Lipophilic organic cations are novel environmental dopaminergic toxins that may contribute to the etiology of Parkinson's disease

Abstract

Specific uptake through dopamine transporter (DAT) followed by the inhibition of the mitochondrial complex I has been accepted as the mechanism for specific dopaminergic toxicity of 1-methyl-phenylpyridium (MPP+), the most commonly used Parkinson’s disease toxin model. However, MPP+ is taken up into many cell types through a number of other transporters suggesting that, in addition to the uptake, intrinsic vulnerability of dopaminergic cells may also contribute to their high sensitivity to MPP+. To test this possibility, a group of hydrophobic cyanines were employed in a comparative study based on their unique characteristics and structural similarity to MPP+. Here we show that cyanines freely accumulate in dopaminergic (MN9D, SH-SY5Y) as well as in liver (HepG2) cell lines, but are specifically and highly toxic to dopaminergic cells (IC50s ~100 nM) demonstrating that1000 fold more toxic than MPP+. They cause mitochondrial membrane depolarization, mitochondrial complex I inhibition with potencies similar to the best known mitochondrial complex I inhibitor rotenone, and intracellular ATP depletion without cell specificity. However, they increase reactive oxygen species (ROS) levels specifically in dopaminergic cells leading to the apoptotic cell death, parallel to well characterized PD models, MPP+ and rotenone. We propose that the specific sensitivity of dopaminergic cells towards all of these mitochondrial toxins (cyanine, MPP+ and rotenone) is most likely due to the expression of low levels of antioxidant enzymes together with the presence of high levels of oxidatively sensitive dopamine (DA) in these cells. The key similarities in structure and toxicity profile between MPP+ and these cyanines further suggest that the lipophilic, cationic cyanine dyes and other similar organic cations could be potent dopaminergic toxins, similar to MPP+. Based on the above findings, these cyanines may be stronger in vivo dopaminergic toxins than MPP+ and their in vivo toxicities must be evaluated.