Mechanism underlying anti-apoptotic activity of a (-)deprenyl-related propargylamine, rasagiline.
A potent inhibitor of type B monoamine oxidase, (-)deprenyl, is known to protect or rescue dying neurons, independent of inhibition of the enzyme activity. After long term administration to rodents, a propargylamine structurally related to (-)deprenyl, (R)(+)-N-propargyl-1-aminoindan (rasagiline) increased the activities of anti-oxidative enzymes, superoxide dismutase and catalase. Rasagiline protected in vitro dopamine cells from apoptosis induced by oxidative stress or neurotoxins. The mechanism of the anti-apoptotic effect was studied by in vitro experiments using human dopaminergic neuroblastoma, SH-SY5Y cells. Peroxynitrite-generating N-morpholino sydonimine (SIN-1) induced apoptosis in SH-SY5Y cells via disruption of mitochondrial membrane potential (DeltaPsim), followed by caspase 3 activation. Rasagiline prevented the loss of DeltaPsim, the initial step to apoptosis, and also following caspase 3-activation and DNA fragmentation. The results suggest that rasagiline may interact with the specific molecule in the mitochondria and suppress the death signal transduction. By the anti-apoptotic function, rasagiline may rescue or protect declining neurons in aging and neurodegenerative disorders, such as Parkinson's disease.
Maruyama
W
W
Department of Basic Gerontology, Laboratory of Biochemistry and Metabolism, National Institute for Longevity Sciences, Gengo, Morioka-cho, Obu 474-8522, Aichi, Japan. maruyama@nils.go.jp
Yamamoto
T
T
Kitani
K
K
Carrillo
M C
MC
Youdim
M
M
Naoi
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives; D011437:Propylamines; D051381:Rats; D011916:Rats, Inbred F344; D012642:Selegiline / Q000031:analogs & derivatives / Q000737:chemistry; D014407:Tumor Cells, Cultured
D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011437:Propylamines; C031967:rasagiline; C009054:propargylamine; D012642:Selegiline; C002385:linsidomine; D010293:Pargyline; D008981:Molsidomine