Objectives Amiodarone exerts neuroprotective effects against various cellular insults and the therapeutic antiarrhythmic-like effect may result from its neuroprotective effects.The phosphatidylinositol-3-kinase/protein kinase B (Akt) pathway is a key signaling pathway in mediating cell survival.However,no information is available regarding the interaction of PI3K and amiodarone.Methods RGC-5 cells treated with amiodarone were used as a model to study the protective effect of amiodarone and underlying mechanisms.Methylthiazolyltetrazolium (MTT) assay,Hoechst staining were used to study the protective effects of amiodarone against cell damage caused by serum-deprivation.Pretreatments with various pathway inhibitors were used to investigate the possible pathways involved in the protection of amiodarone.The phosphorylation of Akt were analyzed by Western blotting.Results Serum-deprivation decreased the phosphorylation of Akt and lead to the apoptosis of RGC-5 cells.Low doses of amiodarone (1 μM) concentration-dependently protected RGC-5 cells against serum-deprivation.The protective effect of amiodarone was reversed by LY294002 and Wortmannin,two PI3K inhibitors,and Akt inhibitor Ⅷ,whereas mitogen-activated protein kinase kinase (MAPK kinase) inhibitor PD98059 and the p38 MAPK inhibitor PD160316 had no effect.