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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

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

Elisenda Sanz, Albert Quintana, Valentina Battaglia, Antonio Toninello, Juan Hidalgo, Santiago Ambrosio, Massimo Valoti, Jose Luis Marco, Keith F Tipton, Mercedes Unzeta

J Neurochem. 2008 Jun 1;105(6):2404-17.

PMID: 18331475

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP133845633	PF9601N		133845-63-3	Price

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