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Rasagiline Promotes Regeneration of Substantia Nigra Dopaminergic Neurons in Post-MPTP-induced Parkinsonism via Activation of Tyrosine Kinase Receptor Signaling Pathway

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Abstract

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)α, PKCε, 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.

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Notes

  1. The abstract entitled “Early rasagiline therapy shows long-term benefit for Parkinson’s disease” was presented by the Parkinson Study group in the 9th International Congress of Parkinson’s disease and Movement Disorder, New Orleans, 2005.

Abbreviations

BDNF:

Brain-derived neurotrophic factor

DA:

Dopamine

Fasl:

Fas ligand

GDNF:

Glial cell line-derived neurotrophic factor

GSK:

Glycogen synthase kinase

mGluR:

Metabotropic glutamate receptor

MAO:

Monoamine oxidase

MPP+:

1 Methyl-4 phenylpyridinium

MPTP:

N-methyl- 4 phenyl 1,2,3,6 tetrahydropyridine

NGF:

Nerve growth factor

PI3K:

Phosphatidylinositol 3 Kinase

PD:

Parkinson’s disease

PKC:

Protein kinase C

SNpc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

Trk:

Tyrosine receptor kinase

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Acknowledgments

The support of Teva Pharmaceutical Co. (Netanya, Israel) and Technion-Research and Development (Haifa, Israel), Michael J. Fox Foundation (New York, USA) and National Parkinson Foundation (Miami, USA) are gratefully acknowledged.

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Authors and Affiliations

  1. Eve Topf Center of Excellence for Neurodegenerative Diseases Research, Department of Pharmacology, Technion-Rappaport Faculty of Medicine, P.O. Box 9697, Haifa, 31096, Israel

    Silvia A. Mandel, Yotam Sagi & Tamar Amit

Authors
  1. Silvia A. Mandel
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  2. Yotam Sagi
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  3. Tamar Amit
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Correspondence to Silvia A. Mandel.

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Special issue dedicated to Dr. Moussa Youdim.

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Mandel, S.A., Sagi, Y. & Amit, T. Rasagiline Promotes Regeneration of Substantia Nigra Dopaminergic Neurons in Post-MPTP-induced Parkinsonism via Activation of Tyrosine Kinase Receptor Signaling Pathway. Neurochem Res 32, 1694–1699 (2007). https://doi.org/10.1007/s11064-007-9351-8

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