title: Simvastatin induces neuroprotection in 6-OHDA-lesioned PC12 via the PI3K/AKT/caspase 3 pathway and anti-inflammatory responses.
abstract: BACKGROUND
  In addition to their original applications for lowering cholesterol, statins display multiple neuroprotective effects. Inflammatory reactions and the PI3K/AKT/caspase 3 pathway are strongly implicated in dopaminergic neuronal death in Parkinson's disease (PD). This study aims to investigate how simvastatin affects 6-hydroxydopamine-lesioned PC12 via regulating PI3K/AKT/caspase 3 and modulating inflammatory mediators.
  
  
  METHODS
  6-hydroxydopamine-treated PC12 cells were used to investigate the neuroprotection of simvastatin, its association with the PI3K/AKT/caspase 3 pathway, and antiinflammatory responses. Dopamine transporters (DAT) and tyrosine hydroxylase (TH) were examined in 6-hydroxydopamine-treated PC12 after simvastatin treatment.
  
  
  RESULTS
  Simvastatin-mediated neuroprotection was associated with a robust reduction in the upregulation induced by 6-OHDA of inflammatory mediators including IL-6, COX2, and TNF-α. The downregulated DAT and TH levels in 6-OHDA-lesioned PC12 were restored after simvastatin treatment. Simvastatin reversed 6-OHDA-induced downregulation of PI3K/Akt phosphorylation and attenuated 6-OHDA-induced upregulation of caspase 3 in PC12. Furthermore, the PI3K inhibitor LY294002 pronouncedly abolished the simvastatin-mediated attenuation in caspase 3.
  
  
  CONCLUSIONS
  Our results demonstrate that simvastatin provides robust neuroprotection against dopaminergic neurodegeneration, partially via antiinflammatory mechanisms and the PI3K/Akt/caspase 3 pathway. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD and might elucidate the molecular mechanisms of simvastatin effects in PD.
authors.affiliation: Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Yun-Qi
authors.initials: YQ
authors.lastname: Xu
authors.forename: Ling
authors.initials: L
authors.lastname: Long
authors.forename: Jun-Qiang
authors.initials: JQ
authors.lastname: Yan
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Meng-Qiu
authors.initials: MQ
authors.lastname: Pan
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Gao
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Can-Sheng
authors.initials: CS
authors.lastname: Zhu
authors.forename: Bei-Sha
authors.initials: BS
authors.lastname: Tang
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000032:analysis / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D016627:Oxidopamine; D019821:Simvastatin; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D053148:Caspase 3