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Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety

  • Conference paper
Parkinson’s Disease and Related Disorders

Part of the book series: Journal of Neural Transmission. Supplementa ((NEURALTRANS,volume 70))

Summary

Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson’s drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCα, PKCɛ and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neurotrophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of procaspase- 3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCγ mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propargylamine both regulated amyloid precursor protein (APP) processing towards the nonamyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl–4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.

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Authors and Affiliations

  1. Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, P.O.B. 9697, 31096, Haifa, Israel

    Dr. O. Weinreb, T. Amit, O. Bar-Am, Y. Sagi, S. Mandel & M. B. H. Youdim

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  1. Dr. O. Weinreb
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  2. T. Amit
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  3. O. Bar-Am
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  4. Y. Sagi
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  5. S. Mandel
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  6. M. B. H. Youdim
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Editor information

Editors and Affiliations

  1. Klinik und Poliklinik für Psychiatrie und Psychotherapie, Würzburg, Germany

    P. Riederer  & M. Gerlach  & 

  2. Universitätsklinikum der TU Dresden, Dresden, Germany

    H. Reichmann

  3. Israel Institute of Technology, Haifa, Israel

    M. B. H. Youdim

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© 2006 Springer-Verlag

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Weinreb, O., Amit, T., Bar-Am, O., Sagi, Y., Mandel, S., Youdim, M.B.H. (2006). Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. In: Riederer, P., Reichmann, H., Youdim, M.B.H., Gerlach, M. (eds) Parkinson’s Disease and Related Disorders. Journal of Neural Transmission. Supplementa, vol 70. Springer, Vienna . https://doi.org/10.1007/978-3-211-45295-0_69

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  • DOI: https://doi.org/10.1007/978-3-211-45295-0_69

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