MPP+-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine
Identifieur interne : 002459 ( Main/Exploration ); précédent : 002458; suivant : 002460MPP+-induced cytotoxicity in neuroblastoma cells: Antagonism and reversal by guanosine
Auteurs : Kathleen M. Pettifer [Canada] ; Shucui Jiang [Canada] ; Christian Bau [Canada] ; Patrizia Ballerini [Italie] ; Iolanda D Limonte [Italie] ; Eva S. Werstiuk [Canada] ; Michel P. Rathbone [Canada]Source :
- Purinergic Signalling [ 1573-9538 ] ; 2007.
Abstract
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 (
Url:
DOI: 10.1007/s11302-007-9073-z
PubMed: 18404453
PubMed Central: 2072917
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>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<sup>+</sup>
, 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<sup>+</sup>
-induced cytotoxicity and examined the molecular mechanisms mediating its effects. Exposure of neuroblastoma cells to MPP<sup>+</sup>
(10 μM–5 mM for 24–72 h) induced DNA fragmentation in a time-dependent manner (<italic>p</italic>
< 0.05). Administration of guanosine (100 μM) <italic>before, concomitantly with</italic>
or, importantly, <italic>after</italic>
the addition of MPP<sup>+</sup>
abolished MPP<sup>+</sup>
-induced DNA fragmentation. Addition of MPP<sup>+</sup>
(500 μM) to cells increased caspase-3 activity over 72 h (<italic>p</italic>
< 0.05), and this was abolished by pre- or co-treatment with guanosine. Exposure of cells to pertussis toxin prior to MPP<sup>+</sup>
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<sup>+</sup>
nor guanosine had any significant effect on α-synuclein expression. Thus, guanosine antagonizes and reverses MPP<sup>+</sup>
-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.</p>
</div>
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