Chronic low-dose oxidative stress induces caspase-3-dependent PKCdelta proteolytic activation and apoptosis in a cell culture model of dopaminergic neurodegeneration.
Oxidative stress has been implicated as a key event in the degenerative process of dopaminergic neurons; however, the cellular mechanisms underlying chronic oxidative stress-induced neurodegeneration remain to be established. In this study, N27 cells, a dopaminergic neuronal cell line derived from rat mesencephalon, exposed to low doses of H(2)O(2) (0-30 muM for 12-24 hr) exhibited dose- and time-dependent increases in cytotoxicity and ROS generation. In addition, the H(2)O(2)-induced neurotoxicity was accompanied by increased caspase-3 activity and PKCdelta cleavage. Notably, treatment with antioxidants Trolox and MnTBAP or PKCdelta cleavage inhibitor z-DIPD-fmk significantly protected against oxidative stress-induced apoptotic cell death. These results demonstrate that the N27 cell line is a useful model for the study of the chronic low-dose oxidative stress-induced apoptotic cell death cascade and that caspase-3-dependent PKCdelta proteolytic activation may be important in the apoptotic process in dopaminergic neurons undergoing chronic oxidative insult.
Carvour
Martha
M
Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, and Department of Biomedical Sciences, Iowa State University, Ames, Iowa, USA.
Song
Chunjuan
C
Kaul
Siddharth
S
Anantharam
Vellareddy
V
Kanthasamy
Anumantha
A
Kanthasamy
Arthi
A
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D051745:Protein Kinase C-delta; D053148:Caspase 3; D004298:Dopamine