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Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCdelta phosphorylation.

AbstractOBJECTIVE:
The present study aims to investigate the role of protein kinase C delta subtype (PKCdelta) phosphorylation in the process of 6-hydroxydopamine (6-OHDA)-induced dopaminergic cell death, and demonstrate the molecular basis of neurological disorders, such as Parkinson's disease.
METHODS:
The pheochromocytoma (PC12) cell line was employed in the present study. Cells were treated with 2 mumol/L PKCdelta inhibitor Rottlerin, 10 nmol/L protein kinase C delta subtype (PKCdelta) inhibitor bisindolylmaleimide I, or 5 nmol/L Gö6976 that could specifically inhibit the calcium-dependent PKCdelta isoforms, respectively. PKC activator phorbol-12-myristate-13-acetate (PMA, 100 nmol/L) was also used in this study. All these agents were added to the medium before cells were incubated with 6-OHDA. Cells with no treatment served as control. The cytotoxicity of 6-OHDA was determined by methyl thiazolyl tetrazolium (MTT) reduction assay and PKCdelta phosphorylation levels in various groups were measured by western blotting.
RESULTS:
Bisindolylmaleimide I and Gö6976 exerted no significant attenuation on the cytotoxicity of 6-OHDA, nor any effects on PKCdelta phosphorylation in PC12 cells. However, Rottlerin could inhibit the phosphorylation of PKCdelta and attenuate 6-OHDA-induced cell death, and the cell viability was raised to (69.6+/-2.63)% of that in control group (P<0.05). In contrast, PMA induced a significant increase in PKCdelta phosphorylation and also strengthened the cytotoxic effects of 6-OHDA. The cell viability of PMA-treated PC12 cells decreased to (49.8+/-5.06)% of that in control group (P<0.001).
CONCLUSION:
Rottlerin can protect PC12 cells from cytotoxicity of 6-OHDA probably by inhibiting PKCdelta phosphorylation. The results suggest that PKCdelta may be a key regulator of neuron loss in Parkinson's disease.
AuthorsYing Fan, Yan-Qiao Zhang, Dian-Jun Sun, Yi-Na Zhang, Xiao-Wei Wu, Jing Li
JournalNeuroscience bulletin (Neurosci Bull) Vol. 25 Issue 4 Pg. 187-95 (Aug 2009) ISSN: 1995-8218 [Electronic] China
PMID19633700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Acetophenones
  • Adrenergic Agents
  • Benzopyrans
  • Carbazoles
  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • Phorbol Esters
  • bisindolylmaleimide I
  • Go 6976
  • 12-O-retinoylphorbol-13-acetate
  • Oxidopamine
  • rottlerin
  • Protein Kinase C
  • Dopamine
Topics
  • Acetophenones (pharmacology)
  • Adrenergic Agents (toxicity)
  • Animals
  • Benzopyrans (pharmacology)
  • Carbazoles (pharmacology)
  • Cell Survival (drug effects)
  • Dopamine (metabolism)
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Gene Expression Regulation, Enzymologic (drug effects)
  • Indoles (pharmacology)
  • Maleimides (pharmacology)
  • Oxidopamine (toxicity)
  • PC12 Cells
  • Phorbol Esters (pharmacology)
  • Phosphorylation (drug effects)
  • Protein Kinase C (metabolism)
  • Rats
  • Time Factors

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