nor-4 and linsidomine

Nitric oxide (NO) has been reported to modulate the vascular endothelial growth factor (VEGF) gene by accumulating hypoxia-inducible factor-1alpha (HIF-1alpha) protein, but there is a contradiction among effects of various NO donors. The effects of NO donors including S-nitroso-N-acetyl-penicillamine (SNAP), S-nitroso-glutathione (GSNO), 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene (NOC18), 3-[(+/-)-(E)-ethyl-2(')-[(E)-hydroxyimino]-5-nitro-3-hexenecarbamoyl]-pyridine (NOR4), 3-morpholinosydnonimine (SIN-1), and nitroprusside (SNP) on the VEGF reporter gene were examined. SNAP, GSNO, NOC18, and NOR4 enhanced the VEGF reporter activity under normoxia and modulated the hypoxic induction. In contrast, SNP had only an inhibitory effect. An NO scavenger attenuated the reporter activation by NO donors except NOR4, but did not ameliorate the inhibitory effect of SNP. A reducing compound dithiothreitol suppressed NO-induced activation of the VEGF reporter gene. SNAP, GSNO, and NOC18 induced the accumulation of HIF-1alpha protein, while others did not. These results suggest that SNAP, GSNO, and NOC compounds are suitable for pharmacological studies in HIF-1-mediated VEGF gene activation by NO.

Topics: Blotting, Northern; Blotting, Western; Cell Nucleus; Dithiothreitol; Dose-Response Relationship, Drug; Endothelial Growth Factors; Genes, Reporter; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Luciferases; Lymphokines; Molsidomine; Nitric Oxide; Nitric Oxide Donors; Nitrites; Nitroprusside; Oxidation-Reduction; Penicillamine; Plasmids; Promoter Regions, Genetic; Pyridines; Reducing Agents; RNA; RNA, Messenger; S-Nitrosoglutathione; Transcription Factors; Triazenes; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In Parkinson's disease the cell death of dopamine neurons has been proposed to be mediated by an apoptotic death process, in which nitric oxide may be involved. This article reports the induction of apoptosis by nitric oxide and peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells and the antiapoptotic activity of (-)-deprenyl. After the cells were treated with a nitric oxide donor, NOR-4, or a peroxynitrite donor, SIN-1, DNA damage was quantitatively studied using a single-cell gel electrophoresis (comet) assay. NOR-4 and SIN-1 induced DNA damage dose-dependently. Cycloheximide and alkaline treatment of the cells prevented the DNA damage, indicating that the damage is apoptotic and that it depends on the intracellular signal transduction. Superoxide dismutase and the antioxidants reduced glutathione and alpha-tocopherol protected the cells from the DNA damage. (-)-Deprenyl protected the cells from the DNA damage induced by nitric oxide or peroxynitrite almost completely. The protection by (-)-deprenyl was significant even after it was washed from the cells, indicating that (-)-deprenyl may activate the intracellular system against apoptosis. These results suggest that (-)-deprenyl or related compounds may be neuroprotective to dopamine neurons through its antiapoptotic activity.

Topics: Antiparkinson Agents; Apoptosis; DNA Damage; Dopamine; Electrophoresis, Agar Gel; Humans; Molsidomine; Monoamine Oxidase Inhibitors; Neuroblastoma; Nitrates; Nitric Oxide; Oxidants; Pyridines; Selegiline; Tumor Cells, Cultured