title: Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post-MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway.
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)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.
authors: 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
authors: Silvia A
authors: SA
authors: Mandel
authors: Yotam
authors: Y
authors: Sagi
authors: Tamar
authors: T
authors: Amit
mesh_terms: 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
chemical_list: D007189:Indans; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C031967:rasagiline; D020813:Receptor, trkB
references: J Neurochem. 2005 Dec;95(5):1363-72
references: 16277616
references: Neurochem Int. 2004 May;44(6):393-400
references: 14687604
references: Mol Pharmacol. 2006 Apr;69(4):1492-8
references: 16434614
references: Exp Neurol. 2004 Jun;187(2):455-9
references: 15144871
references: Eur J Pharmacol. 1985 Oct 22;116(3):313-7
references: 3935467
references: J Neural Transm (Vienna). 2006 Jan;113(1):21-32
references: 15843867
references: CNS Drug Rev. 2005 Summer;11(2):183-94
references: 16007239
references: Ann N Y Acad Sci. 2001 Jun;939:450-8
references: 11462801
references: Biochem Biophys Res Commun. 1997 Sep 18;238(2):569-73
references: 9299553
references: Clin Neuropharmacol. 2000 Nov-Dec;23(6):324-30
references: 11575866
references: J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):314-9
references: 9527140
references: FASEB J. 2005 Nov;19(13):1899-901
references: 16148027
references: Mol Cell Biol. 2002 Feb;22(3):916-26
references: 11784866
references: Adv Neurol. 1999;80:495-9
references: 10410762
references: FASEB J. 2004 Sep;18(12):1471-3
references: 15247150
references: Trends Pharmacol Sci. 2004 Sep;25(9):471-80
references: 15559249
references: Neuroreport. 1998 Jul 13;9(10):2365-9
references: 9694229
references: J Neurochem. 2006 Nov;99(4):1033-48
references: 17054441
references: Eur J Pharmacol. 1999 Feb 5;366(2-3):127-35
references: 10082192
references: J Pharmacol Exp Ther. 2002 May;301(2):753-64
references: 11961082
references: Neurobiol Dis. 2007 Jan;25(1):35-44
references: 17055733
references: Eur J Pharmacol. 1996 Nov 7;315(1):19-30
references: 8960860
references: Ann N Y Acad Sci. 2005 Aug;1053:348-55
references: 16179541
references: J Cell Biol. 1999 Sep 6;146(5):955-66
references: 10477751
references: Nature. 1984 Oct 4-10;311(5985):467-9
references: 6332989
references: Arch Neurol. 2004 Apr;61(4):561-6
references: 15096406
references: J Neural Transm (Vienna). 1999;106(7-8):593-606
references: 10907720
references: Neurosci Lett. 1999 Jul 23;270(1):45-8
references: 10454142
references: Mov Disord. 2006 May;21(5):616-23
references: 16450340
references: Br J Pharmacol. 2001 Jan;132(2):500-6
references: 11159700
references: Lancet. 2005 Mar 12-18;365(9463):947-54
references: 15766996
references: J Neurochem. 2001 Sep;78(5):1073-82
references: 11553681
references: J Neurochem. 2002 Aug;82(4):913-23
references: 12358797
references: J Neural Transm Suppl. 2000;(60):171-86
references: 11205138
references: Nature. 1995 Jan 26;373(6512):335-9
references: 7830766
references: Bioessays. 2004 Jan;26(1):80-90
references: 14696044
references: Brain Res. 1998 Apr 6;789(1):9-22
references: 9602028
references: Nat Med. 2005 Jul;11(7):703-4
references: 16015352
references: Neurology. 2003 Apr 22;60(8):1234-40
references: 12707423
references: CNS Drugs. 2005;19(9):723-43
references: 16142989
references: J Cell Sci. 2004 Nov 15;117(Pt 24):5731-7
references: 15522889
references: Gene Ther. 2002 Mar;9(6):381-9
references: 11960314
references: J Neurosci Res. 2005 Jan 1-15;79(1-2):172-9
references: 15573406
references: Nature. 1996 Mar 21;380(6571):252-5
references: 8637574
references: FASEB J. 2003 Dec;17(15):2325-7
references: 14525944