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Protection from MPTP‐induced neurotoxicity in differentiating mouse N2a neuroblastoma cells
Author(s) -
De Girolamo Luigi A.,
Hargreaves Alan J.,
Billett E. Ellen
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00066.x
Subject(s) - mptp , neurotoxicity , neuroprotection , sh sy5y , programmed cell death , pharmacology , chemistry , biology , microbiology and biotechnology , apoptosis , cell culture , biochemistry , neuroblastoma , neuroscience , toxicity , dopamine , genetics , dopaminergic , organic chemistry
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 µ m ) 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 µ m ) 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 osidase (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.