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MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine
Guanosine exerts neuroprotective effects in the central nervous system. Apoptosis, a morphological form of programmed cell death, is implicated in the pathophysiology of Parkinson’s disease (PD). MPP(+), a dopaminergic neurotoxin, produces in vivo and in vitro cellular changes characteristic of PD,...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Springer Netherlands
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072917/ https://www.ncbi.nlm.nih.gov/pubmed/18404453 http://dx.doi.org/10.1007/s11302-007-9073-z |
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author | Pettifer, Kathleen M. Jiang, Shucui Bau, Christian Ballerini, Patrizia D’Alimonte, Iolanda Werstiuk, Eva S. Rathbone, Michel P. |
author_facet | Pettifer, Kathleen M. Jiang, Shucui Bau, Christian Ballerini, Patrizia D’Alimonte, Iolanda Werstiuk, Eva S. Rathbone, Michel P. |
author_sort | Pettifer, Kathleen M. |
collection | PubMed |
description | Guanosine exerts neuroprotective effects in the central nervous system. Apoptosis, a morphological form of programmed cell death, is implicated in the pathophysiology of Parkinson’s disease (PD). MPP(+), a dopaminergic neurotoxin, produces in vivo and in vitro cellular changes characteristic of PD, such as cytotoxicity, resulting in apoptosis. Undifferentiated human SH-SY5Y neuroblastoma cells had been used as an in vitro model of Parkinson’s disease. We investigated if extracellular guanosine affected MPP(+)-induced cytotoxicity and examined the molecular mechanisms mediating its effects. Exposure of neuroblastoma cells to MPP(+) (10 μM–5 mM for 24–72 h) induced DNA fragmentation in a time-dependent manner (p < 0.05). Administration of guanosine (100 μM) before, concomitantly with or, importantly, after the addition of MPP(+) abolished MPP(+)-induced DNA fragmentation. Addition of MPP(+) (500 μM) to cells increased caspase-3 activity over 72 h (p < 0.05), and this was abolished by pre- or co-treatment with guanosine. Exposure of cells to pertussis toxin prior to MPP(+) eliminated the anti-apoptotic effect of guanosine, indicating that this effect is dependent on a Gi protein-coupled receptor, most likely the putative guanosine receptor. The protection by guanosine was also abolished by the selective inhibitor of the enzyme PI-3-K/Akt/PKB (LY294002), confirming that this pathway plays a decisive role in this effect of guanosine. Neither MPP(+) nor guanosine had any significant effect on α-synuclein expression. Thus, guanosine antagonizes and reverses MPP(+)-induced cytotoxicity of neuroblastoma cells via activation of the cell survival pathway, PI-3-K/Akt/PKB. Our results suggest that guanosine may be an effective pharmacological intervention in PD. |
format | Text |
id | pubmed-2072917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-20729172008-02-27 MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine Pettifer, Kathleen M. Jiang, Shucui Bau, Christian Ballerini, Patrizia D’Alimonte, Iolanda Werstiuk, Eva S. Rathbone, Michel P. Purinergic Signal Original Paper Guanosine exerts neuroprotective effects in the central nervous system. Apoptosis, a morphological form of programmed cell death, is implicated in the pathophysiology of Parkinson’s disease (PD). MPP(+), a dopaminergic neurotoxin, produces in vivo and in vitro cellular changes characteristic of PD, such as cytotoxicity, resulting in apoptosis. Undifferentiated human SH-SY5Y neuroblastoma cells had been used as an in vitro model of Parkinson’s disease. We investigated if extracellular guanosine affected MPP(+)-induced cytotoxicity and examined the molecular mechanisms mediating its effects. Exposure of neuroblastoma cells to MPP(+) (10 μM–5 mM for 24–72 h) induced DNA fragmentation in a time-dependent manner (p < 0.05). Administration of guanosine (100 μM) before, concomitantly with or, importantly, after the addition of MPP(+) abolished MPP(+)-induced DNA fragmentation. Addition of MPP(+) (500 μM) to cells increased caspase-3 activity over 72 h (p < 0.05), and this was abolished by pre- or co-treatment with guanosine. Exposure of cells to pertussis toxin prior to MPP(+) eliminated the anti-apoptotic effect of guanosine, indicating that this effect is dependent on a Gi protein-coupled receptor, most likely the putative guanosine receptor. The protection by guanosine was also abolished by the selective inhibitor of the enzyme PI-3-K/Akt/PKB (LY294002), confirming that this pathway plays a decisive role in this effect of guanosine. Neither MPP(+) nor guanosine had any significant effect on α-synuclein expression. Thus, guanosine antagonizes and reverses MPP(+)-induced cytotoxicity of neuroblastoma cells via activation of the cell survival pathway, PI-3-K/Akt/PKB. Our results suggest that guanosine may be an effective pharmacological intervention in PD. Springer Netherlands 2007-10-03 2007-09 /pmc/articles/PMC2072917/ /pubmed/18404453 http://dx.doi.org/10.1007/s11302-007-9073-z Text en © Springer Science + Business Media B.V. 2007 |
spellingShingle | Original Paper Pettifer, Kathleen M. Jiang, Shucui Bau, Christian Ballerini, Patrizia D’Alimonte, Iolanda Werstiuk, Eva S. Rathbone, Michel P. MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine |
title | MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine |
title_full | MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine |
title_fullStr | MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine |
title_full_unstemmed | MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine |
title_short | MPP(+)-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine |
title_sort | mpp(+)-induced cytotoxicity in neuroblastoma cells: antagonism and reversal by guanosine |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072917/ https://www.ncbi.nlm.nih.gov/pubmed/18404453 http://dx.doi.org/10.1007/s11302-007-9073-z |
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