title: The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson's disease.
abstract: Tetrahydroisoquinoline (TIQ) derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie, Japan.
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukuhara
authors.forename: Saeko
authors.initials: S
authors.lastname: Tada-Oikawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D017209:Apoptosis / Q000187:drug effects*; D001345:Autoradiography; D016227:Benzoquinones / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003300:Copper / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D009243:NAD / Q000378:metabolism; D009447:Neuroblastoma; D010618:Phenanthrolines / Q000494:pharmacology; D010759:Phosphorus Isotopes / Q000378:metabolism; D012490:Salsoline Alkaloids / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000737:chemistry; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D016166:Free Radical Scavengers; D010618:Phenanthrolines; D010759:Phosphorus Isotopes; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D009243:NAD; C004532:quinone; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045304:Cytochromes c; C020784:norsalsolinol; C002478:bathocuproine; D014446:Tyrosine 3-Monooxygenase; D053148:Caspase 3; C022616:thiazolyl blue; D003849:Deoxyguanosine; C029892:cupric chloride