title: Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways.
abstract: BACKGROUND
  Lithium is currently used in the treatment of mental illness. We have previously reported that lithium stimulated the protein kinase B/Forkhead box O1 (Akt/FoxO1) pathway in rats. However, little information is available regarding its neuroprotective role of this pathway and underlying mechanisms.
  
  
  OBJECTIVE
  PC12 cells treated with serum deprivation were used as a toxicity model to study the protective effect of lithium and its underlying mechanisms.
  
  
  METHODS
  Cell viability was determined by methyl thiazolyl tetrazolium assay and Hoechst staining. FoxO1 subcellular location and its overexpression were used to study the underlying mechanisms. Various pathway inhibitors were used to investigate the possible pathways, while the phosphorylation of Akt and FoxO1 was analyzed by Western blot.
  
  
  RESULTS
  Lithium pretreatment dose-dependently reduced PC12 cell apoptosis induced by serum starvation. The protective effect of lithium was abolished by LY294002, a PI3K-specific inhibitor, and Akt inhibitor Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MEK kinase) inhibitor U0126 had no effect. Lithium induced the phosphorylation of Akt and FoxO1 in a time- and concentration-dependent manner. Lithium-induced phosphorylation of Akt and FoxO1 is mediated by the PI3K/Akt pathway. Serum deprivation caused nuclear translocation of FoxO1 while application of lithium reversed the effect of serum deprivation. Moreover, overexpression of FoxO1 enhanced cell apoptosis induced by serum withdrawal. Finally, lithium was found to reduce the exogenous and endogenous FoxO1 protein levels in PC12 cells in a concentration-dependent fashion.
  
  
  CONCLUSIONS
  The protective effect of lithium against serum starvation cell death is mediated by the PI3K/Akt/FoxO1 pathway.
authors.affiliation: Faculty of Health Science, University of Macau, Room 4021, Building E12, Avenida de Universidade Taipa, Macau, People's Republic of China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center and Neurophamacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510060, People's Republic of China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center and Neurophamacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510060, People's Republic of China.
authors.forename: Fu
authors.initials: F
authors.lastname: Shang
authors.affiliation: Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, 510060, People's Republic of China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD, 4102, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Little
authors.affiliation: Douglas Hospital Research Center, McGill University, Montreal, Canada.
authors.forename: Remi
authors.initials: R
authors.lastname: Quirion
authors.affiliation: Faculty of Health Science, University of Macau, Room 4021, Building E12, Avenida de Universidade Taipa, Macau, People's Republic of China. whzheng1231@gmail.com.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000187:drug effects*; D008094:Lithium / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000187:drug effects*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D000071161:Forkhead Box Protein O1
chemical_list: D002070:Butadienes; D002867:Chromones; D016895:Culture Media, Serum-Free; D051858:Forkhead Transcription Factors; D008094:Lithium; D009025:Morpholines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009570:Nitriles; D051058:Oncogene Protein v-akt; C113580:U 0126; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Apoptosis; Lithium; Neuroprotection; PI3K/Akt/FoxO1; Serum deprivation