Document Detail

Subtoxic concentration of manganese synergistically potentiates 1-methyl-4-phenylpyridinium-induced neurotoxicity in PC12 cells.
MedLine Citation:
PMID:  12535785     Owner:  NLM     Status:  MEDLINE    
Endogenous or exogenous substances that are toxic to dopaminergic cells have been proposed as possible cause of idiopathic Parkinson's disease (PD). 1-Methyl-4-phenylpyridinium (MPP(+)) and manganese are dopaminergic neurotoxins causing a parkinsonism-like syndrome. Here, we studied the possible synergistic reaction between these two neurotoxins using rat PC12 pheochromocytoma cells. MPP(+) induced a delayed neurotoxicity in PC12 cells. Although low concentration of manganese did not cause cell damage, it markedly enhanced MPP(+)-induced neurotoxicity with characteristics of apoptosis, such as DNA laddering and activation of caspase-3. To understand the mechanism of enhancement of subtoxic concentration of manganese on MPP(+)-induced neurotoxicity, we investigated the reactive oxygen species (ROS) generation using a molecular probe, 2',7'-dichlorofluorescein diacetate. Although subtoxic concentration of manganese alone did not induce ROS increase, it significantly enhanced the ROS generation induced by MPP(+). We also determined the intracellular MPP(+) content. A time- and concentration-dependent increase of MPP(+) levels was found in PC12 cells treated with MPP(+). The accumulation of MPP(+) by PC12 cells was not affected by manganese. Taken together, these studies suggest that co-treatment with MPP(+) and manganese may induce synergistic neurotoxicity in PC12 cells and that subtoxic concentration of manganese may potentiate the effect of MPP(+) by an ROS-dependent pathway.
Ren-Gang Wang; Xing-Zu Zhu
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Brain research     Volume:  961     ISSN:  0006-8993     ISO Abbreviation:  Brain Res.     Publication Date:  2003 Jan 
Date Detail:
Created Date:  2003-01-21     Completed Date:  2003-04-01     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0045503     Medline TA:  Brain Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  131-8     Citation Subset:  IM    
Department of Pharmacology, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
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MeSH Terms
1-Methyl-4-phenylpyridinium / pharmacology*
Dose-Response Relationship, Drug
Drug Synergism
Manganese / administration & dosage*
Neurotoxins / pharmacology*
Osmolar Concentration
PC12 Cells
Reactive Oxygen Species / metabolism
Reg. No./Substance:
0/Neurotoxins; 0/Reactive Oxygen Species; 48134-75-4/1-Methyl-4-phenylpyridinium; 7439-96-5/Manganese

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