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. 2006 Jun 7;11(2):183–194. doi: 10.1111/j.1527-3458.2005.tb00269.x

Neuroprotection by Rasagiline: A New Therapeutic Approach to Parkinson's Disease?

Fabio Blandini 1,✉
PMCID: PMC6741719  PMID: 16007239

ABSTRACT

Neuronal death in Parkinson's disease (PD) may originate from the reciprocal interactions of a restricted number of conditions, such as mitochondrial defects, oxidative stress and protein mishandling, which would favor a state of apoptotic cell death in the nigrostriatal pathway. The search for pharmacological treatments able to counteract the nigrostriatal degeneration, possibly by interfering with these phenomena, has recently raised considerable interest in rasagiline [R(+)‐N‐propargyl‐1‐aminoindan], a potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO‐B). Rasagiline, like selegiline, is a propargylamine, but is ∼10 times more potent. Unlike selegiline, rasagiline is not metabolized to amphetamine and/or methamphetamine and is devoid of sympathomimetic activity. Numerous experimental studies, conducted both in vitro and in vivo, have shown that rasagiline possesses significant protective properties on neuronal populations. The pro‐survival effects of the drug appear to be linked to its propargyl moiety, rather than to the inhibitory effect on MAO‐B. Rasagiline's major metabolite, aminoindan — which possesses intrinsic neuroprotective activity — may also contribute to the beneficial effects of the parent compound.

Rasagiline has been recently evaluated in early PD patients, with results that are consistent with slowing the progression of the disease. Therefore, the neuroprotective activity shown by the drug under experimental conditions may be reflected in the clinic, thus providing new perspectives for the treatment of PD.

Keywords: Apoptosis, L‐DOPA, Monoamine oxidase, Neurodegeneration, Rasagiline, Substantia nigra

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REFERENCES

  • 1. Abu‐Raya S, Blaugrund E, Trembovler V, Shilderman‐Bloch E, Shohami E, Lazarovici P. Rasagiline, a monoamine oxidase‐B inhibitor, protects NGF‐differentiated PC12 cells against oxygen‐glucose deprivation. J Neurosci Res 1999;58:456–463. [PubMed] [Google Scholar]
  • 2. Abu‐Raya S, Tabakman R, Blaugrund E, Trembovler V, Lazarovici P. Neuroprotective and neurotoxic effects of monoamine oxidase‐B inhibitors and derived metabolites under ischemia in PC12 cells. Eur J Pharmacol 2002;434:109–116. [DOI] [PubMed] [Google Scholar]
  • 3. Akao Y, Maruyama W, Shimizu S, Yi H, et al. 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 2002;82:913–923. [DOI] [PubMed] [Google Scholar]
  • 4. Am OB, Amit T, Youdim MB. Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti‐Parkinson drugs rasagiline and selegiline. Neurosci Lett 2004;355:169–172. [DOI] [PubMed] [Google Scholar]
  • 5. Anglade P, Vyas S, Javoy‐Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol 1997;12:25–31. [PubMed] [Google Scholar]
  • 6. Banasiak KJ, Xia Y, Haddad GG. Mechanisms underlying hypoxia‐induced neuronal apoptosis. Prog Neurobiol 2000;62:215–249. [DOI] [PubMed] [Google Scholar]
  • 7. Bar‐Am O, Yogev‐Falach M, Amit T, Sagi Y, Youdim MB. Regulation of protein kinase C by the anti‐Parkinson drug, MAO‐B inhibitor, rasagiline and its derivatives, in vivo. J Neurochem 2004;89:1119–1125. [DOI] [PubMed] [Google Scholar]
  • 8. Beal MF. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses Ann Neurol 1992;31:119–130. [DOI] [PubMed] [Google Scholar]
  • 9. Belzacq AS, Brenner C. The adenine nucleotide translocator: A new potential chemotherapeutic target. Curr Drug Targets 2003;4:517–524. [DOI] [PubMed] [Google Scholar]
  • 10. Belzacq AS, Vieira HL, Verrier F, et al. Bcl‐2 and Bax modulate adenine nucleotide translocase activity. Cancer Res 2003;63:541–546. [PubMed] [Google Scholar]
  • 11. Betarbet R, Sherer TB, MacKenzie G, Garcia‐Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000;3:1301–1306. [DOI] [PubMed] [Google Scholar]
  • 12. Blandini F, Armentero MT, Fancellu R, Blaugrund E, Nappi G. Neuroprotective effect of rasagiline in a rodent model of Parkinson's disease. Exp Neurol 2004;187:455–459. [DOI] [PubMed] [Google Scholar]
  • 13. Blandini F, Cosentino M, Mangiagalli A, et al. Modifications of apoptosis‐related protein levels in lymphocytes of patients with Parkinson's disease. The effect of dopaminergic treatment. J Neural Transm 2004;111:1017–1030. [DOI] [PubMed] [Google Scholar]
  • 14. Blandini F, Nappi G, Tassorelli C, Martignoni E. Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog Neurobiol 2000;62:63–88. [DOI] [PubMed] [Google Scholar]
  • 15. Blandini F, Porter RH, Greenamyre JT. Glutamate and Parkinson's disease. Mol Neurobiol 1996;12:73–94. [DOI] [PubMed] [Google Scholar]
  • 16. Blum D, Torch S, Lambeng N, et al. Molecular pathways involved in the neurotoxicity of 6‐OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson's disease. Prog Neurobiol 2001;65:135–172. [DOI] [PubMed] [Google Scholar]
  • 17. Brenner C, Marzo I, Kroemer G. A revolution in apoptosis: From a nucleocentric to a mitochondriocentric perspective. Exp Gerontol 1998;33:543–553. [DOI] [PubMed] [Google Scholar]
  • 18. Burke RE and Kholodilov NG. Programmed cell death: Does it play a role in Parkinson's disease Ann Neurol 1998;44(Suppl 1):S126–S133. [DOI] [PubMed] [Google Scholar]
  • 19. Cotzias GC, van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967;276:374–379. [DOI] [PubMed] [Google Scholar]
  • 20. Dodel RC, Du Y, Bales KR, Ling Z, Carvey PM, Paul SM. Caspase‐3‐like proteases and 6‐hydroxydopamine induced neuronal cell death. Brain Res Mol Brain Res 1999;64:141–148. [DOI] [PubMed] [Google Scholar]
  • 21. Durkin JP, Tremblay R, Chakravarthy B, et al. Evidence that the early loss of membrane protein kinase C is a necessary step in the excitatory amino acid‐induced death of primary cortical neurons. J Neurochem 1997;68:1400–1412. [DOI] [PubMed] [Google Scholar]
  • 22. Eliash S, Shteter N, Eilam R. Neuroprotective effect of rasagiline, a monoamine oxidase‐B inhibitor, on spontaneous cell degeneration in a rat model. J Neural Transm 2005;In press. [DOI] [PubMed] [Google Scholar]
  • 23. Eliash S, Speiser Z, Cohen S. Rasagiline and its (S) enantiomer increase survival and prevent stroke in salt‐loaded stroke‐prone spontaneously hypertensive rats. J Neural Transm 2001;108:909–923. [DOI] [PubMed] [Google Scholar]
  • 24. Finberg JP, Youdim MB. Pharmacological properties of the anti‐Parkinson drug rasagiline: Modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours. Neuropharmacology 2002;43:1110–1118. [DOI] [PubMed] [Google Scholar]
  • 25. Fornai F, Lenzi P, Gesi M, et al. Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. J Neurosci 2003;23:8955–8966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Forno LS. Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol 1996;55:259–272. [DOI] [PubMed] [Google Scholar]
  • 27. Freedman N, Mishani E, Krausz Y, Blaugrund E, Ehrlich D, Chisin R. In vivo measurement of brain monoamine oxidase B (MAO‐B) activity after rasagiline treatment, using L‐[11C]deprenyl and positron emission tomography (PET). Mov Disord 2005;20(Suppl 10):S89. [Google Scholar]
  • 28. Giladi N, Rascol O, Brooks DJ, et al. Rasagiline treatment can improve freezing of gait in advanced Parkinson's disease: A prospective randomized, double blind, placebo and entacapone controlled study. Neurology 2004;62(Suppl 5):S329–330. [Google Scholar]
  • 29. Greenamyre JT. Glutamatergic influences on the basal ganglia. Clin Neuropharmacol 2001;24:65–70. [DOI] [PubMed] [Google Scholar]
  • 30. Halestrap AP. The mitochondrial permeability transition: Its molecular mechanism and role in reperfusion injury. Biochem Soc Symp 1999;66:181–203. [DOI] [PubMed] [Google Scholar]
  • 31. Hartley A, Stone JM, Heron C, Cooper JM, Schapira AH. Complex I inhibitors induce dose‐dependent apoptosis in PC12 cells: Relevance to Parkinson's disease. J Neurochem 1994;63:1987–1990. [DOI] [PubMed] [Google Scholar]
  • 32. Hartmann A, Hunot S, Michel PP, et al. Caspase‐3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease. Proc Natl Acad Sci USA 2000;97:2875–2880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Hartmann A, Michel PP, Troadec JD, et al. Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease J Neurochem 2001;76:1785–1793. [DOI] [PubMed] [Google Scholar]
  • 34. Hartmann A, Troadec JD, Hunot S, et al. Caspase‐8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis. J Neurosci 2001;21:2247–2255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Heikkila RE, Duvoisin RC, Finberg JP, Youdim MB. Prevention of MPTP‐induced neurotoxicity by AGN‐1133 and AGN‐1135, selective inhibitors of monoamine oxidase‐B. Eur J Pharmacol 1985;116:313–317. [DOI] [PubMed] [Google Scholar]
  • 36. Hirsch EC, Hunot S, Faucheux B, et al. Dopaminergic neurons degenerate by apoptosis in Parkinson's disease. Mov Disord 1999;14:383–385. [DOI] [PubMed] [Google Scholar]
  • 37. Hirsch EC, Hunot S, Hartmann A. Mechanism of cell death in experimental models of Parkinson's disease. Funct Neurol 2000;15:229–237. [PubMed] [Google Scholar]
  • 38. Huang W, Chen Y, Shohami E, Weinstock M. Neuroprotective effect of rasagiline, a selective monoamine oxidase‐B inhibitor, against closed head injury in the mouse. Eur J Pharmacol 1999;366:127–135. [DOI] [PubMed] [Google Scholar]
  • 39. Jellinger KA. Cell death mechanism in Parkinson's disease. J Neural Transm 2000;107:1–29. [DOI] [PubMed] [Google Scholar]
  • 40. Jenner P. Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov Disord 1998;13(Suppl 1):24–34. [PubMed] [Google Scholar]
  • 41. Jenner P. Oxidative stress in Parkinson's disease. Ann Neurol 2003;53(Suppl 3):S26–S36. [DOI] [PubMed] [Google Scholar]
  • 42. Kalivendi SV, Cunningham S, Kotamraju S, Joseph J, Hillard CJ, Kalyanaraman B. Alpha‐synuclein up‐regulation and aggregation during MPP+‐induced apoptosis in neuroblastoma cells: Intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem 2004;279:15240–15247. [DOI] [PubMed] [Google Scholar]
  • 43. Kupsch A, Sautter J, Gotz ME, et al. Monoamine oxidase‐inhibition and MPTP‐induced neurotoxicity in the non‐human primate: Comparison of rasagiline (TVP 1012) with selegiline. J Neural Transm 2001;108:985–1009. [DOI] [PubMed] [Google Scholar]
  • 44. Lamensdorf I, Youdim MB, Finberg JP. Effect of long‐term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo J Neurochem 1996;67:1532–1539. [DOI] [PubMed] [Google Scholar]
  • 45. Lang‐Rollin I, Vekrellis K, Wang Q, Rideout HJ, Stefanis L. Application of proteasomal inhibitors to mouse sympathetic neurons activates the intrinsic apoptotic pathway. J Neurochem 2004;90:1511–1520. [DOI] [PubMed] [Google Scholar]
  • 46. Lemasters JJ, Nieminen AL, Qian T, et al. The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1998;1366:177–196. [DOI] [PubMed] [Google Scholar]
  • 47. Le Witt, PA. Clinical trials of neuroprotection for Parkinson's disease. Neurology 2004;63:S23–S31. [DOI] [PubMed] [Google Scholar]
  • 48. Maher P. How protein kinase C activation protects nerve cells from oxidative stress‐induced cell death. J Neurosci 2001;21:2929–2938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Markey SP and Schmuff NR. The pharmacology of the parkinsonian syndrome producing neurotoxin MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) and structurally related compounds. Med Res Rev 1986;6:389–429. [DOI] [PubMed] [Google Scholar]
  • 50. Marshall KA, Daniel SE, Cairns N, Jenner P, Halliwell B. Upregulation of the anti‐apoptotic protein Bcl‐2 may be an early event in neurodegeneration: Studies on Parkinson's and incidental Lewy body disease. Biochem Biophys Res Commun 1997;240:84–87. [DOI] [PubMed] [Google Scholar]
  • 51. Maruyama W, Akao Y, Carrillo MC, Kitani K, Youdium MB, Naoi M. Neuroprotection by propargylamines in Parkinson's disease: Suppression of apoptosis and induction of prosurvival genes. Neurotoxicol Teratol 2002;24:675–682. [DOI] [PubMed] [Google Scholar]
  • 52. Maruyama W, Akao Y, Youdim MB, Naoi M. Neurotoxins induce apoptosis in dopamine neurons: protection by N‐propargylamine‐1(R)‐ and (S)‐aminoindan, rasagiline and TV1022. J Neural Transm 2000;Suppl:171–186. [DOI] [PubMed] [Google Scholar]
  • 53. Maruyama W, Nitta A, Shamoto‐Nagai M, et al. N‐Propargyl‐1(R)‐aminoindan, rasagiline, increases glial cell line‐derived neurotrophic factor (GDNF) in neuroblastoma SH‐SY5Y cells through activation of NF‐B transcription factor. Neurochem Int 2004;44:393–400. [DOI] [PubMed] [Google Scholar]
  • 54. Maruyama W, Youdim MB, Naoi M. Antiapoptotic properties of rasagiline, N‐propargylamine‐1(R)‐aminoindan, and its optical (S)‐isomer, TV1022. Ann NY Acad Sci 2001;939:320–329. [DOI] [PubMed] [Google Scholar]
  • 55. McNaught KS, Perl DP, Brownell AL, Olanow CW. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann Neurol 2004;56:149–162. [DOI] [PubMed] [Google Scholar]
  • 56. Migliore L, Petrozzi L, Lucetti C, et al. Oxidative damage and cytogenetic analysis in leukocytes of Parkinson's disease patients. Neurology 2002;58:1809–1815. [DOI] [PubMed] [Google Scholar]
  • 57. Mitchell IJ, Lawson S, Moser B, et al. Glutamate‐induced apoptosis results in a loss of striatal neurons in the parkinsonian rat. Neuroscience 1994;63:1–5. [DOI] [PubMed] [Google Scholar]
  • 58. Mitchell IJ, Lawson S, Moser B, et al. Glutamate‐induced apoptosis results in a loss of striatal neurons in the parkinsonian rat. Neuroscience 1994;63:1–5. [DOI] [PubMed] [Google Scholar]
  • 59. Mochizuki H, Goto K, Mori H, Mizuno Y. Histochemical detection of apoptosis in Parkinson's disease. J Neurol Sci 1996;137:120–123. [DOI] [PubMed] [Google Scholar]
  • 60. Mogi M, Togari A, Kondo T, et al. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J Neural Transm 2000;107:335–341. [DOI] [PubMed] [Google Scholar]
  • 61. Mytilineou C, McNaught KS, Shashidharan P, et al. Inhibition of proteasome activity sensitizes dopamine neurons to protein alterations and oxidative stress. J Neural Transm 2004;111:1237–1251. [DOI] [PubMed] [Google Scholar]
  • 62. Nagatsu T, Mogi M, Ichinose H, Togari A. Changes in cytokines and neurotrophins in Parkinson's disease. J Neural Transm 2000;Suppl:277–290. [DOI] [PubMed] [Google Scholar]
  • 63. Naoi M, Maruyama W, Akao Y, Yi H. Mitochondria determine the survival and death in apoptosis by an endogenous neurotoxin, N‐methyl(R)salsolinol, and neuroprotection by propargylamines. J Neural Transm 2002;109:607–621. [DOI] [PubMed] [Google Scholar]
  • 64. Obeso JA, Olanow CW, Nutt JG. Levodopa motor complications in Parkinson's disease. Trends Neurosci 2000;23:S2–S7. [DOI] [PubMed] [Google Scholar]
  • 65. Oh C, Murray B, Bhattacharya N, Holland D, Tatton WG. (‐)‐Deprenyl alters the survival of adult murine facial motoneurons after axotomy: Increases in vulnerable C57BL strain but decreases in motor neuron degeneration mutants. J Neurosci Res 1994;38:64–74. [DOI] [PubMed] [Google Scholar]
  • 66. Parkinson Study Group. DATATOP: A multicenter controlled clinical trial in early Parkinson's disease. Parkinson Study Group. Arch Neurol 1989;46:1052–1060. [DOI] [PubMed] [Google Scholar]
  • 67. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa‐treated Parkinson's disease patients. Ann Neurol 1997;42:747–755. [DOI] [PubMed] [Google Scholar]
  • 68. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: The TEMPO Study. Arch Neurol 2002;59:1937–1943. [DOI] [PubMed] [Google Scholar]
  • 69. Parkinson Study Group. A controlled, randomized, delayed‐start study of rasagiline in early Parkinson disease. Arch Neurol 2004;61:561–566. [DOI] [PubMed] [Google Scholar]
  • 70. Parkinson Study Group. A randomized placebo‐controlled trial of rasagiline in levodopa‐treated patients with Parkinson disease and motor fluctuations: The PRESTO study. Arch Neurol 2005;62:241–248. [DOI] [PubMed] [Google Scholar]
  • 71. Petrucelli L and Dawson TM. Mechanism of neurodegenerative disease: Role of the ubiquitin proteasome system. Ann Med 2004;36:315–320. [DOI] [PubMed] [Google Scholar]
  • 72. Rabey JM, Sagi I, Huberman M, et al. Rasagiline mesylate, a new MAO‐B inhibitor for the treatment of Parkinson's disease: A double‐blind study as adjunctive therapy to levodopa. Clin Neuropharmacol 2000;23:324–330. [DOI] [PubMed] [Google Scholar]
  • 73. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): Arandomised, double‐blind, parallel‐group trial. Lancet 2005;365:947–954. [DOI] [PubMed] [Google Scholar]
  • 74. Reynolds GP, Elsworth JD, Blau K, Sandler M, Lees AJ, Stern GM. Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol 1978;6:542–544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Riederer P, Lachenmayer L, Laux G. Clinical applications of MAO‐inhibitors. Curr Med Chem 2004;11:2033–2043. [DOI] [PubMed] [Google Scholar]
  • 76. Rinne UK, Larsen JP, Siden A, Worm‐Petersen J. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998;51:1309–1314. [DOI] [PubMed] [Google Scholar]
  • 77. Schapira AH. Causes of neuronal death in Parkinson's disease. Adv Neurol 2001;86:155–162. [PubMed] [Google Scholar]
  • 78. Sherer TB, Betarbet R, Greenamyre JT. Pathogenesis of Parkinson's disease. Curr Opin Investig Drugs 2001;2:657–662. [PubMed] [Google Scholar]
  • 79. Speiser Z, Levy R, Cohen S. Effects of N‐propargyl‐1‐(R)aminoindan (rasagiline) in models of motor and cognition disorders. J Neural Transm 1998;52(Suppl):287–300. [DOI] [PubMed] [Google Scholar]
  • 80. Speiser Z, Mayk A, Eliash S, Cohen S. Studies with rasagiline, a MAO‐B inhibitor, in experimental focal ischemia in the rat. J Neural Transm 1999;106:593–606. [DOI] [PubMed] [Google Scholar]
  • 81. Stern MB, Marek KL, Friedman J, et al. Double‐blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients. Mov Disord 2004;19:916–923. [DOI] [PubMed] [Google Scholar]
  • 82. Stocchi F, LARGO Study Group. Effect of rasagiline on severity of OFF in Parkinson's disease. Mov Disord 2004;19(Suppl 9):S208–209. [Google Scholar]
  • 83. Suleiman MS, Halestrap AP, Griffiths EJ. Mitochondria: A target for myocardial protection. Pharmacol Ther 2001;89:29–46. [DOI] [PubMed] [Google Scholar]
  • 84. Tatton NA. Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease. Exp Neurol 2000;166:29–43. [DOI] [PubMed] [Google Scholar]
  • 85. Tatton NA. Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease. Exp Neurol 2000;166:29–43. [DOI] [PubMed] [Google Scholar]
  • 86. Tatton NA and Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience 1997;77:1037–1048. [DOI] [PubMed] [Google Scholar]
  • 87. Thebault JJ, Guillaume M, Levy R. Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: A potent, selective, and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy 2004;24:1295–1305. [DOI] [PubMed] [Google Scholar]
  • 88. van Cruchten S and Van Den BW. Morphological and biochemical aspects of apoptosis, oncosis and necrosis. Anat Histol Embryol 2002;31:214–223. [DOI] [PubMed] [Google Scholar]
  • 89. Waibel S, Reuter A, Malessa S, Blaugrund E, Ludolph AC. Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J Neurol 2004;251:1080–1084. [DOI] [PubMed] [Google Scholar]
  • 90. Weinreb O, Bar‐Am O, Amit T, Chillag‐Talmor O, Youdim MB. Neuroprotection via pro‐survival protein kinase C isoforms associated with Bcl‐2 family members. FASEB J 2004;18:1471–1473. [DOI] [PubMed] [Google Scholar]
  • 91. Wilson MR. Apoptotic signal transduction: Emerging pathways. Biochem Cell Biol 1998;76:573–582. [DOI] [PubMed] [Google Scholar]
  • 92. Youdim MB, Amit T, Falach‐Yogev M, Am OB, Maruyama W, Naoi M. The essentiality of Bcl‐2, PKC and proteasome‐ubiquitin complex activations in the neuroprotective‐antiapoptotic action of the anti‐Parkinson drug, rasagiline. Biochem Pharmacol 2003;66:1635–1641. [DOI] [PubMed] [Google Scholar]
  • 93. Youdim MB, Gross A, Finberg JP. Rasagiline [N‐propargyl‐1R(+)‐aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol 2001;132:500–506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Youdim MB, Riederer PF. A review of the mechanisms and role of monoamine oxidase inhibitors in Parkinson's disease. Neurology 2004;63:S32–S35. [DOI] [PubMed] [Google Scholar]
  • 95. Youdim MB, Wadia A, Tatton W, Weinstock M. The anti‐Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo Ann NY Acad Sci 2001;939:450–458. [DOI] [PubMed] [Google Scholar]
  • 96. Youdim MB, Weinstock M. Molecular basis of neuroprotective activities of rasagiline and the anti‐Alzheimer drug TV3326 [(N‐propargyl‐(3R)aminoindan‐5‐yl)‐ethyl methyl carbamate]. Cell Mol Neurobiol 2001;21:555–573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97. Youdim MB and Weinstock M. Therapeutic applications of selective and non‐selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology 2004;25:243–250. [DOI] [PubMed] [Google Scholar]
  • 98. Zhang J, Price JO, Graham DG, Montine TJ. Secondary excitotoxicity contributes to dopamine‐induced apoptosis of dopaminergic neuronal cultures. Biochem Biophys Res Commun 1998;248:812–816. [DOI] [PubMed] [Google Scholar]

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