dicumarol and Astrocytoma

Cell swelling is associated with the activation of an increase in the osmosensitive taurine release (OTR) rate, which serves to decrease cell volume as part of a process known as regulatory volume decrease. OTR, which is sensitive to many pharmacological agents including anion channel blockers and signalling pathway modulators, has also been suggested to play a role in cell cycle progression. At non-cytotoxic concentrations, the anion channel blocker NPPB (25 microM), the extra-cellular signal-regulated kinase inhibitor PD98059 (50 microM), and the c-Jun NH2-terminal kinase inhibitor SP 600125 (5 microM) each decreased the OTR rate by > or =50%, decreased cell proliferation, and increased G0/G1 cell cycle arrest.

Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Animals; Anthracenes; Apoptosis; Astrocytoma; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dicumarol; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Imidazoles; Ion Channels; JNK Mitogen-Activated Protein Kinases; Necrosis; Niflumic Acid; Nitrobenzoates; Osmolar Concentration; Pyridines; Rats; Taurine

The autooxidation of L-Dopa, a catecholamine used in the symptomatic treatment of Parkinson's disease, generally yields reactive oxygen species and neurotoxic quinones. NAD(P)H:quinone oxidoreductase (NQO) is a flavoenzyme that is implicated in the detoxication of quinones, including those formed during L-Dopa autooxidation. Through the action of this enzyme, deleterious redox-labile quinones are turned into less toxic and more stable hydroquinones that are amenable to further detoxication and/or cellular excretion. In the present study, using primary rat astrocytes and C6 astroglioma as a model to evaluate the neuroprotective response of astroglial cells upon exposure to L-Dopa, we demonstrate that this compound, or more correctly its quinone (auto)oxidation products, up-regulates astroglial NQO in a time- and concentration-dependent way as assessed at the level of mRNA expression, protein level, and enzymatic activity. Moreover, under similar conditions cellular glutathione content was enhanced. It is concluded that, similar to glutathione, the oxidative stress limiting NQO is likely to contribute to the capacity of astroglial cells to protect dopaminergic neurons against L-Dopa, and, hence, may be considered as a potential target for the development of neuroprotective strategies for Parkinson's disease.

Topics: Animals; Animals, Newborn; Astrocytes; Astrocytoma; Cells, Cultured; Dicumarol; Gene Expression Regulation, Enzymologic; Indomethacin; Levodopa; NAD(P)H Dehydrogenase (Quinone); Polymerase Chain Reaction; Rats; Tumor Cells, Cultured