Protein kinase C delta mediated cytotoxicity of 6-Hydroxydopamine via sustained extracellular signal-regulated kinase 1/2 activation in PC12 cells

Objectives: The incidence of Parkinson's disease (PD) is increasing as the global population ages. 6-hydroxydopamine (6-OHDA) can induce PD-like neuropathology and biochemical changes in both in vitro and in vivo models. Therefore, clarification of the molecular mechanism of 6-OHDA-induced cell...

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Bibliographic Details
Published in:Neurological research (New York) 2014-01, Vol.36 (1), p.53-64
Main Authors: Fan, Ying, Li, Jing, Zhang, Yan-Qiao, Jiang, Li-Hong, Zhang, Yi-Na, Yan, Chao-Qi
Format: Article
Language:English
Subjects:
6-Hydroxydopamine
Adrenergic Agents - toxicity
Animals
Apoptosis
Apoptosis - drug effects
Cell Death - drug effects
Cell Shape - drug effects
Cell Survival - drug effects
Enzyme Activation
Extracellular signal-regulated kinases (ERK)
Extracellular Signal-Regulated MAP Kinases - metabolism
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Neurons - drug effects
Neurons - physiology
Oxidopamine - toxicity
Parkinson's disease
PC12 Cells
Phosphorylation - drug effects
Protein kinase C
Protein Kinase C - antagonists & inhibitors
Protein Kinase C - metabolism
Protein Kinase C-delta - antagonists & inhibitors
Protein Kinase C-delta - metabolism
Rats
Rottlerin
Subtype delta
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Summary:Objectives: The incidence of Parkinson's disease (PD) is increasing as the global population ages. 6-hydroxydopamine (6-OHDA) can induce PD-like neuropathology and biochemical changes in both in vitro and in vivo models. Therefore, clarification of the molecular mechanism of 6-OHDA-induced cell death might contribute to the understanding of the pathogenesis of PD. Methods: With this goal in mind, we investigated the role of protein kinase C delta (PKC delta) in 6-OHDA-dependent death using the pheochromocytoma cell line, PC12. Cells were treated with 6-OHDA to induce toxicity with or without pretreatment using rottlerin (a PKC delta inhibitor), bisindolylmaleimide I (a general PKC inhibitor), Gö6976 (a PKC inhibitor selective for calcium-dependent PKC isoforms), or phorbol-12-myristate-13-acetate (PMA, a PKC activator). Results: Phorbol-12-myristate-13-acetate decreased cell survival and increased the rate of apoptosis while rottlerin increased cell survival and decreased the rate of apoptosis. In contrast, neither bisindolylmaleimide I nor Gö6976 affected 6-OHDA-induced cell death. Western analysis demonstrated that phosphorylation of PKC delta on Thr 505 as well as extracellular signal-regulated kinase (ERK) phosphorylation increased after exposure to 6-OHDA. This increase in PKC delta phosphorylation was potentiated by PMA. However, rottlerin attenuated the 6-OHDA-stimulated increase in PKC delta and ERK phosphorylation. Conclusion: These data suggest that PKC delta, rather than classic-type PKC (alpha, beta1, beta2, gamma), participates in 6-OHDA-induced neurotoxicity in PC12 cells, and PKC delta activity is required for subsequent ERK activation during cell death.
ISSN:0161-6412
1743-1328
DOI:10.1179/1743132813Y.0000000267