Inhibition of glycogen synthase kinase-3 reduces L-DOPA-induced neurotoxicity
- Authors
- Koh, Seong-Ho; Song, Chiwon; Noh, Min Young; Kim, Hyun Young; Lee, Kyu-Yong; Lee, Young Joo; Kim, Juhan; Kim, Seung Hyun; Kim, Hee-Tae
- Issue Date
- May-2008
- Publisher
- ELSEVIER IRELAND LTD
- Keywords
- L-DOPA; glycogen synthase kinase-3; neurotoxicity
- Citation
- TOXICOLOGY, v.247, no.2-3, pp.112 - 118
- Indexed
- SCIE
SCOPUS
- Journal Title
- TOXICOLOGY
- Volume
- 247
- Number
- 2-3
- Start Page
- 112
- End Page
- 118
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/178705
- DOI
- 10.1016/j.tox.2008.02.007
- ISSN
- 0300-483X
- Abstract
- The neurotoxicity of L-3,4-dihydroxyphenylalanine (L-DOPA), used for the treatment of Parkinson's disease, remains controversial. Although there are many reports suggesting that long-term treatment of L-DOPA causes neuronal death, an increasing body of recent evidence has proposed that L-DOPA might be neuroprotective rather than neurotoxic. We investigated the effect Of L-DOPA on neuronally differentiated PC12 (nPC12) cells by treating cells with various concentrations Of L-DOPA for 24h. We also studied whether glycogen synthase kinase (GSK)-3 activation is related to L-DOPA-induced neurotoxicity by simultaneously treating cells with several concentrations Of L-DOPA and a GSK-3 inhibitor for 24 h. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, cell counting kit-8, and DAPI staining all showed that L-DOPA decreased nPC12 cell viability at high concentrations. In addition, 100 mu M L-DOPA treatment significantly increased the activity of GSK-3 and death signals including cytochrome c, activated caspase-3 and cleaved PARP, and decreased survival signals including heat shock transcription factor-1 in a concentration-dependent manner. Treatment with GSK-3 inhibitor VIII or lithium chloride prevented L-DOPA-induced cell death. Together, these results suggest that L-DOPA induces neuronal cell death at high concentrations and that the neurotoxic effect Of L-DOPA might be mediated in part by GSK-3 activation.
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