The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells

J Neural Transm (Vienna). 2002 Apr;109(4):467-81. doi: 10.1007/s007020200038.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiparkinson Agents / chemistry
  • Antiparkinson Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • DNA Damage / drug effects*
  • DNA Damage / physiology
  • Dopamine / physiology
  • Humans
  • Indans / chemistry
  • Indans / pharmacology*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Neuroblastoma / physiopathology
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Peroxynitrous Acid / adverse effects*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / physiology


  • Antiparkinson Agents
  • Indans
  • Neuroprotective Agents
  • rasagiline
  • Peroxynitrous Acid
  • Dopamine