Guanosine protects human neuroblastoma cells from oxidative stress and toxicity induced by Amyloid-beta peptide oligomers.
Amyloid-beta (Abeta) peptide aggregation forms such as soluble oligomers (O) have a causal role in neuronal dysfunction and death associated with Alzheimer?s Disease (AD). The main efforts for the development of neuroprotective drugs are therefore focused on preventing Abeta production, aggregation or downstream neurotoxic events. We therefore investigated the effect of guanosine (GUO), a guanine based purine, that exerts neurotrophic and neuroprotective effects. The GUO showed the ability to reduce neuronal death in terms of apoptosis, but not necrosis, elicited by Abeta1-42O in human neuroblastoma SH-SY5Y cells. The neuroprotective effect was recorded only when the GUO was added simultaneously to treatment of the SH-SY5Y cells with Abeta1-42O. By contrast, the GUO treatment of SH-SY5Y cells before and after the appearance of beta1-42O toxicity had no neuroprotective effects. The employment of specific inhibitors showed the involvement of neuronal survival pathways, such as PI3K?Akt and MAPK-ERK for the GUO anti-apoptotic effects observed. In parallel, the SH-SY5Y cells treated with GUO, in experimental conditions similar to those adopted to evaluate neuronal death, showed a marked decrease of the early reactive oxygen species formation induced by Abeta1-42O and pro-oxidant H2O2. In the same neuronal model, GUO was also shown to inhibit the extra- and intra-cellular Abeta1-42 release as well as the beta-secretase activity evoked by H2O2 pro-oxidant action. Based on these findings, GUO and other guanine based purines appear to be a promising class of compounds with neuroprotective properties that may play an important role in the therapy of AD.
Tarozzi
A
A
Department of Pharmacology, Alma Mater Studiorum-University of Bologna, Bologna, Italy. andrea.tarozzi@unibo.it
Merlicco
A
A
Morroni
F
F
Bolondi
C
C
Di Iorio
P
P
Ciccarelli
R
R
Romano
S
S
Giuliani
P
P
Hrelia
P
P
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D006151:Guanosine / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D006151:Guanosine; D051057:Proto-Oncogene Proteins c-akt