Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism.
The anti-Parkinson monoamine oxidase (MAO)-B inhibitor rasagiline (Azilect) was shown to possess neuroprotective activities, involving the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). Employing conventional neurochemical techniques, transcriptomics and proteomic screening tools combined with a biology-based clustering method, we show that rasagiline, given chronically post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), exerts neurorescue/neurotrophic activity in mice midbrain dopamine neurons. Rasagiline induced 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 effector phosphatidylinositol 3 kinase (PI3K) protein. Confirmatory Western and immunohistochemical analyses indicated activation of the substrate of PI3K, Akt and phosphorylative inactivation of glycogen synthase kinase-3beta and Raf1. Thus, the activation of Ras-PI3K-Akt survival pathway may contribute to rasagiline-mediated neurorescue effect. It is interesting to determine whether a similar effect is seen in parkinsonian patients after long-term treatment with rasagiline.
Sagi
Yotam
Y
Eve Topf and USA National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, POB 9697, 31096 Haifa, Israel.
Mandel
Silvia
S
Amit
Tamar
T
Youdim
Moussa B H
MB
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D007150:Immunohistochemistry; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
D018076:DNA, Complementary; D015259:Dopamine Agents; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C031967:rasagiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D020794:Receptor Protein-Tyrosine Kinases; D004298:Dopamine