Document Detail

Protection from MPTP-induced neurotoxicity in differentiating mouse N2a neuroblastoma cells.
MedLine Citation:
PMID:  11158235     Owner:  NLM     Status:  MEDLINE    
We have shown previously that subcytotoxic concentrations of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) inhibit axon outgrowth and are associated with increased neurofilament heavy chain (NF-H) phosphorylation in differentiating mouse N2a neuroblastoma cells while higher doses (> 100 microM) cause cell death. In this work we assessed the ability of potential neuroprotective agents to alleviate both MPTP-induced cell death (cytotoxicity) and MPTP-induced NF-H phosphorylation/reduction in axon outgrowth (neurotoxicity) in N2a cells induced to differentiate by dbcAMP. The neurotoxic effects of MPTP occurred in the absence of significant alterations in energy status or mitochondrial membrane potential. The hormone oestradiol (100 microM) reduced the cytotoxic effect of MPTP, but blocked di-butyryl cyclic AMP (dbcAMP)-induced differentiation, i.e. axon outgrowth. Both the cytotoxic and neurotoxic effects of MPTP were reduced by the monoamine oxidase (MAO) inhibitors deprenyl and, to a lesser extent, clorgyline. Alleviation of both neurotoxicity and cytotoxicity was also achieved by conditioned medium derived from rat C6 glioma cells. In contrast, whilst the p38 MAP kinase inhibitor, SB202190, protected cells against MPTP-induced neurotoxicity, it could not maintain cell viability at high MPTP exposures. In each case neuroprotection involved maintenance of the differentiating phenotype linked with attenuation of NF-H hyper-phosphorylation; the latter may represent a mechanism by which neuronal cells can moderate MPTP-induced neurotoxicity. The use of a simplified neuronal cell model, which expresses subtle biochemical changes following neurotoxic insult, could therefore provide a valuable tool for the identification of potential neuroprotective agents.
L A De Girolamo; A J Hargreaves; E E Billett
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  76     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-02-22     Completed Date:  2001-03-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  650-60     Citation Subset:  IM    
Department of Life Sciences, Faculty of Science and Mathematics, Nottingham Trent University, Clifton, Nottingham, UK.
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MeSH Terms
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology*
Adenosine Triphosphate / metabolism
Axons / drug effects,  physiology
Cell Death / drug effects
Cell Differentiation / drug effects
Culture Media, Conditioned / pharmacology
Estradiol / pharmacology
Imidazoles / pharmacology
Intracellular Membranes / physiology
Mitochondria / physiology
Monoamine Oxidase Inhibitors / pharmacology
Neuroblastoma / pathology*,  physiopathology
Neurofilament Proteins / metabolism
Neuroprotective Agents / pharmacology*
Neurotoxins / pharmacology*
Pyridines / pharmacology
Tumor Cells, Cultured
Reg. No./Substance:
0/4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; 0/Culture Media, Conditioned; 0/Imidazoles; 0/Monoamine Oxidase Inhibitors; 0/Neurofilament Proteins; 0/Neuroprotective Agents; 0/Neurotoxins; 0/Pyridines; 108688-71-7/neurofilament protein H; 28289-54-5/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 50-28-2/Estradiol; 56-65-5/Adenosine Triphosphate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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