title: Protective activity of guanosine in an in vitro model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a pathological condition characterized by a progressive neurodegeneration of dopaminergic neurons with the consequent reduction of dopamine content in the substantia nigra. The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to mimic the neuropathology of PD in both in vivo and in vitro experimental models. We found that, as expected, in dopaminergic human SH-SY5Y neuroblastoma cells the toxin reduced cell viability causing programmed cell death as assessed by an increase in DNA fragmentation. We also examined, in these cells, the activation/inactivation of several pro and anti apoptotic signaling pathways by 6-OHDA including p-38 kinase (p-38), c-Jun N-terminal kinase (JNK), protein kinase B (also known as Akt), glycogen synthase kinase-3β (GSK3β), and Bcl-2 protein. Guanine-based purines, exert neuroprotective effects and we previously reported that guanosine activates cell survival pathways including PI3K/Akt/PKB signaling in different kinds of cells including glia and neuroblastoma cells. In the present study we found that guanosine (300 µM) protected SH-SY5Y neuroblastoma cells when they were exposed to 6-OHDA, promoting their survival. Guanosine reduced the 6-OHDA mediated activation of p-38 and JNK. Moreover the nucleoside potentiated the early increase in the phosphorylation of the anti-apoptotic kinase Akt and the increase in the expression of the anti-apoptotic Bcl-2 protein induced by 6-OHDA. In summary our results show that guanosine results to be neuroprotective in a recognized in vitro model of PD thus suggesting that it could represent a new potential pharmacological tool to be studied in the therapeutic approach to PD.
authors.affiliation: Department of Experimental and Clinical Sciences, University of Chieti-Pescara, Chieti, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Giuliani
authors.forename: S
authors.initials: S
authors.lastname: Romano
authors.forename: P
authors.initials: P
authors.lastname: Ballerini
authors.forename: R
authors.initials: R
authors.lastname: Ciccarelli
authors.forename: N
authors.initials: N
authors.lastname: Petragnani
authors.forename: S
authors.initials: S
authors.lastname: Cicchitti
authors.forename: M
authors.initials: M
authors.lastname: Zuccarini
authors.forename: S
authors.initials: S
authors.lastname: Jiang
authors.forename: M P
authors.initials: MP
authors.lastname: Rathbone
authors.forename: F
authors.initials: F
authors.lastname: Caciagli
authors.forename: P
authors.initials: P
authors.lastname: Di Iorio
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003470:Culture Media / Q000494:pharmacology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D006151:Guanosine / Q000627:therapeutic use*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine / Q000009:adverse effects; D010300:Parkinson Disease / Q000188:drug therapy*; D010766:Phosphorylation; D015398:Signal Transduction; D013378:Substantia Nigra / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D003470:Culture Media; D018696:Neuroprotective Agents; D006151:Guanosine; D016627:Oxidopamine; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases