title: Protective effects of statins on L-DOPA neurotoxicity due to the activation of phosphatidylinositol 3-kinase and free radical scavenging in PC12 cell culture.
abstract: Neurotoxic effects have been suggested for l-3,4-dihydroxyphenylalanine (L-DOPA), while neuroprotective effects have been proposed for statins. We investigated whether certain statins (simvastatin or pitavastatin) could inhibit L-DOPA neurotoxicity. Neuronally-differentiated PC12 (nPC12) cells were treated with L-DOPA and/or statins for 24h, and their viabilities were measured using a cell counting kit, trypan blue staining, and 4',6-diamidino-2-phenylindole (DAPI) staining. Free radical and specific intracellular signaling protein levels were measured with 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. High concentrations of l-DOPA reduced nPC12 cell viability, but combined treatment with statins restored viability. Treatment with 200 μM L-DOPA increased free radical and hydroxyl radical levels, but combined treatment with 5 μM statins decreased these levels. Survival-related signaling proteins were decreased in nPC12 cells treated with 200 μM L-DOPA, but combined treatment with 5μM statins significantly increased the levels of these proteins. Treatment with 200 μM L-DOPA significantly increased death-related signaling proteins, while combined treatment with 5 μM statins reduced the levels of these proteins. Pretreatment with LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, before combined treatment with statins and L-DOPA almost completely blocked the protective effects of statins. These results indicate that statins reduce L-DOPA neurotoxicity by lowering oxidative stress and by enhancing survival signals and inhibiting death signals via activation of the PI3K pathway.
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Koh
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Park
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Choi
authors.forename: Kyu-Yong
authors.initials: KY
authors.lastname: Lee
authors.forename: Sangjae
authors.initials: S
authors.lastname: Kim
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Hee-Tae
authors.initials: HT
authors.lastname: Kim
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats
chemical_list: D000978:Antiparkinson Agents; D016166:Free Radical Scavengers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D007980:Levodopa; D019869:Phosphatidylinositol 3-Kinases