MPP+-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine
| Autor: | Michel P. Rathbone, Christian Bau, Kathleen M. Pettifer, Patrizia Ballerini, Shucui Jiang, Eva S. Werstiuk, Iolanda D'Alimonte |
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| Rok vydání: | 2007 |
| Předmět: |
Programmed cell death
Cytotoxicity Guanosine Apoptosis DNA fragmentation Biology Pertussis toxin Cell survival 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Neurotoxin Molecular Biology Protein kinase B 030304 developmental biology Original Paper 0303 health sciences Cell Biology SH-SY5Y human neuroblastoma cells Molecular biology 3. Good health Caspase-3 chemistry Parkinson’s disease 1-methyl–4-phenyl-pyridinium (MPP+) 030217 neurology & neurosurgery |
| Zdroj: | Purinergic Signalling |
| ISSN: | 1573-9546 1573-9538 |
| Popis: | 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 muM-5 mM for 24-72 h) induced DNA fragmentation in a time-dependent manner (p0.05). Administration of guanosine (100 muM) before, concomitantly with or, importantly, after the addition of MPP(+) abolished MPP(+)-induced DNA fragmentation. Addition of MPP(+) (500 muM) to cells increased caspase-3 activity over 72 h (p0.05), 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 alpha-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. |
| Databáze: | OpenAIRE |
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