Abstract
In Parkinson’s and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (—)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-κB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.
Keywords
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Abe T, Isobe C Murata T, Sato C, Tohgi H (2003) Alteration of 8-hydroxyguanosine concentrations in the cerebrospinal fluid and serum from patients with Parkinson’s disease. Neurosci Lett 336: 105–108
Akao Y, Maruyama W, Shimizu S, Yi H, Nakagawa Y, Shamoto-Nagai M, Youdim MBH, Tsujimoto Y, Naoi M (2002a) Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1 (R)-aminoindan. J Neurochem 82: 913–923
Akao Y, Maruyama W, Yi H, Shamoto-Nagai M, Youdim MBH, Naoi M (2002b) An anti-Parkinson’s disease drug, N-propargyl-l(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic Bcl-2 in dopaminergic SH-SY5Y cells. Neurosci Lett 326: 105–108
Bauer M, Meyer M, Grimm L, Meitinger T, Zimmer J, Gasser T, Ueffing M, Widmer HR (2000) Nonviral glial cell-derived neurotrophic factor gene transfer enhances survival of cultured dopaminergic neurons and improves their function after transplantation in a rat model of Parkinson’s disease. Hum Gene Ther 11: 1529–1541
Birkmayer W, Riederer P, Ambrozi L, Youdim MBH (1977) Implication of combined treatment with “Madopar” and L-deprenyl in Parkinson’s disease. A long-term study. Lancet 309: 439–443
Brabeck C, Pfeiffer R, Leake A, Beneke S, Meyer R, Biirkle A (2003) L-Selegiline potentiates the cellular poly(ADP-ribosyl)ation response to ionizing radiation. J Pharm Exp Ther 306: 973–979
Carrillo MC, Minami C, Kitani K, Maruyama W, Ohashi K, Yamamoto T, Naoi M, Kanai K, Youdim MBH (2000) Enhancing effect of rasagiline on Superoxide dismutase and catalase activities in the dopaminergic system in rat. Life Sci 67: 577–585
Dawson TM, Dawson VL (2002) Neuroprotective and neurorestorative strategies for Parkinson’s disease. Nature Neurosci Suppl 5: 1058–1061
Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou J-C (1999) Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 144: 891–901
Eckert A, Steiner B, Marques C, Leutz S, Roming H, Haass C, Muller WE (2001) Elevated vulnerability to oxidative tress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation. J Neurosci Res 64: 183–192
Eriksen JL, Wszolek Z, Petrucelli L (2005) Molecular pathogenesis of Parkinson disease. Arch Neurol 62: 353–357
Everett H, Barry M, Sun X, Lee SF, Franz C, Berthiaume LG, McFadden G, Bleackley RC (2002) The myxoma provirus protein, Ml 1L, prevents apoptosis by direct interaction with the mitochondrial permeability transition pore. J Exp Med 196: 1127–1139
Gill SS, Patel N, Hotton CR, O’Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P (2003) Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 9: 589–595
Hara RH, Thomas B, Cascio MB, Bae B-I, Hester LG, Dawson VL, Dawson TM, Sawa A, Synder SH (2006) Neuroprotection by pharmacological blockade of the GAPDH death cascade. Proc Natl Acad Sci USA 103: 3887–3889
Hirai C, Takahata K, Shimizu S, Yoneda F, Hayashi K, Katuki H, Akaike A (2005) Effects of R-(—)-BPAP on the expressions of neurotrophins and their receptors in mesencephalic slices. Biol Pharm Bull 28: 1524–1526
Jacotot E, Ferri KF, Hamel CE1, Brenner C, Druillennec S, Hoebeke J, Rustin P, Metivier D, Lenoir C, Geuskens M, Vierira HLA, Loeffler M, Belzaq A-S, Briand J-P, Zamzami N, Edelman L, Xie ZH, Reed JC, Roques N, Kroemer G (2001) Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV viral protein R and Bcl-2. J Exp Med 193: 509–519
Kitani K, Minami C, Maruyama W, Kanai S, Ivy GO, Carrillo MC (2000) Common properties for propargylamines of enhancing Superoxide dismutase and catalase activities in the dopaminergic system in the rat: implications for the life prolonging effect of (—)deprenyl. J Neural Transm Suppl 60: 139–156
Kroemer G (1997) The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 3: 614–620
Lucken-Ardjomande S, Martinou J-C (2005) Newcomers in the process of mitochondrial permeabilization. J Cell Sci 118: 473–483
Mandel S, Grünblatt E, Riederer P, Gerlach M, Levites Y, Youdim MBH (2003) Neuroprotective strategies in Parkinson’s disease. CNS Drugs 17: 729–762
Mandel S, Weinreb O, Amit T, Youdim MBH (2005) Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. Brain Res Rev 48: 379–387
Maruyama W, Bouton AA, Davis BS, Dostert P, Naoi M (2001a) Enantio-specific induction of apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells: suppression of apoptosis by N-(2-heptyl)-N-methylpropargylamine. J Neural Transm 108: 11–24
Maruyama W, Youdim MBH, Naoi M (2001b) Antiapoptotic properties of rasagiline, N-propargylamine-l(R)-aminoindan, and its optical (S)- isomer, TV1022. Ann NY Acad Sci 939: 320–329
Maruyama W, Akao Y, Youdim MBH, Davis BA, Naoi M (2002a) Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem 78: 727–735
Maruyama W, Akao Y, Carrillo MC, Kitani K, Youdim MBH, Naoi M (2002b) Neuroprotection by propargylamines in Parkinson’s disease. Suppression of apoptosis and induction of prosurvival genes. Neurotoxicol Tertol 24: 675–682
Maruyama W, Takahashi T, Youdim MBH, Naoi M (2002c) The antiparkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. J Neural Transm 109: 467–481
Maruyama W, Winstock M, Youdim MBH, Nagai M, Naoi M (2003) Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. Neurosci Lett 341: 233–236
Maruyama W, Nitta A, Shamoto-Nagai M, Hirata H, Akao Y, Furukawa S, Nabeshima T, Naoi M (2004a) N-Propargyl-l(R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-κB transcription factor. Neurochem Int 44: 393–400
Maruyama W, Yi H, Takahashi T, Shimizu S, Ohde H, Yoneda F, Iwasa K, Naoi M (2004b) Neuroprotective function of R-(—)-(benzofuran-2-yl)-2-propylamino-pentane, [R-(—)-BPAP], against apoptosis induced by N-methyl(R)salsolinol, an endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoma SH-SY5Y cells. Life Sci 75: 107–117
McStay GP, Clarke SJ, Halestrap AP (2002) Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J 367: 541–548
Michell AW, Lewis SJG, Barker RA (2004) Biomarkers and Parkinson’s disease. Brain 127: 1693–1705
Naoi M, Maruyama W, Akao Y, Yi H (2002a) Dopamine-derived endogenous N-methyl-(R)-salsolinol. Its role in Parkinson’s disease. Neurotoxicol Teratol 24: 579–591
Naoi M, Maruyama W, Akao Y, Yi H (2002b) Mitochondrial determine the survival and death in apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, and neuroprotection by propargylamines. J Neural Transm 109: 607–621
Naoi M, Maruyama W, Akao Y, Yi H, Yamaoka Y (2006) Involvement of type A monoamine oxidase in neurodegeneration: regulation of mitochondrial signaling leading to cell death or neuroprotection. J Neural Transm Suppl 71: 67–77
Narita M, Shimizu S, Ito T, Chittenden T, Litz RJ, Matsuda H, Tsujimoto Y (1998) Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci USA 95: 14681–14686
Nitta A, Murai R, Maruyama K, Furukawa S (2002) FK506 protects dopaminergic degeneration through induction of GDNF in rodent brains. In: Mizuno Y, Fisher A, Hanin I (eds) Mapping the progress of Alzheimer’s and Parkinson’s disease. Kluwer Academic/Plenum Publishers, New York, pp 446–467
Pälhagen S, Heinonen E, Hägglund J, Kaugesaar T, Mäki-Ikola O, Palm R, the Swedish Parkinson Study Group (2006) Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 66: 1200–1206
Parkinson Study Group (2002) A controlled trial of rasagiline in early Parkinson disease. Arch Neurol 59: 1937–1943
Parkinson Study Group (2004) A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 61: 561–566
Riederer P, Lachenmayer L, Laux G (2004) Clinical applications of MAO-inhibitors. Curr Med Chem 11: 2033–2043
Riederer PF (2004) Views on neurodegeneration as a basis for neuroprotective strategies. Med Sci Monit 10: RA287–290
Sagi Y, Mandel S, Amit T, Youdim MBH (2007) Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism. Neurobiol Dis 25: 35–44
Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54: 823–827
Schapira AHV, Olanow CW (2004) Neuroprotection in Parkinson disease. Mysteries, myths and misconceptions. JAMA 291: 358–364
Shimizu S, Eguchi Y, Kamiike W, Funahashi Y, Mignon A, Lacronique V, Matsuda H, Tsujimoto Y (1998) Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc Natl Acad Sci USA 95: 1455–1459
Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399: 483–487
Simpkins N, Jankovic J (2003) Neuroprotection in Parkinson disease. Arch Intern Med 163: 1650–1654
Suchowersky O, Gronseth G, Permutter J, Reich S, Zesiewics T, Weiner Wl (2006) Practice parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review). Neurology 66: 976–982
Tatton WG, Chalmers-Redman RM, Ju WJ, Mammen M, Carlile GW, Pong AW, Tatton NA (2002) Propargylamines induce antiapoptotic new protein synthesis in serum-and nerve growth factor (NGF)-with-drawn, NGF-differentiated PC-12 cells. J Pharmacol Exp Ther 301: 753–764
Tsujimoto Y, Shimizu S (2000) Bcl-2 family: Life-or-death switch. FEBS Lett 466: 6–10
Vila M, Przedborski S (2004) Genetic clues to the pathogenesis of Parkinson’s disease. Nat Med 10: S58–S62
Weinreb O, Bar-Am O, Amit T, Chillag-Talmor O, Youdim MBH (2004) Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family protein. FASEB J 18: 1471–1473
Yi H, Akao Y, Maruyama W, Chen K, Shih J, Naoi M (2006a) Type A monoamine oxidase is the target of an endogenous dopaminergic neurotoxin, N-methyl-(R)salsolinol, leading to apoptosis in SH-SY5Y cells. J Neurochem 96: 541–549
Yi H, Maruyama W, Akao Y, Takahashi T, Iwasa K, Youdim MBH, Naoi M (2006b) N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2. J Neural Transm 113: 21–32
Yogev-Falach M, Bar-Am O, Amit T, Weinreb O, Youdim MBH (2006) A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing. FASEB 20: 2177–2179
Youdim MBH, Gross A, Finberg JPM (2001) Rasagiline [N-propargy-lR(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol 132: 500–506
Youdim MBH, Amit T, Falach-Yogev M, Am OB, Maruyama W, Naoi M (2003a) The Essentiality of bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. Biochem Pharmacol 66: 1635–1641
Youdim MB, Amit T, Bar-Am O, Weinstock M, Yogev-Falach M (2003b) Amyloid processing and signal transduction properties of antiparkinson-antialzheimer neuroprotective drugs rasagiline and TV3326. Ann NYAcad Sci 993: 378–386
Youdim MBH, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nature Rev Neurosci 7: 295–309
Zhou G, Miura Y, Shoji H, Yamada S, Matsushi T (2001) Platelet monoamine oxidase B and plasma beta-phenethylamine in Parkinson’s disease. J Neurol Neurosurg Psychaitry 70: 229–231
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag
About this paper
Cite this paper
Naoi, M., Maruyama, W., Yi, H., Akao, Y., Yamaoka, Y., Shamoto-Nagai, M. (2007). Neuroprotection by propargylamines in Parkinson’s disease: intracellular mechanism underlying the anti-apoptotic function and search for clinical markers. In: Gerlach, M., Deckert, J., Double, K., Koutsilieri, E. (eds) Neuropsychiatric Disorders An Integrative Approach. Journal of Neural Transmission. Supplementa, vol 72. Springer, Vienna. https://doi.org/10.1007/978-3-211-73574-9_15
Download citation
DOI: https://doi.org/10.1007/978-3-211-73574-9_15
Publisher Name: Springer, Vienna
Print ISBN: 978-3-211-73573-2
Online ISBN: 978-3-211-73574-9
eBook Packages: MedicineMedicine (R0)