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.