MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakamura, K.
Right arrow Articles by Kang, U. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakamura, K.
Right arrow Articles by Kang, U. J.

Vol. 58, Issue 2, 271-278, August 2000

The Selective Toxicity of 1-Methyl-4-phenylpyridinium to Dopaminergic Neurons: The Role of Mitochondrial Complex I and Reactive Oxygen Species Revisited

Ken Nakamura, Vytautas P. Bindokas, Jeremy D. Marks, David A. Wright, David M. Frim, Richard J. Miller, and Un Jung Kang

Committee on Neurobiology (K.N., R.J.M., U.J.K.), Departments of Neurology (D.A.W., U.J.K.), Neurobiology, Pharmacology & Physiology (V.P.B., R.J.M., U.J.K.), Pediatrics (J.D.M., D.M.F.), and Surgery (D.M.F.), The University of Chicago, Chicago, Illinois

1-Methyl-4-phenylpyridinium (MPP+) is selectively toxic to dopaminergic neurons and has been studied extensively as an etiologic model of Parkinson's disease (PD) because mitochondrial dysfunction is implicated in both MPP+ toxicity and the pathogenesis of PD. MPP+ can inhibit mitochondrial complex I activity, and its toxicity has been attributed to the subsequent mitochondrial depolarization and generation of reactive oxygen species. However, MPP+ toxicity has also been noted to be greater than predicted by its effect on complex I inhibition or reactive oxygen species generation. Therefore, we examined the effects of MPP+ on survival, mitochondrial membrane potential (Delta Psi m), and superoxide and reduced glutathione levels in individual dopaminergic and nondopaminergic mesencephalic neurons. MPP+ (5 µM) selectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their Delta Psi m. In contrast, the specific complex I inhibitor rotenone, at a dose (20 nM) that was less toxic than MPP+ to dopaminergic neurons, depolarized Delta Psi m to a greater extent than MPP+. In addition, neither rotenone nor MPP+ increased superoxide in dopaminergic neurons, and MPP+ failed to alter levels of reduced glutathione. Therefore, we conclude that increased superoxide and loss of Delta Psi m may not represent primary events in MPP+ toxicity, and complex I inhibition alone is not sufficient to explain the selective toxicity of MPP+ to dopaminergic neurons. Clarifying the effects of MPP+ on energy metabolism may provide insight into the mechanism of dopaminergic neuronal degeneration in PD.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Toxicol SciHome page
R. M. LoPachin and T. Gavin
Response to "Paraquat: The Red Herring of Parkinson's Disease Research"
Toxicol. Sci., May 1, 2008; 103(1): 219 - 221.
[Full Text] [PDF]

Home page
 Toxicol SciHome page
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]

Home page
 Toxicol SciHome page
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]

Home page
 J. Biol. Chem.Home page
G.-R. Kweon, J. D. Marks, R. Krencik, E. H. Leung, P. T. Schumacker, K. Hyland, and U. J. Kang
Distinct Mechanisms of Neurodegeneration Induced by Chronic Complex I Inhibition in Dopaminergic and Non-dopaminergic Cells
J. Biol. Chem., December 10, 2004; 279(50): 51783 - 51792.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
N. Weissmann, N. Ebert, M. Ahrens, H. A. Ghofrani, R. T. Schermuly, J. Hanze, L. Fink, F. Rose, J. Conzen, W. Seeger, et al.
Effects of Mitochondrial Inhibitors and Uncouplers on Hypoxic Vasoconstriction in Rabbit Lungs
Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 721 - 732.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. J. Crocker, P. D. Smith, V. Jackson-Lewis, W. R. Lamba, S. P. Hayley, E. Grimm, S. M. Callaghan, R. S. Slack, E. Melloni, S. Przedborski, et al.
Inhibition of Calpains Prevents Neuronal and Behavioral Deficits in an MPTP Mouse Model of Parkinson's Disease
J. Neurosci., May 15, 2003; 23(10): 4081 - 4091.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
T. B. Sherer, R. Betarbet, A. K. Stout, S. Lund, M. Baptista, A. V. Panov, M. R. Cookson, and J. T. Greenamyre
An In Vitro Model of Parkinson's Disease: Linking Mitochondrial Impairment to Altered alpha -Synuclein Metabolism and Oxidative Damage
J. Neurosci., August 15, 2002; 22(16): 7006 - 7015.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
P. C. Waldmeier, J.-J. Feldtrauer, T. Qian, and J. J. Lemasters
Inhibition of the Mitochondrial Permeability Transition by the Nonimmunosuppressive Cyclosporin Derivative NIM811
Mol. Pharmacol., July 1, 2002; 62(1): 22 - 29.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics