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Abstract: It is well known that chronic ethanol consumption damages CNS through oxidative stress which results in many dysfunctions. Recently, it has been demonstrated that as a promising strategy to treat several neurological diseases, transplanted bone marrow-derived mesenchymal stem cells (MSCs) can secrete lots of protective factors that in turn promote function recovery. In the present study, we assessed the potential effects of MSCs conditioned medium (MSC-CM) against chronic ethanol-associated damage on PC12 cells and primary cortical neurons. We found that pretreatment with MSC-CM notably improved cell survival, prevented chronic ethanol-associated apoptosis and abolished the robust deterioration in oxidative status. In addition, we also discovered that chronic ethanol exposure induced an inactivation of phosphatidylinositol-3-kinase (PI3K)/Akt and a lasting activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both PC12 cells and primary cortical neurons which were able to be reversed by MSC-CM. The PI3K inhibitor (LY294002) was able to reduce the antioxidative and cytoprotective effects conferred by MSC-CM, in part, and the ERK1/2 inhibitor (PD98059) was able to elicit significant protection from chronic ethanol cytotoxicity but not rescue the deterioration in oxidative status induced by chronic ethanol. Taken together, these findings provide the first evidence that MSCs might have potent antioxidant action to shield the apoptotic impairment from chronic ethanol exposure in PC12 cells and neurons, which is involved in upregulation of PI3K/Akt and modulation of ERK1/2 activation, at least partially. [Copyright &y& Elsevier]