title: Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety.
abstract: Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCalpha, PKCepsilon and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neurotrophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of pro-caspase-3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCgamma mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propargylamine both regulated amyloid precursor protein (APP) processing towards the non-amyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl-4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.
authors.affiliation: Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel. worly@tx.technion.ac.il
authors.forename: O
authors.initials: O
authors.lastname: Weinreb
authors.forename: T
authors.initials: T
authors.lastname: Amit
authors.forename: O
authors.initials: O
authors.lastname: Bar-Am
authors.forename: Y
authors.initials: Y
authors.lastname: Sagi
authors.forename: S
authors.initials: S
authors.lastname: Mandel
authors.forename: M B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D018696:Neuroprotective Agents; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D016564:Amyloid beta-Protein Precursor; D007189:Indans; D018696:Neuroprotective Agents; D011437:Propylamines; C031967:rasagiline; C009054:propargylamine; D010293:Pargyline