przedborski S (2005) Pathogenesis of nigral cell death in Parkinson’s disease. Parkinsonism Relat Disord 11(Suppl 1):S3-S7

    Article  PubMed  Google Scholar 

  • Richards ML, Sadee W (1986) Human neuroblastoma cell lines as models of catechol uptake. Brain Res 384:132–137

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Moreno A, Sistiaga A, Lerma J, Sanchez-Prieto J (1998) Switch from facilitation to inhibition of excitatory synaptic transmission by group I mGluR desensitization. Neuron 21:1477–1486

    Article  PubMed  CAS  Google Scholar 

  • Sagara Y, Schubert D (1998) The activation of metabotropic glutamate receptors protects nerve cells from oxidative stress. J Neurosci 18:6662–6671

    PubMed  CAS  Google Scholar 

  • Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5:554–559

    Article  PubMed  CAS  Google Scholar 

  • Sistiaga A, Herrero I, Conquet F, Sanchez-Prieto J (1998) The metabotropic glutamate receptor 1 is not involved in the facilitation of glutamate release in cerebrocortical nerve terminals. Neuropharmacology 37:1485–1492

    Article  PubMed  CAS  Google Scholar 

  • Storch A, Ludolph AC, Schwarz J (2004) Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration. J Neural Transm 111:1267–1286

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP, Davis RE, Parker WD (1996) Origin and functional consequences of the complex I defect in Parkinson’s disease. Ann Neurol 40:663–671

    Article  PubMed  CAS  Google Scholar 

  • Valerio A, Rizzonelli P, Paterlini M, Moretto G, Knopfel T, Kuhn R, Memo M, Spano P (1997) mGluR5 metabotropic glutamate receptor distribution in rat and human spinal cord: a developmental study. Neurosci Res 28:49–57

    Article  PubMed  CAS  Google Scholar 

  • Wang C, Sadovova N, Ali HK, Duhart HM, Fu X, Zou X, Patterson TA, Binienda ZK, Virmani A, Paule MG, Slikker W Jr, Ali SF (2007) l-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture. Neuroscience 144:46–55

    Article  PubMed  CAS  Google Scholar 

  • Yang J, Liu X, Bhalla K, Kim CN, Ibrado A, Cai J (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from Italian Ministry of Education, University and Scientific Research-PRIN 2004, 2005 and 2006; Center of Study and Research on Ageing, Brescia; MIUR Center of Excellence for Innovative Diagnostics and Therapeutics (IDET) of Brescia University.

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Authors and Affiliations

  1. Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Viale Europa 11, Brescia, 25123, Italy

    I. Sarnico, F. Boroni, M. Benarese, S. Sigala, A. Lanzillotta, P. Spano & M. Pizzi

  2. Istituto Ricovero e Cura a Carattere Scientifico, S. Camillo Hospital, 30100, Venice, Italy

    L. Battistin & P. Spano

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  1. I. Sarnico
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  2. F. Boroni
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  5. A. Lanzillotta
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  8. M. Pizzi
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Correspondence to M. Pizzi.

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Sarnico, I., Boroni, F., Benarese, M. et al. Activation of NF-κB p65/c-Rel dimer is associated with neuroprotection elicited by mGlu5 receptor agonists against MPP+ toxicity in SK-N-SH cells. J Neural Transm 115, 669–676 (2008). https://doi.org/10.1007/s00702-007-0007-2

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  • DOI: https://doi.org/10.1007/s00702-007-0007-2

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