title: Hypoxic preconditioning alleviates ethanol neurotoxicity: the involvement of autophagy.
abstract: Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. A sublethal preconditioning has been proposed as a neuroprotective strategy against several central nervous system neurodegenerative diseases. We have recently demonstrated that autophagy is a protective response to alleviate ethanol toxicity. A modest hypoxic preconditioning (1 % oxygen) did not cause neurotoxicity but induced autophagy (Tzeng et al. Free Radic Biol Med 49: 839-846, 2010). We, therefore, hypothesize that the modest hypoxic preconditioning may offer a protection against ethanol-induced neurotoxicity. We showed here that the modest hypoxic preconditioning (1 % oxygen) for 8 h significantly alleviated ethanol-induced death of SH-SY5Y neuroblastoma cells. Under the normoxia condition, cell viability in ethanol-exposed cultures (316 mg/dl for 48 h) was 49 ± 6 % of untreated controls; however, with hypoxic preconditioning, cell viability in the ethanol-exposed group increased to 78 ± 7 % of the controls (p < 0.05; n = 3). Bafilomycin A1, an inhibitor of autophagosome and lysosome fusion, blocked hypoxic preconditioning-mediated protection. Similarly, inhibition of autophagic initiation by wortmannin also eliminated hypoxic preconditioning-mediated protection. In contrast, activation of autophagy by rapamycin further enhanced neuroprotection caused by hypoxic preconditioning. Taken together, the results confirm that autophagy is a protective response against ethanol neurotoxicity and the modest hypoxic preconditioning can offer neuroprotection by activating autophagic pathways.
authors.affiliation: Department of Molecular and Biochemical Pharmacology, University of Kentucky College of Medicine, 132 Health Sciences Research Building, 1095 Veterans Drive, Lexington, KY, 40536, USA.
authors.forename: Haiping
authors.initials: H
authors.lastname: Wang
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bower
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
mesh_terms: D001343:Autophagy; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D009474:Neurons / Q000187:drug effects*
chemical_list: D000431:Ethanol