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Perturbation of dopamine metabolism by 3‐amino‐2‐phenylpropenes causes increased oxidative stress leading to SH‐SY5Y cell death
Author(s) -
Samms Warren C.,
Wimalasena K.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a819
Subject(s) - sh sy5y , chemistry , oxidative stress , intracellular , programmed cell death , dopamine , microbiology and biotechnology , reactive oxygen species , apoptosis , cell culture , biochemistry , neuroblastoma , biology , endocrinology , genetics
We have recently characterized a series of 3‐amino‐2‐phenylpropene (APP) derivatives as reversible inhibitors for the bovine adrenal chromaffin granule vesicular monoamine transporter (VMAT). Halogen substitution on the 4′‐position of the aromatic ring gradually increases VMAT inhibition potency from 4′‐F to 4′‐I, parallel to the hydrophobicity of the halogen. We show that these derivatives are taken up into both neuronal and non‐neuronal cells, and into resealed chromaffin granule ghosts efficiently through passive diffusion. More importantly, these derivatives are highly toxic to the human neuroblastoma SH‐SY5Y, but not toxic to M‐1, Hep G2 or HEK‐293 non‐neuronal cells at similar concentrations. They drastically perturb dopamine (DA) uptake, storage, and metabolism and deplete intracellular catecholamines in SH‐SY5Y cells as detected through HPLC‐electrochemical methods. Additionally, 4′‐IAPP treatment significantly increases intracellular reactive oxygen species (ROS) and decreases reduced glutathione levels in SH‐SY5Y cells. DNA fragmentation further supports that cell death is likely due to an ROS‐mediated apoptotic pathway. Based on these and other findings, we propose that the drastic perturbation of DA metabolism in SH‐SY5Y cells by 4′‐halo APP derivatives causes the high oxidative stress leading to cell death. Supported by NIH NS 39423.