The parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity - PubMed (original) (raw)
. 2000 Dec 8;275(49):38581-8.
doi: 10.1074/jbc.M005385200.
Affiliations
- PMID: 10969076
- DOI: 10.1074/jbc.M005385200
Free article
The parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity
J Lotharius et al. J Biol Chem. 2000.
Free article
Abstract
Uptake of the Parkinsonism-inducing toxin, 1-methyl-4-phenylpyridinium (MPP(+)), into dopaminergic terminals is thought to block Complex I activity leading to ATP loss and overproduction of reactive oxygen species (ROS). The present study indicates that MPP(+)-induced ROS formation is not mitochondrial in origin but results from intracellular dopamine (DA) oxidation. Although a mean lethal dose of MPP(+) led to ROS production in identified dopaminergic neurons, toxic doses of the Complex I inhibitor rotenone did not. Concurrent with ROS formation, MPP(+) redistributed vesicular DA to the cytoplasm prior to its extrusion from the cell by reverse transport via the DA transporter. MPP(+)-induced DA redistribution was also associated with cell death. Depleting cells of newly synthesized and/or stored DA significantly attenuated both superoxide production and cell death, whereas enhancing intracellular DA content exacerbated dopaminergic sensitivity to MPP(+). Lastly, depleting cells of DA in the presence of succinate completely abolished MPP(+)-induced cell death. Thus, MPP(+) neurotoxicity is a multi-component process involving both mitochondrial dysfunction and ROS generated by vesicular DA displacement. These results suggest that in the presence of a Complex I defect, misregulation of DA storage could lead to the loss of nigrostriatal neurons in Parkinson's disease.
Similar articles
- The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited.
Nakamura K, Bindokas VP, Marks JD, Wright DA, Frim DM, Miller RJ, Kang UJ. Nakamura K, et al. Mol Pharmacol. 2000 Aug;58(2):271-8. doi: 10.1124/mol.58.2.271. Mol Pharmacol. 2000. PMID: 10908294 - Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons.
Bilsland J, Roy S, Xanthoudakis S, Nicholson DW, Han Y, Grimm E, Hefti F, Harper SJ. Bilsland J, et al. J Neurosci. 2002 Apr 1;22(7):2637-49. doi: 10.1523/JNEUROSCI.22-07-02637.2002. J Neurosci. 2002. PMID: 11923429 Free PMC article. - Toxic effects of MPP(+) and MPTP in PC12 cells independent of reactive oxygen species formation.
Fonck C, Baudry M. Fonck C, et al. Brain Res. 2001 Jun 29;905(1-2):199-206. doi: 10.1016/s0006-8993(01)02551-3. Brain Res. 2001. PMID: 11423095 - MPP(+)-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress.
Hsieh YC, Mounsey RB, Teismann P. Hsieh YC, et al. Naunyn Schmiedebergs Arch Pharmacol. 2011 Aug;384(2):157-67. doi: 10.1007/s00210-011-0660-8. Epub 2011 Jun 12. Naunyn Schmiedebergs Arch Pharmacol. 2011. PMID: 21667279 Free PMC article.
Cited by
- Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression.
Benskey M, Behrouz B, Sunryd J, Pappas SS, Baek SH, Huebner M, Lookingland KJ, Goudreau JL. Benskey M, et al. Neurotoxicology. 2012 Jun;33(3):321-31. doi: 10.1016/j.neuro.2012.02.001. Epub 2012 Feb 9. Neurotoxicology. 2012. PMID: 22342763 Free PMC article. - Manganese superoxide dismutase protects against 6-hydroxydopamine injury in mouse brains.
Callio J, Oury TD, Chu CT. Callio J, et al. J Biol Chem. 2005 May 6;280(18):18536-42. doi: 10.1074/jbc.M413224200. Epub 2005 Mar 8. J Biol Chem. 2005. PMID: 15755737 Free PMC article. - DJ-1 has a role in antioxidative stress to prevent cell death.
Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H. Taira T, et al. EMBO Rep. 2004 Feb;5(2):213-8. doi: 10.1038/sj.embor.7400074. Epub 2004 Jan 23. EMBO Rep. 2004. PMID: 14749723 Free PMC article. - An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage.
Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT. Sherer TB, et al. J Neurosci. 2002 Aug 15;22(16):7006-15. doi: 10.1523/JNEUROSCI.22-16-07006.2002. J Neurosci. 2002. PMID: 12177198 Free PMC article. - Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin's lymphoma.
Meredith EJ, Holder MJ, Rosén A, Lee AD, Dyer MJ, Barnes NM, Gordon J. Meredith EJ, et al. Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13485-90. doi: 10.1073/pnas.0605993103. Epub 2006 Aug 28. Proc Natl Acad Sci U S A. 2006. PMID: 16938864 Free PMC article.