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The Journal of Neuroscience, April 26, 2006, 26(17):4481-4491; doi:10.1523/JNEUROSCI.4922-05.2006

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Neurobiology of Disease
Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

Shih-Ling Hsuan,^1 * Heather M. Klintworth,^1 * and Zhengui Xia^1,2

¹Toxicology Program, Department of Environmental and Occupational Health Sciences, and ²Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195-7234

Correspondence should be addressed to Dr. Zhengui Xia, Department of Environmental and Occupational Health Sciences, University of Washington, Health Science Building, Box 357234, Room F561C, Seattle, WA 98195-7234. Email: zxia{at}u.washington.edu

Administration of rotenone to rats reproduces many features of Parkinson’s disease, including dopaminergic neuron degeneration, and provides a useful model to study the pathogenesis of Parkinson’s disease. However, the cell death mechanisms induced by rotenone and potential neuroprotective mechanisms against rotenone are not well defined. Here we report that rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells is attenuated by pretreatment with several growth factors, most notably basic fibroblast growth factor (bFGF). bFGF activated both extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3-kinase) pathways in SH-SY5Y cells. Ectopic activation of ERK1/2 or PI3-kinase protected against rotenone, whereas inhibition of either pathway attenuated bFGF protection. Reducing the expression of the proapoptotic protein Bcl-2-associated death protein (BAD) by small interfering RNA rendered SH-SY5Y cells resistant to rotenone, implicating BAD in rotenone-induced cell death. Interestingly, bFGF induced a long-lasting phosphorylation of BAD at serine 112, suggesting BAD inactivation through the ERK1/2 signaling pathway. Moreover, primary cultured dopaminergic neurons from mesencephalon were more sensitive to rotenone-induced cell death than nondopaminergic neurons in the same culture. The loss of dopaminergic neurons was blocked by bFGF, an inhibition dependent on ERK1/2 and PI3-kinase signaling. These data suggest that rotenone-induced dopaminergic cell death requires BAD and identify bFGF and its activation of ERK1/2 and PI3-kinase signaling pathways as novel intervention strategies to block cell death in the rotenone model of Parkinson’s disease.

Key words: rotenone; apoptosis; bFGF; ERK1/2; PI3-kinase; BAD; neuron

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Received Nov. 18, 2005; revised Feb. 19, 2006; accepted March 16, 2006.

Correspondence should be addressed to Dr. Zhengui Xia, Department of Environmental and Occupational Health Sciences, University of Washington, Health Science Building, Box 357234, Room F561C, Seattle, WA 98195-7234. Email: zxia{at}u.washington.edu

This article has been cited by other articles:

				W.-S. Choi, S. E. Kruse, R. D. Palmiter, and Z. Xia Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat PNAS, September 30, 2008; 105(39): 15136 - 15141. [Abstract] [Full Text] [PDF]

				J. Jin, G. J. Li, J. Davis, D. Zhu, Y. Wang, C. Pan, and J. Zhang Identification of Novel Proteins Associated with Both {alpha}-Synuclein and DJ-1 Mol. Cell. Proteomics, May 1, 2007; 6(5): 845 - 859. [Abstract] [Full Text] [PDF]

				H. Klintworth, K. Newhouse, T. Li, W.-S. Choi, R. Faigle, and Z. Xia Activation of c-Jun N-Terminal Protein Kinase Is a Common Mechanism Underlying Paraquat- and Rotenone-Induced Dopaminergic Cell Apoptosis Toxicol. Sci., May 1, 2007; 97(1): 149 - 162. [Abstract] [Full Text] [PDF]

				M. Timmer, K. Cesnulevicius, C. Winkler, J. Kolb, E. Lipokatic-Takacs, J. Jungnickel, and C. Grothe Fibroblast Growth Factor (FGF)-2 and FGF Receptor 3 Are Required for the Development of the Substantia Nigra, and FGF-2 Plays a Crucial Role for the Rescue of Dopaminergic Neurons after 6-Hydroxydopamine Lesion J. Neurosci., January 17, 2007; 27(3): 459 - 471. [Abstract] [Full Text] [PDF]

				J. Feng Microtubule: A Common Target for Parkin and Parkinson's Disease Toxins Neuroscientist, December 1, 2006; 12(6): 469 - 476. [Abstract] [PDF]

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