QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.127597v1 323/2/499    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Watabe, M. Articles by Nakaki, T. Search for Related Content PubMed PubMed Citation Articles by Watabe, M. Articles by Nakaki, T.

TOXICOLOGY

Mitochondrial Complex I Inhibitor Rotenone-Elicited Dopamine Redistribution from Vesicles to Cytosol in Human Dopaminergic SH-SY5Y Cells

Department of Pharmacology, Teikyo University School of Medicine, Tokyo, Japan

Parkinson's disease is a chronic neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Rotenone, a pesticide, produces selective degeneration of dopaminergic neurons and motor dysfunction in rats. To determine the mechanisms underlying rotenone-induced neuronal death, we investigated whether intracellular dopamine plays a role in rotenone (0.1–0.4 µM)-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. The 40% decrease of dopamine content by inhibition of dopamine synthesis suppressed rotenone-induced apoptosis. On the other hand, the 30% increase of dopamine content by inhibition of dopamine metabolism enhanced rotenone-induced apoptosis. Depletion of intracellular dopamine using reserpine (0.1–10 µM) also prevented rotenone-induced apoptosis, and this effect was counteracted by dopamine (10–100 µM) replenishment. Inhibition of dopamine reverse transport increased cytosolic dopamine and enhanced rotenone-induced apoptosis. We examined the intracellular localization of dopamine in rotenone-treated cells immunocytochemically and quantitatively. Rotenone induced dopamine redistribution from vesicles to the cytosol. In this process, rotenone stimulated reactive oxygen species and protein carbonylation and decreased an antioxidant, glutathione. Addition of an antioxidant, N-acetylcysteine (3 mM), prevented dopamine being expelled from vesicles and inhibited rotenone-induced apoptosis. Our findings demonstrate that rotenone-generated reactive oxygen species are involved in dopamine redistribution to the cytosol, which in turn may play a role in rotenone-induced apoptosis of dopaminergic cells.

Address correspondence to: Dr. Toshio Nakaki, Department of Pharmacology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan. E-mail: nakaki{at}med.teikyo-u.ac.jp

This article has been cited by other articles:

				M. Watabe and T. Nakaki Mitochondrial Complex I Inhibitor Rotenone Inhibits and Redistributes Vesicular Monoamine Transporter 2 via Nitration in Human Dopaminergic SH-SY5Y Cells Mol. Pharmacol., October 1, 2008; 74(4): 933 - 940. [Abstract] [Full Text] [PDF]