Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes.
In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT.
Laboratory of Biochemistry and Metabolism, Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Aichi 474-8522, Japan. maruyama@nils.go.jp
Wakako
W
Maruyama
Yukihiro
Y
Akao
Maria Chrisina
MC
Carrillo
Ken-ichi
K
Kitani
Moussa B H
MB
Youdium
Makoto
M
Naoi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011437:Propylamines / Q000494:pharmacology* / Q000627:therapeutic use; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D018696:Neuroprotective Agents; D011437:Propylamines; C009054:propargylamine; D010293:Pargyline; D004298:Dopamine