N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2.
Propargylamine derivatives, rasagiline and (-)deprenyl, are anti-Parkinson agents and protect neurons from cell death as shown by in vivo and in vitro experiments. The studies on the chemical structure-activity relationship proved that the propargyl moiety is essentially required for the neuroprotective function. In this paper, neuroprotective activity of free N-propargylamine was studied using SH-SY5Y cells expressing only type A monoamine oxidase (MAO) against apoptosis induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. N-Propargylamine prevented apoptosis, whereas N-methylpropargylamine and propiolaldehyde did not. N-Propargylamine stabilized mitochondrial membrane potential and induced anti-apoptotic Bcl-2 at 1 microM-10 nM. N-Propargylamine inhibited MAO-A in competition to substrate with the apparent K(i) value of 28 microM, which was significantly higher than the concentration required for neuroprotection. It indicates that MAO inhibition is not prerequisite for the protective function of N-propargylamine. The anti-apoptotic function of N-propargylamine is discussed in terms of neuroprotection by propargylamines in neurodegenerative diseases, including Parkinson's disease.
Yi
H
H
Department of Neurosciences, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan.
Maruyama
W
W
Akao
Y
Y
Takahashi
T
T
Iwasa
K
K
Youdim
M B H
MB
Naoi
M
M
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012490:Salsoline Alkaloids / Q000633:toxicity*; D044005:Tetrahydroisoquinolines / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D018696:Neuroprotective Agents; D011437:Propylamines; D019253:Proto-Oncogene Proteins c-bcl-2; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C009054:propargylamine; D010293:Pargyline; C032837:salsoline