Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post-MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway.
The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. It is interesting to determine whether a similar effect is seen in Parkinsonian patients after long-term treatment with rasagiline, which may have implications as a possible disease modifying agent.
Mandel
Silvia A
SA
Eve Topf Center of Excellence for Neurodegenerative Diseases Research, Department of Pharmacology, Technion-Rappaport Faculty of Medicine, P.O. Box 9697, Haifa, 31096, Israel. mandel@tx.tchnion.ac.il
Sagi
Yotam
Y
Amit
Tamar
T
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000188:drug therapy / Q000473:pathology*; D009416:Nerve Regeneration / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020813:Receptor, trkB / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects
D007189:Indans; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C031967:rasagiline; D020813:Receptor, trkB
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