The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells.
Clinical trials for treatment of Parkinson's disease suggest that (-)deprenyl (selegiline), an inhibitor of type B monoamine oxidase, may slow the disease progression. However, the mechanism underlying protection of nigral dopamine neurons by selegiline remains an enigma. Recently, rasagiline, (R)(+)-N-propargyl-1-aminoindan, was reported to be neuroprotective by in vivo and in vitro experiments, which is another selective irreversible inhibitor of type B monoamine oxidase and not metabolized into amphetamine-like derivatives as in the case of selegiline. In this paper, the mechanism of the neuroprotection was examined using human dopaminergic neuroblastoma SH-SY5Y cells against apoptosis induced by peroxynitrite generated from SIN-1. After treatment with SIN-1, the apoptotic DNA damage in the cells was quantified by a single cell gel electrophoresis (comet) assay and by staining with Hoechst 33342. Change in mitochondrial membrane potential, Deltapsim, was measured by use of a fluorescent indicator, JC-1. Rasagiline reduced apoptosis with much more potency than selegiline, and the protection required 20 min pre-incubation before SIN-1 treatment. The protection by rasagiline was proved to be due to stabilization of mitochondrial membrane potential against the collapse induced by SIN-1, whereas rasagiline did not scavenge peroxynitrite directly. The studies on structure-activity relationship showed that a propargylamine group and a hydrophobic group with an adequate intermediate space were required for the protection. These results suggest that rasagiline may protect declining neurons through its anti-apoptotic activity in neurodegenerative diseases.
Maruyama
W
W
Laboratory of Biochemistry and Metabolism, Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Aichi, Japan.
Takahashi
T
T
Youdim
M
M
Naoi
M
M
D000978:Antiparkinson Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000502:physiology; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000009:adverse effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology
D000978:Antiparkinson Agents; D007189:Indans; D018696:Neuroprotective Agents; C031967:rasagiline; D030421:Peroxynitrous Acid; D004298:Dopamine