Neuroprotection by (-)-deprenyl and related compounds.
There is an increasing number of data by in vitro and in vivo experiments, indicating that (-)-deprenyl is neuroprotective to dopamine neurons, even though detailed mechanism remains to be clarified. In this paper neuroprotection by (-)-deprenyl and structurally related compounds was examined in concern with the suppression of apoptosis induced by a reactive oxygen species, peroxynitrite generated from SIN-1. The apoptotic DNA damage was quantitatively determined using dopaminergic SH-SYSY cells and by a single cell gel electrophoresis (comet) assay. DNA damage induced by peroxynitrite was proved to be apoptotic by prevention of the damage by cycloheximide or actinomycin-D. (-)-Deprenyl and other propargylamines protected the cells from apoptosis in a dose-dependent way. (-)-Deprenyl protected the cells even after it was washed out, suggesting that it may initiate the intracellular process to repress the apoptotic death program. The study on the structure-activity relationship of (-)-deprenyl analogues revealed that a N-propargyl residue with adequate size of hydrophobic structure is essentially required for the anti-apoptotic activity. These results suggest that (-)-deprenyl and related compounds may protect neurons from apoptosis and be applicable to delay the deterioration of neurons during advancing ageing and in neurodegenerative disorders.
Maruyama
W
W
Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Japan. maruyama@nils.go.jp
Naoi
M
M
D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002417:Cattle; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D007189:Indans / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009566:Nitrates / Q000633:toxicity; D016877:Oxidants / Q000633:toxicity; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012642:Selegiline / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000662:Amphetamines; D000975:Antioxidants; D004273:DNA, Neoplasm; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D009566:Nitrates; D016877:Oxidants; C031967:rasagiline; C039642:peroxynitric acid; D012642:Selegiline; C017861:desmethylselegiline