Protective effects of statins on L-DOPA neurotoxicity due to the activation of phosphatidylinositol 3-kinase and free radical scavenging in PC12 cell culture
- Authors
- Koh, Seong-Ho; Park, Hyun-Hee; Choi, Na-Young; Lee, Kyu-Yong; Kim, Sangjae; Lee, Young Joo; Kim, Hee-Tae
- Issue Date
- Jan-2011
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- L-DOPA; Statin; Phosphatidylinositol 3-kinase; Neurotoxicity
- Citation
- BRAIN RESEARCH, v.1370, pp.53 - 63
- Indexed
- SCIE
SCOPUS
- Journal Title
- BRAIN RESEARCH
- Volume
- 1370
- Start Page
- 53
- End Page
- 63
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/169316
- DOI
- 10.1016/j.brainres.2010.11.021
- ISSN
- 0006-8993
- 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 24 h, 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 mu M L-DOPA increased free radical and hydroxyl radical levels, but combined treatment with 5 mu M statins decreased these levels. Survival-related signaling proteins were decreased in nPC12 cells treated with 200 mu M L-DOPA, but combined treatment with 5 mu M statins significantly increased the levels of these proteins. Treatment with 200 mu M L-DOPA significantly increased death-related signaling proteins, while combined treatment with 5 mu M 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.
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