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Protective effect of creatine against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells: Involvement of intracellular signaling pathways.

Abstract：

:The guanidine-like compound creatine exerts bioenergetic, antiexcitotoxic, antioxidant and neuroprotective properties; however, the intracellular mechanisms responsible for these effects are still not well established. The purpose of this study was to investigate the protective effect of creatine against 6-hydroxydopamine (6-OHDA)-induced cell death in neuroblastoma SH-SY5Y cells and the possible intracellular signaling pathways involved in such effect. Exposure of SH-SY5Y cells to 100-300μM of 6-OHDA for 24h caused a significant concentration-dependent cell death measured as a diminution of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) reduction and as an increase in the extracellular release of lactate dehydrogenase. SH-SY5Y cells incubated for 24 or 48h with creatine (10-5000μM) was not cytotoxic. However, pre and co-treatment with creatine (0.3-1000μM) for 24h reduced 6-OHDA-induced toxicity. The protective effect afforded by creatine against 6-OHDA-induced toxicity was reversed by inhibitors of different protein kinases, i.e. phosphatidylinositol-3 kinase (PI3K) (LY294002), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) (KN-93), protein kinase A (H-89), mitogen-activated protein kinase kinase 1/2 (MEK1/2) (PD98059) and protein kinase C (PKC) (chelerythrine). Furthermore, creatine prevented the 6-OHDA-induced dephosphorylation of glycogen synthase kinase-3β (GSK-3β) at the serine 9 residue. In conclusion, the results of this study show that creatine can protect against 6-OHDA-induced toxicity and its protective mechanism is related to a signaling pathway that involves PI3K, PKC, PKA, CaMKII, MEK1/2 and GSK-3β.

journal_name

Neuroscience

journal_title

Neuroscience

authors

Cunha MP,Martín-de-Saavedra MD,Romero A,Parada E,Egea J,Del Barrio L,Rodrigues AL,López MG

doi

10.1016/j.neuroscience.2013.02.030

subject

Has Abstract

pub_date

2013-05-15 00:00:00

pages

185-94

eissn

0306-4522

issn

1873-7544

pii

S0306-4522(13)00164-4

journal_volume

238

pub_type

杂志文章

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Protective effect of creatine against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells: Involvement of intracellular signaling pathways.