title: Dopamine-induced death of PC12 cells is prevented by a substituted tetrahydronaphthalene.
abstract: The ability of dopamine to induce apoptosis in a variety of cell types, including PC12 cells and neurons, has been well documented. Under non-reducing conditions, dopamine can be oxidized to semi-quinone and quinone species, which have the ability to arylate proteins and lead to the formation of covalent adducts. Potentially, it is the arylation of substrates critical to cell survival and/or the formation of toxic adducts which leads to the death observed after dopamine treatment. We have previously described the ability of a substituted monohydroxy-tetra-hydronaphthalene (DATN) to bind proteins that are susceptible to arylation by dopamine and related catecholamines. As DATN can prevent the covalent incorporation of dopamine into substrate molecules, we hypothesized that this compound could have a protective effect on cells that undergo apoptotic death in response to dopamine exposure. We report here that DATN prevents the dopamine-induced apoptotic death of PC12 cells in a dose-dependent manner. DATN did not prevent the oxidative stress associated with dopamine treatment, as lipid peroxide production was not influenced by DATN treatment. The ability of DATN to prevent dopamine-induced cell death was selective for this insult, as this compound did not influence the death of PC12 cells induced by hydrogen peroxide (H(2)O(2)). Consistent with this finding, DATN did not alter lipid peroxidation, nor oxidation of intracellular dichlorodihydrofluorescein subsequent to H(2)O(2) treatment. Consistent with a reduction in apoptotic death, the increase in caspase-3 activity associated with dopamine treatment was also prevented by DATN. These observations suggest that DATN may act to prevent one of the pathways linking dopamine and oxidative stress to caspase-3 activation. We propose that the inhibition of substrate arylation by the products of dopamine oxidation may provide a useful strategy for the prevention of dopamine-induced cell death.
authors.affiliation: Department of Physiology, Queen's University, Botterell Hall, Kingston, Ont., Canada K7L 3N6.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Song
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Slot
authors.forename: Roby W J
authors.initials: RW
authors.lastname: Ryan
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Ross
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D013764:Tetrahydronaphthalenes; D004298:Dopamine