Anti-apoptotic function of L-(-)deprenyl (Selegiline) and related compounds.
(-)Deprenyl has been proposed to be neuroprotective to dopamine neurons in the parkinsonian brains. To clarify the mechanism, the effects of (-)deprenyl and structurally related compounds on apoptosis induced by a neurotoxin, N-methyl(R)-salsolinol, and reactive oxygen species, nitric oxide and peroxynitrite, were examined in dopaminergic SH-SY5Y cells. DNA damage was quantified by the single cell gel electrophoresis (comet) assay. (-)-Deprenyl protected the cells from apoptosis in a dose-dependent way, which required pre-treatment at least for 20 min. The effect was confirmed even after washing out of (-)deprenyl, indicating that (-)-deprenyl initiates the intracellular process to antagonize the apoptotic death program. The studies on the structure-activity relationship reveal that N-propargyl residue with hydrophobic structure is essential for the anti-apoptotic function. These results suggest that (-)deprenyl and related compounds may be applicable as neuroprotective agents in neurodegenerative diseases.
Naoi
M
M
Institute of Applied Biochemistry, Mitake, Gifu, Japan.
Maruyama
W
W
Yagi
K
K
Youdim
M
M
D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D053938:DNA Fragmentation; D006801:Humans; D009498:Neurotoxins / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy; D012490:Salsoline Alkaloids / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D000978:Antiparkinson Agents; D009498:Neurotoxins; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; D012642:Selegiline; C032837:salsoline