QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 26, 2003, 23(34):10756-10764

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (133) Citing Articles via Google Scholar Google Scholar Articles by Sherer, T. B. Articles by Greenamyre, J. T. Search for Related Content PubMed PubMed Citation Articles by Sherer, T. B. Articles by Greenamyre, J. T.

 Previous Article  |  Next Article 

Cellular/Molecular
Mechanism of Toxicity in Rotenone Models of Parkinson's Disease

Todd B. Sherer,^1,2 Ranjita Betarbet,^1,2 Claudia M. Testa,^1,2 Byoung Boo Seo,⁵ Jason R. Richardson,^1,4 Jin Ho Kim,⁶ Gary W. Miller,^1,4 Takao Yagi,⁵ Akemi Matsuno-Yagi,⁵ and J. Timothy Greenamyre^1,2,3

¹Center for Neurodegenerative Disease, Departments of ²Neurology and ³Pharmacology, and ⁴Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, ⁵Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and ⁶Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South Korea

Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and -synuclein-positive cytoplasmic inclusions (Betarbet et al., 2000; Sherer et al., 2003). Here, we examined mechanisms of rotenone toxicity using three model systems. In SK-N-MC human neuroblastoma cells, rotenone (10 nM to 1 µM) caused dose-dependent ATP depletion, oxidative damage, and death. To determine the molecular site of action of rotenone, cells were transfected with the rotenone-insensitive single-subunit NADH dehydrogenase of Saccharomyces cerevisiae (NDI1), which incorporates into the mammalian ETC and acts as a "replacement" for endogenous complex I. In response to rotenone, NDI1-transfected cells did not show mitochondrial impairment, oxidative damage, or death, demonstrating that these effects of rotenone were caused by specific interactions at complex I. Although rotenone caused modest ATP depletion, equivalent ATP loss induced by 2-deoxyglucose was without toxicity, arguing that bioenergetic defects were not responsible for cell death. In contrast, reducing oxidative damage with antioxidants, or by NDI1 transfection, blocked cell death. To determine the relevance of rotenone-induced oxidative damage to dopaminergic neuronal death, we used a chronic midbrain slice culture model. In this system, rotenone caused oxidative damage and dopaminergic neuronal loss, effects blocked by -tocopherol. Finally, brains from rotenone-treated animals demonstrated oxidative damage, most notably in midbrain and olfactory bulb, dopaminergic regions affected by Parkinson's disease. These results, using three models of increasing complexity, demonstrate the involvement of oxidative damage in rotenone toxicity and support the evaluation of antioxidant therapies for Parkinson's disease.

Key words: mitochondria; oxidative stress; NADH dehydrogenase; dopamine; organotypic; -tocopherol

---

Received Aug 11, 2003; revised September 30, 2003; accepted October 1, 2003.

This article has been cited by other articles:

				C. Costa, V. Belcastro, A. Tozzi, M. Di Filippo, M. Tantucci, S. Siliquini, A. Autuori, B. Picconi, M. G. Spillantini, E. Fedele, et al. Electrophysiology and Pharmacology of Striatal Neuronal Dysfunction Induced by Mitochondrial Complex I Inhibition J. Neurosci., August 6, 2008; 28(32): 8040 - 8052. [Abstract] [Full Text] [PDF]

				C. Press and J. Milbrandt Nmnat Delays Axonal Degeneration Caused by Mitochondrial and Oxidative Stress J. Neurosci., May 7, 2008; 28(19): 4861 - 4871. [Abstract] [Full Text] [PDF]

				W. Yang, L. Chen, Y. Ding, X. Zhuang, and U. J. Kang Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice Hum. Mol. Genet., December 1, 2007; 16(23): 2900 - 2910. [Abstract] [Full Text] [PDF]

				M. Marella, B. B. Seo, A. Matsuno-Yagi, and T. Yagi Mechanism of Cell Death Caused by Complex I Defects in a Rat Dopaminergic Cell Line J. Biol. Chem., August 17, 2007; 282(33): 24146 - 24156. [Abstract] [Full Text] [PDF]

				T. Yamashita, E. Nakamaru-Ogiso, H. Miyoshi, A. Matsuno-Yagi, and T. Yagi Roles of Bound Quinone in the Single Subunit NADH-Quinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae J. Biol. Chem., March 2, 2007; 282(9): 6012 - 6020. [Abstract] [Full Text] [PDF]

				E. H. Norris, K. Uryu, S. Leight, B. I. Giasson, J. Q. Trojanowski, and V. M.-Y. Lee Pesticide Exposure Exacerbates {alpha}-Synucleinopathy in an A53T Transgenic Mouse Model Am. J. Pathol., February 1, 2007; 170(2): 658 - 666. [Abstract] [Full Text] [PDF]

				S. Ramachandiran, J. M. Hansen, D. P. Jones, J. R. Richardson, and G. W. Miller Divergent Mechanisms of Paraquat, MPP+, and Rotenone Toxicity: Oxidation of Thioredoxin and Caspase-3 Activation Toxicol. Sci., January 1, 2007; 95(1): 163 - 171. [Abstract] [Full Text] [PDF]

				J. R. Richardson, W. M. Caudle, T. S. Guillot, J. L. Watson, E. Nakamaru-Ogiso, B. B. Seo, T. B. Sherer, J. T. Greenamyre, T. Yagi, A. Matsuno-Yagi, et al. Obligatory Role for Complex I Inhibition in the Dopaminergic Neurotoxicity of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Toxicol. Sci., January 1, 2007; 95(1): 196 - 204. [Abstract] [Full Text] [PDF]

				C. Malagelada, E. J. Ryu, S. C. Biswas, V. Jackson-Lewis, and L. A. Greene RTP801 Is Elevated in Parkinson Brain Substantia Nigral Neurons and Mediates Death in Cellular Models of Parkinson's Disease by a Mechanism Involving Mammalian Target of Rapamycin Inactivation J. Neurosci., September 27, 2006; 26(39): 9996 - 10005. [Abstract] [Full Text] [PDF]

				S.-L. Hsuan, H. M. Klintworth, and Z. Xia 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. J. Neurosci., April 26, 2006; 26(17): 4481 - 4491. [Abstract] [Full Text] [PDF]

				R. Ved, S. Saha, B. Westlund, C. Perier, L. Burnam, A. Sluder, M. Hoener, C. M. P. Rodrigues, A. Alfonso, C. Steer, et al. Similar Patterns of Mitochondrial Vulnerability and Rescue Induced by Genetic Modification of {alpha}-Synuclein, Parkin, and DJ-1 in Caenorhabditis elegans J. Biol. Chem., December 30, 2005; 280(52): 42655 - 42668. [Abstract] [Full Text] [PDF]

				A. Panov, S. Dikalov, N. Shalbuyeva, G. Taylor, T. Sherer, and J. T. Greenamyre Rotenone Model of Parkinson Disease: MULTIPLE BRAIN MITOCHONDRIA DYSFUNCTIONS AFTER SHORT TERM SYSTEMIC ROTENONE INTOXICATION J. Biol. Chem., December 23, 2005; 280(51): 42026 - 42035. [Abstract] [Full Text] [PDF]

				L. Silvestri, V. Caputo, E. Bellacchio, L. Atorino, B. Dallapiccola, E. M. Valente, and G. Casari Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism Hum. Mol. Genet., November 15, 2005; 14(22): 3477 - 3492. [Abstract] [Full Text] [PDF]

				J. R. Richardson, Y. Quan, T. B. Sherer, J. T. Greenamyre, and G. W. Miller Paraquat Neurotoxicity is Distinct from that of MPTP and Rotenone Toxicol. Sci., November 1, 2005; 88(1): 193 - 201. [Abstract] [Full Text] [PDF]

				L. Bao, M. V. Avshalumov, and M. E. Rice Partial Mitochondrial Inhibition Causes Striatal Dopamine Release Suppression and Medium Spiny Neuron Depolarization via H2O2 Elevation, Not ATP Depletion J. Neurosci., October 26, 2005; 25(43): 10029 - 10040. [Abstract] [Full Text] [PDF]

				Y. Ren, W. Liu, H. Jiang, Q. Jiang, and J. Feng Selective Vulnerability of Dopaminergic Neurons to Microtubule Depolymerization J. Biol. Chem., October 7, 2005; 280(40): 34105 - 34112. [Abstract] [Full Text] [PDF]

				S. H. Wilson and W. A. Suk Framework For Environmental Exposure Research: The Disease-First Approach Mol. Interv., October 1, 2005; 5(5): 262 - 267. [Full Text] [PDF]

				R. H. Kim, P. D. Smith, H. Aleyasin, S. Hayley, M. P. Mount, S. Pownall, A. Wakeham, A. J. You-Ten, S. K. Kalia, P. Horne, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress PNAS, April 5, 2005; 102(14): 5215 - 5220. [Abstract] [Full Text] [PDF]

				E. A. Jonas, J. A. Hickman, J. M. Hardwick, and L. K. Kaczmarek Exposure to Hypoxia Rapidly Induces Mitochondrial Channel Activity within a Living Synapse J. Biol. Chem., February 11, 2005; 280(6): 4491 - 4497. [Abstract] [Full Text] [PDF]

				A. H. Lockwood Human Testing of Pesticides: Ethical and Scientific Considerations Am J Public Health, November 1, 2004; 94(11): 1908 - 1916. [Abstract] [Full Text] [PDF]

				J. T. Sanderson, J. Hordijk, M. S. Denison, M. F. Springsteel, M. H. Nantz, and M. van den Berg Induction and Inhibition of Aromatase (CYP19) Activity by Natural and Synthetic Flavonoid Compounds in H295R Human Adrenocortical Carcinoma Cells Toxicol. Sci., November 1, 2004; 82(1): 70 - 79. [Abstract] [Full Text] [PDF]

				A. Terzi, M. Iraz, S. Sahin, A. Ilhan, N. Idiz, and E. Fadillioglu Protective effects of erdosteine on rotenone-induced oxidant injury in liver tissue Toxicology and Industrial Health, July 1, 2004; 20(6-10): 141 - 147. [Abstract] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help