Antioxidant effect of erythropoietin on 1-methyl-4-phenylpyridinium-induced neurotoxicity in PC12 cells.
The neuroprotective effects of erythropoietin on 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress and apoptosis in cultured PC12 cells as well as the underlying mechanism were investigated. Treatment of PC12 cells with MPP(+) caused the loss of cell viability, which was associated with the elevation in apoptotic rate, the formation of reactive oxygen species and the disruption of mitochondrial transmembrane potential. It was also shown that MPP(+) significantly induced upregulation of Bax/Bcl-2 ratio and activation of caspase-3. In contrast, erythropoietin reversed these phenotypes and had its maximum protective effect at 1 U/ml. The effect of erythropoietin was mediated by the phosphatidylinositol 3-kinase (PI3K) signaling pathway since erythropoietin failed to rescue cells from MPP(+) insult in the presence of the PI3K inhibitor, LY 294002. In addition, the downstream effector of PI3K, Akt, was activated by erythropoietin, and Akt activation was inhibited by LY 294002. Furthermore, the effect of erythropoietin on reactive oxygen species levels was also blocked by LY 294002. These results show that erythropoietin may provide a useful therapeutic strategy for the treatment of oxidative stress-induced neurodegenerative diseases such as Parkinson disease.
Wu
Yan
Y
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
Shang
You
Y
Sun
Shenggang
S
Liu
Rengang
R
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
D000975:Antioxidants; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D053148:Caspase 3; D015655:1-Methyl-4-phenylpyridinium