title: L-DOPA modulates cell viability through the ERK-c-Jun system in PC12 and dopaminergic neuronal cells.
abstract: L-DOPA causes neurotoxicity by modulating the Epac-ERK system in PC12 cells. This study investigated the effects of a single treatment with L-DOPA and multiple treatments with L-DOPA (MT-LD) on ERK1/2 and JNK1/2-c-Jun systems. In PC12 cells, a toxic L-DOPA concentration (200 μM) induced sustained ERK1/2 and JNK1/2 phosphorylation that was inhibited by the Epac inhibitor brefeldin A, but not by the PKA inhibitor H89. This ERK1/2 and JNK1/2 phosphorylation was also inhibited by ERK1/2 (U0126) and JNK1/2 (SP600125) inhibitors, respectively, but sustained ERK1/2 phosphorylation was not affected by JNK1/2 phosphorylation. A non-toxic L-DOPA concentration (20 μM) induced c-Jun phosphorylation (Ser73) via transient ERK1/2 phosphorylation, whereas the toxic L-DOPA concentration induced c-Jun phosphorylation (Ser63) and c-Jun expression via Epac-sustained ERK1/2-JNK1/2 phosphorylation, which then enhanced cleaved caspase-3 expression. MT-LD (20 μM) initially enhanced c-Jun phosphorylation (Ser73) (for 1-4 days), but later (5-6 days) induced c-Jun phosphorylation (Ser63) and c-Jun expression. In the 6-hydroxydopamine-lesioned rat model of Parkinson's disease, L-DOPA administration (10 mg/kg) protected against neurotoxicity through c-Jun phosphorylation (Ser73) for 1-2 weeks. However, L-DOPA administration (10 or 30 mg/kg) showed neurotoxicity through c-Jun phosphorylation (Ser63) and c-Jun expression via ERK1/2 phosphorylation for 3-4 weeks. Thus, in PC12 cells, non-toxic L-DOPA treatment maintained cell survival through c-Jun phosphorylation (Ser73). By contrast, toxic L-DOPA treatment or MT-LD (20 μM) induced c-Jun phosphorylation (Ser63) and c-Jun expression via Epac-dependent sustained ERK1/2 and JNK1/2 phosphorylation, which subsequently led to cell death. These results were validated by those obtained after long-term L-DOPA administration in a rat model of Parkinson's disease. Our data indicate that L-DOPA causes neurotoxicity via the ERK1/2-c-Jun system in dopaminergic neuronal cells.
authors.affiliation: College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 1, Chungdae-ro, Seowon-gu, Cheongju 28644, Republic of Korea.
authors.forename: Keun Hong
authors.initials: KH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 1, Chungdae-ro, Seowon-gu, Cheongju 28644, Republic of Korea.
authors.forename: Keon Sung
authors.initials: KS
authors.lastname: Shin
authors.affiliation: College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 1, Chungdae-ro, Seowon-gu, Cheongju 28644, Republic of Korea.
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Zhao
authors.affiliation: College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 1, Chungdae-ro, Seowon-gu, Cheongju 28644, Republic of Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 1, Chungdae-ro, Seowon-gu, Cheongju 28644, Republic of Korea.
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Center for Bioresource and Health, Chungbuk National University, 1, Chungdae-ro, Seowon-gu, Cheongju 28644, Republic of Korea. Electronic address: myklee@chungbuk.ac.kr.
authors.forename: Myung Koo
authors.initials: MK
authors.lastname: Lee
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007980:Levodopa / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008636:Mesencephalon / Q000166:cytology; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D018663:Adrenergic Agents; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D007980:Levodopa; D016627:Oxidopamine; D053148:Caspase 3
keywords: ERK1/2; Epac; L-DOPA; PC12 cells; Rat model of Parkinson's disease; c-Jun