Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine*
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Animals
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Blotting, Western
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Cell Survival / drug effects
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Cells, Cultured
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DNA, Complementary / biosynthesis
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DNA, Complementary / genetics
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Dopamine / physiology*
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Dopamine Agents*
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Enzyme Activation / drug effects
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Gene Expression Regulation / physiology
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Immunohistochemistry
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Indans / pharmacology*
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Male
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Mice
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Mice, Inbred C57BL
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Monoamine Oxidase Inhibitors / pharmacology*
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Nerve Degeneration / pathology
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Nerve Degeneration / prevention & control
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology
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Neuroprotective Agents / pharmacology*
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Parkinson Disease, Secondary / chemically induced
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Parkinson Disease, Secondary / drug therapy*
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Parkinson Disease, Secondary / pathology*
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Receptor Protein-Tyrosine Kinases / drug effects
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Receptor Protein-Tyrosine Kinases / physiology*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Substantia Nigra / drug effects
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Substantia Nigra / pathology
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Substantia Nigra / physiology*
Substances
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DNA, Complementary
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Dopamine Agents
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Indans
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Monoamine Oxidase Inhibitors
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Nerve Tissue Proteins
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Neuroprotective Agents
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rasagiline
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Receptor Protein-Tyrosine Kinases
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Dopamine