Evidence for non-oxidative dopamine cytotoxicity: potent activation of NF-kappa B and lack of protection by anti-oxidants.
A stable aromatic acid decarboxylase expressing the Chinese hamster ovary cell line was developed to study the cytotoxic properties of intracellular and extracellular dopamine. The relative impermeability of cells to dopamine, but not to L-DOPA, allows the differentiation of extracellular and intracellular dopamine cytotoxicity. In contrast to extracellular dopamine, intracellular dopamine toxicity was resistant to antioxidant protection, and did not require melanin formation for its toxicity. Furthermore, we demonstrated a rapid and potent activation of the stress-inducible transcription factor NF-kappa B by intracellular dopamine, which was also largely insensitive to antioxidant inhibition. A distinctly slower and less potent NF-kappa B activation by extracellular dopamine was blocked by antioxidants and acetylsalicylic acid. Our results indicate the existence of a non-oxidative mechanism of dopamine cytotoxicity. Mitigating intracellular dopamine toxicity could be a novel strategy of slowing the progressive degeneration of dopaminergic neurons in Parkinson's disease.
Weingarten
P
P
Department of Pharmacology, University of California, Irvine 92697, USA.
Bermak
J
J
Zhou
Q Y
QY
D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D006224:Cricetinae; D004298:Dopamine / Q000502:physiology*; D005978:Glutathione / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007980:Levodopa / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D016328:NF-kappa B; D011994:Recombinant Proteins; D007980:Levodopa; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D001241:Aspirin; D004298:Dopamine; D000111:Acetylcysteine