title: Salsolinol, a dopamine-derived tetrahydroisoquinoline, induces cell death by causing oxidative stress in dopaminergic SH-SY5Y cells, and the said effect is attenuated by metallothionein.
abstract: The endogenous neurotoxin, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), has been considered a potential neurotoxin in the etiology of Parkinson's disease (PD). Salsolinol and N-methyl(R)-salsolinol were identified in the brains and cerebrospinal fluid (CSF) of PD patients. Oxidative stress is known to be one of the major contributing factors in the cascade that may finally leads to the cell death in PD. The present study was undertaken to understand the role of salsolinol in oxidative-mediated neuronal toxicity in dopaminergic SH-SY5Y cells, and the neuroprotective effects of metallothionein (MT) against salsolinol toxicity in MT overexpressing (MT(trans)) fetal mesencephalic cells. Salsolinol increased the production of reactive oxygen species (ROS) and significantly decreased glutathione (GSH) levels and cell viability in SH-SY5Y cells. Salsolinol also decreased intracellular ATP levels and induced nuclear condensation in these cells. Salsolinol-induced depletion in cell viability was completely prevented by N-acetylcysteine in SH-SY5Y cells, and also prevented by MT in MT(trans) fetal mesencephalic cells compared to control(wt) cells. The extent of nuclear condensation and caspase activation was also less in MT(trans) cells than control(wt) cells. These results suggest that salsolinol causes oxidative stress by decreasing the levels of GSH and by increasing ROS production, and these events may lead to the death of dopaminergic cell. Furthermore, MT overexpression may protect dopaminergic neurons against salsolinol-induced neurotoxicity, most probably by the inhibition of oxidative stress and apoptotic pathways including caspase-3 activation.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
authors.forename: Sawitri
authors.initials: S
authors.lastname: Wanpen
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
authors.forename: Shaik
authors.initials: S
authors.lastname: Shavali
authors.forename: Patcharee
authors.initials: P
authors.lastname: Sangchot
authors.forename: Manuchair
authors.initials: M
authors.lastname: Ebadi
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008668:Metallothionein / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D008668:Metallothionein; C036617:salsolinol; D004298:Dopamine