Novel neuroprotective mechanism of action of rasagiline is associated with its propargyl moiety: interaction of Bcl-2 family members with PKC pathway.
Our studies have provided new insights into the biological mechanism of neuroprotection of the anti-Parkinson drug, rasagiline [N-propargyl-(1R)-aminoindan], involving the association of Bcl-2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal-induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N-propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKCepsilon mRNA; induction of Bcl-X(L), Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCgamma, Bad, and Bax mRNAs. Moreover, these drugs inhibited the cleavage and activation of pro-caspase-3 and poly(ADP-ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC-dependent cell survival activity of rasagiline. Structure activity studies have established that N-propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron-chelating property for the treatment and/or prevention of neurodegenerative diseases.
Weinreb
Orly
O
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.
Amit
Tamar
T
Bar-Am
Orit
O
Chillag-Talmor
Orly
O
Youdim
Moussa B H
MB
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D007189:Indans; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011437:Propylamines; D019253:Proto-Oncogene Proteins c-bcl-2; C031967:rasagiline; C009054:propargylamine; D010293:Pargyline; D011493:Protein Kinase C