Skip to main content
SpringerLink
Log in

Guanosine Protects Glial Cells Against 6-Hydroxydopamine Toxicity

  • Chapter
  • First Online:
Neurotransmitter Interactions and Cognitive Function

Part of the book series: Advances in Experimental Medicine and Biology ((NR,volume 837))

Abstract

Increasing body of evidence indicates that neuron-neuroglia interaction may play a key role in determining the progression of neurodegenerative diseases including Parkinson’s disease (PD), a chronic pathological condition characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra. We have previously reported that guanosine (GUO) antagonizes MPP+-induced cytotoxicity in neuroblastoma cells and exerts neuroprotective effects against 6-hydroxydopamine (6-OHDA) and beta-amyloid-induced apoptosis of SH-SY5Y cells. In the present study we demonstrate that GUO protected C6 glioma cells, taken as a model system for astrocytes, from 6-OHDA-induced neurotoxicity. We show that GUO, either alone or in combination with 6-OHDA activated the cell survival pathways ERK and PI3K/Akt. The involvement of these signaling systems in the mechanism of the nucleoside action was strengthened by a reduction of the protective effect when glial cells were pretreated with U0126 or LY294002, the specific inhibitors of MEK1/2 and PI3K, respectively. Since the protective effect on glial cell death of GUO was not affected by pretreatment with a cocktail of nucleoside transporter blockers, GUO transport and its intracellular accumulation were not at play in our in vitro model of PD. This fits well with our data which pointed to the presence of specific binding sites for GUO on rat brain membranes. On the whole, the results described in the present study, along with our recent evidence showing that GUO when administered to rats via intraperitoneal injection is able to reach the brain and with previous data indicating that it stimulates the release of neurotrophic factors, suggest that GUO, a natural compound, by acting at the glial level could be a promising agent to be tested against neurodegeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abe K, Saito H (2000) Neurotrophic effect of basic fibroblast growth factor is mediated by the p42/p44 mitogen-activated protein kinase cascade in cultured rat cortical neurons. Brain Res Dev Brain Res 122:81–85

    Article  CAS  PubMed  Google Scholar 

  • Andrew R, Watson DG, Best SA, Midgley JM, Wenlong H, Petty RK (1993) The determination of hydroxydopamines and other trace amines in the urine of Parkinsonian patients and normal controls. Neurochem Res 18:1175–1177

    Article  CAS  PubMed  Google Scholar 

  • Barnum CJ, Tansey MG (2010) Modeling neuroinflammatory pathogenesis of Parkinson’s disease. Prog Brain Res 184:113–132

    Article  CAS  PubMed  Google Scholar 

  • Birkmayer W, Hornykiewicz O (1961) The L-3,4-dihydroxyphenylalanine (DOPA)-effect in Parkinson-akinesia. Wien Klin Wochenschr 73:787–788

    CAS  PubMed  Google Scholar 

  • Blum D, Torch S, Nissou MF, Benabid AL, Verna JM (2000) Extracellular toxicity of 6-hydroxydopamine on PC12 cells. Neurosci Lett 283:193–196

    Article  CAS  PubMed  Google Scholar 

  • Curtius HC, Wolfensberger M, Steinmann B, Redweik U, Siegfried J (1974) Mass fragmentography of dopamine and 6-hydroxydopamine. Application to the determination of dopamine in human brain biopsies from the caudate nucleus. J Chromatogr 99:529–540

    Article  CAS  PubMed  Google Scholar 

  • D’Alimonte I, Ciccarelli R, Di Iorio P, Nargi E, Buccella S, Giuliani P, Rathbone MP, Jiang S, Caciagli F, Ballerini P (2007) Activation of P2X(7) receptors stimulates the expression of P2Y(2) receptor mRNA in astrocytes cultured from rat brain. Int J Immunopathol Pharmacol 20:301–316

    PubMed  Google Scholar 

  • Damier P, Kastner A, Agid Y, Hirsch EC (1996) Does monoamine oxidase type B play a role in dopaminergic nerve cell death in Parkinson’s disease? Neurology 46:1262–1269

    Article  CAS  PubMed  Google Scholar 

  • Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909

    Article  CAS  PubMed  Google Scholar 

  • Di Iorio P, Ballerini P, Traversa U, Nicoletti F, D’Alimonte I, Kleywegt S, Werstiuk ES, Rathbone MP, Caciagli F, Ciccarelli R (2004) The antiapoptotic effect of guanosine is mediated by the activation of the PI 3-kinase/AKT/PKB pathway in cultured rat astrocytes. Glia 46:356–368

    Article  PubMed  Google Scholar 

  • Fitzgerald LW, Kaplinsky L, Kimelberg HK (1990) Serotonin metabolism by monoamine oxidase in rat primary astrocyte cultures. J Neurochem 55:2008–2014

    Article  CAS  PubMed  Google Scholar 

  • Fujita KA, Ostaszewski M, Matsuoka Y, Ghosh S, Glaab E, Trefois C, Crespo I, Perumal TM, Jurkowski W, Antony PM, Diederich N, Buttini M, Kodama A, Satagopam VP, Eifes S, Del Sol A, Schneider R, Kitano H, Balling R (2013) Integrating pathways of Parkinson’s disease in a molecular interaction map. Mol Neurobiol 49:88–102

    Article  PubMed Central  PubMed  Google Scholar 

  • Giuliani P, Ballerini P, Ciccarelli R, Buccella S, Romano S, D’Alimonte I, Poli A, Beraudi A, Peña E, Jiang S, Rathbone MP, Caciagli F, Di Iorio P (2012a) Tissue distribution and metabolism of guanosine in rats following intraperitoneal injection. J Biol Regul Homeost Agents 26:51–65

    CAS  PubMed  Google Scholar 

  • Giuliani P, Romano S, Ballerini P, Ciccarelli R, Petragnani N, Cicchitti S, Zuccarini M, Jiang S, Rathbone MP, Caciagli F, Di Iorio P (2012b) Protective activity of guanosine in an in vitro model of Parkinson’s disease. Panminerva Med 54(1 Suppl 4):43–51

    CAS  PubMed  Google Scholar 

  • Häcker G (2000) The morphology of apoptosis. Cell Tissue Res 301:5–17

    Article  PubMed  Google Scholar 

  • Han BH, Holtzman DM (2000) BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 20:5775–5781

    CAS  PubMed  Google Scholar 

  • Hansson E, Sellstrom A (1983) MAO, COMT, and GABA-T activities in primary astroglial cultures. J Neurochem 40:220–225

    Article  CAS  PubMed  Google Scholar 

  • Inazu M, Kubota N, Takeda H, Zhang J, Kiuchi Y, Oguchi K, Matsumiya T (1999a) Pharmacological characterization of dopamine transport in cultured rat astrocytes. Life Sci 64:2239–2245

    Article  CAS  PubMed  Google Scholar 

  • Inazu M, Takeda H, Ikoshi H, Uchida Y, Kubota N, Kiuchi Y, Oguchi K, Matsumiya T (1999b) Regulation of dopamine uptake by basic fibroblast growth factor and epidermal growth factor in cultured rat astrocytes. Neurosci Res 34:235–244

    Article  CAS  PubMed  Google Scholar 

  • Jin K, Mao XO, Zhu Y, Greenberg DA (2002) MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. J Neurochem 80:119–125

    Article  CAS  PubMed  Google Scholar 

  • Jin CM, Yang YJ, Huang HS, Kai M, Lee MK (2010) Mechanisms of L-DOPA-induced cytotoxicity in rat adrenal pheochromocytoma cells: implication of oxidative stress-related kinases and cyclic AMP. Neuroscience 170:390–398

    Article  CAS  PubMed  Google Scholar 

  • Kulich SM, Chu CT (2001) Sustained extracellular signal‐regulated kinase activation by 6‐hydroxydopamine: implications for Parkinson’s disease. J Neurochem 77:1058–1066

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee C, Park GH, Jang JH (2011) Cellular antioxidant adaptive survival response to 6-hydroxydopamine-induced nitrosative cell death in C6 glioma cells. Toxicology 283:118–128

    Article  CAS  PubMed  Google Scholar 

  • Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJL (1994) Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: evidence that astrocytes play an important role in antioxidative processes in the brain. J Neurochem 62:45–53

    Article  CAS  PubMed  Google Scholar 

  • Mayo JC, Sainz RM, Antolín I, Rodriguez C (1999) Ultrastructural confirmation of neuronal protection by melatonin against the neurotoxin 6-hydroxydopamine cell damage. Brain Res 818:221–227

    Article  CAS  PubMed  Google Scholar 

  • McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483

    Article  PubMed  Google Scholar 

  • McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol 56:149–162

    Article  CAS  PubMed  Google Scholar 

  • Mena MA, García de Yébenes J (2008) Glial cells as players in parkinsonism: the ‘good’, the ‘bad’, and the ‘mysterious’ glia. Neuroscientist 14:544–560

    Article  CAS  PubMed  Google Scholar 

  • Parkinson FE, Ferguson J, Zamzow CR, Xiong W (2006) Gene expression for enzymes and transporters involved in regulating adenosine and inosine levels in rat forebrain neurons, astrocytes and C6 glioma cells. J Neurosci Res 84:801–808

    Article  CAS  PubMed  Google Scholar 

  • Pelton EW, Kimelberg HK, Shipherd SV, Bourke RS (1981) Dopamine and norepinephrine uptake and metabolism by astroglial cells in culture. Life Sci 28:1655–1663

    Article  CAS  PubMed  Google Scholar 

  • Pettifer KM, Kleywegt S, Bau CJ, Ramsbottom JD, Vertes E, Ciccarelli R, Caciagli F, Werstiuk ES, Rathbone MP (2004) Guanosine protects SH-SY5Y cells against beta-amyloid-induced apoptosis. Neuroreport 15:833–836

    Article  CAS  PubMed  Google Scholar 

  • Pettifer KM, Jiang S, Bau C, Ballerini P, D’Alimonte I, Werstiuk ES, Rathbone MP (2007) MPP(+)-induced cytotoxicity in neuroblastoma cells: antagonism and reversal by guanosine. Purinergic Signal 3:399–409

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sagara JI, Miura K, Bannai S (1993) Maintenance of neuronal glutathione by glial cells. J Neurochem 61:1672–1676

    Article  CAS  PubMed  Google Scholar 

  • Su C, Elfeki N, Ballerini P, D’Alimonte I, Bau C, Ciccarelli R, Caciagli F, Gabriele J, Jiang S (2009) Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism. J Neurosci Res 87:617–625

    Article  CAS  PubMed  Google Scholar 

  • Timmons S, Coakley MF, Moloney AM, O’ Neill C (2009) Akt signal transduction dysfunction in Parkinson’s disease. Neurosci Lett 467:30–35

    Article  CAS  PubMed  Google Scholar 

  • Traversa U, Bombi G, Di Iorio P, Ciccarelli R, Werstiuk ES, Rathbone MP (2002) Specific [(3)H]-guanosine binding sites in rat brain membranes. Br J Pharmacol 135:969–976

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Traversa U, Bombi G, Camaioni E, Macchiarulo A, Costantino G, Palmier C, Caciagli F, Pellicciari R (2003) Rat brain guanosine binding site. Biological studies and pseudo-receptor construction. Bioorg Med Chem 11:5417–5425

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

PG and PB contributed to this work equally.

Conflicts of Interest

The authors declare no conflicts of interest in realtion to this article.

Author information

Authors and Affiliations

  1. Department of Experimental and Clinical Sciences, “G. d’Annunzio” University, Chieti-Pescara, 29 via dei Vestini, NPD PalB, 66013, Chieti, Italy

    Patricia Giuliani, Silvana Buccella, Renata Ciccarelli, Silvia Romano, Iolanda D’Alimonte, Francesco Caciagli & Patrizia Di Iorio

  2. Department of Psychological, Humanities and Territory Sciences, School of Medicine and Health Sciences, “G. d’Annunzio” University, Chieti-Pescara, 29 via dei Vestini, NPD PalB, 66013, Chieti, Italy

    Patrizia Ballerini

  3. Department of Medicine, McMaster University, Health Sciences Center, Hamilton, ON, Canada

    Michel P. Rathbone

  4. Department of Nursing, Public Higher Medical Professional School in Opole, 68 Katowicka St., 45-060, Opole, Poland

    Mieczyslaw Pokorski

  5. Institute of Psychology, Opole University, 1 Plac Staszica, 45-052, Opole, Poland

    Mieczyslaw Pokorski

Authors
  1. Patricia Giuliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrizia Ballerini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvana Buccella
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renata Ciccarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michel P. Rathbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Silvia Romano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Iolanda D’Alimonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesco Caciagli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patrizia Di Iorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mieczyslaw Pokorski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Patrizia Ballerini or Mieczyslaw Pokorski .

Editor information

Editors and Affiliations

  1. Institute of Psychology, Opole University, Poland

    Mieczyslaw Pokorski

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Giuliani, P. et al. (2014). Guanosine Protects Glial Cells Against 6-Hydroxydopamine Toxicity. In: Pokorski, M. (eds) Neurotransmitter Interactions and Cognitive Function. Advances in Experimental Medicine and Biology(), vol 837. Springer, Cham. https://doi.org/10.1007/5584_2014_73

Download citation

Publish with us

Policies and ethics

Search

Navigation