Anti-apoptotic effect of Mao-B inhibitor PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] is mediated by p53 pathway inhibition in MPP+-treated SH-SY5Y human dopaminergic cells.
PF9601N [N-(2-propynyl) 2-(5-benzyloxyindol) methylamine] is a non-amphetamine type MAO-B inhibitor that has shown neuroprotective properties in vivo using different experimental models of Parkinson's disease. The mechanisms underlying its neuroprotective effects are poorly understood, but appear to be independent of MAO-B inhibition. We have studied its neuroprotective properties using the human SH-SY5Y dopaminergic cell line exposed to 1-methyl-4-phenylpyridinium (MPP(+)), a cellular model of Parkinson's disease. PF9601N pre-treatment significantly reduced MPP(+)-induced cell death and decreased the activation of one of the main executioner caspases, caspase-3. MPP(+) induced stabilization of transcription factor p53, which led to increased levels of this transcription factor, its nuclear translocation and transactivation of p53 response elements. PF9601N prevented this increase, thus reducing its transcriptional activity. Additional results showed that p53 may mediate its pro-apoptotic actions through caspase-2 under our experimental conditions. PUMA-alpha may also contribute to the p53-induced cell death. Since PF9601N significantly reduced MPP(+)-induced caspase-2 activity and PUMA-alpha levels, this reduction may lead to increased cell survival. Thus, PF9601N is a novel molecule with an apparently novel mechanism of action which has a promising potential as a therapeutic agent in the treatment of neurodegenerative diseases.
Sanz
Elisenda
E
Institut de Neurociències & Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. elisenda.sanz@uab.es
Quintana
Albert
A
Battaglia
Valentina
V
Toninello
Antonio
A
Hidalgo
Juan
J
Ambrosio
Santiago
S
Valoti
Massimo
M
Marco
Jose Luis
JL
Tipton
Keith F
KF
Unzeta
Mercedes
M
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000502:physiology
D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; C470996:N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine; D018696:Neuroprotective Agents; D016159:Tumor Suppressor Protein p53; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium