or486 and Glioma

Heme oxygenase-1 (HO-1) is an inducible enzyme involved in heme catabolism, tissue iron homeostasis and the cellular response to oxidative stress. Elevated HO-1 expression in astrocytes has been observed in association with abnormal iron deposition and increased oxidative stress in Parkinson's disease (PD). Since HO-1 could contribute to these aspects of PD pathobiology we have investigated its regulation in cultured astrocytes and C6 glioma cells. Here we report that dopamine is a potent inducer of HO-1. This induction is not mediated by a classical dopamine receptor and is not mimicked by a range of catecholamines and dopamine metabolites. When the time-course of HO-1 expression was compared between dopamine and hemin, the latter induced the gene immediately while the former did so with a lag. This suggested two distinct signal transduction pathways. However, cycloheximide blocked both hemin- and dopamine-induced HO-1 expression, suggesting that both pathways may involve proteins with short half-lives. Ascorbic acid blocked dopamine induction of HO-1 but had no effect on hemin-induced expression. This suggested that dopamine may signal upstream of the unstable protein by producing pro-oxidant metabolites or byproducts. Inhibition of monoamine oxidases A or B or catechol-O-methyl transferase did not block HO-1 induction by dopamine, indicating that these enzymes were not converting dopamine to an active metabolite. These results suggest that dopamine, released or secreted from affected neurons, may trigger HO-1 expression in neighboring astrocytes. HO-1 and its metabolites could then contribute to the oxidative stress and iron deposition associated with PD.

Topics: 3,4-Dihydroxyphenylacetic Acid; Acetylcysteine; Animals; Ascorbic Acid; Astrocytes; Catechol O-Methyltransferase Inhibitors; Catechols; Cell Line; Cycloheximide; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Glioma; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hemin; Membrane Proteins; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; RNA, Messenger; Selegiline; Time Factors; Tumor Cells, Cultured