title: Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition.
abstract: Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.
authors.affiliation: Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Faculty of Medicine, 31096 Haifa, Israel. Youdim@tx.technion.ac.il
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.forename: Orit
authors.initials: O
authors.lastname: Bar Am
authors.forename: Merav
authors.initials: M
authors.lastname: Yogev-Falach
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
authors.forename: Wakako
authors.initials: W
authors.lastname: Maruyama
authors.forename: Makato
authors.initials: M
authors.lastname: Naoi
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D023281:Genomics / Q000379:methods; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects*; D008959:Models, Neurological; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010539:Permeability / Q000187:drug effects; D011437:Propylamines / Q000494:pharmacology / Q000627:therapeutic use; D011493:Protein Kinase C / Q000378:metabolism; D040901:Proteomics / Q000379:methods
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D011437:Propylamines; C031967:rasagiline; C009054:propargylamine; D010293:Pargyline; D011493:Protein Kinase C