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Parkinson’s Disease
Volume 2012 (2012), Article ID 142372, 13 pages
http://dx.doi.org/10.1155/2012/142372
Research Article

The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression

1Neurochemistry Laboratory, Massachusetts General Hospital (East), CNY2, 149, 13th Street, Charlestown, MA 02129, USA
2MIND, Massachusetts General Hospital, Charlestown, MA 02129, USA
3Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA

Received 1 July 2011; Accepted 29 February 2012

Academic Editor: Paul S. Foster

Copyright © 2012 Sohan Mikkilineni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. G. S. Standaert and A. B. Young, “Treatment of the central nervous system degenerative disorders,” in Goodman & Gilaman's The Pharmacological Basis of Therapeutics, L. L. Brunton, Ed., pp. 527–545, McGraw-Hill, New York, NY, USA, 2005. View at Google Scholar
  2. M. R. DeLong and J. L. Juncos, “Parkinson's disease and other movement disorders,” in Harrison's Neurology in Clinical Medicine, S. L. Hauser, Ed., pp. 295–314, McGraw-Hill, New York, NY, USA, 2006. View at Google Scholar
  3. L. S. Forno, “Neuropathology of Parkinson's disease,” Journal of Neuropathology and Experimental Neurology, vol. 55, no. 3, pp. 259–272, 1996. View at Google Scholar · View at Scopus
  4. I. Cantuti-Castelvetri and D. G. Standaert, “Neuroprotective strategies for Parkinson's disease,” Current Neuropharmacology, vol. 2, pp. 153–168, 2004. View at Google Scholar
  5. K. R. Chaudhuri and Y. Naidu, “Early Parkinson's disease and non-motor issues,” Journal of Neurology, vol. 255, no. 5, pp. 33–38, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. K. R. Chaudhuri and P. Odin, “The challenge of non-motor symptoms in Parkinson's disease,” Progress in Brain Research, vol. 184, pp. 325–341, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. K. R. Chaudhuri and A. H. Schapira, “Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment,” The Lancet Neurology, vol. 8, no. 5, pp. 464–474, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. K. A. Jellinger, “Synuclein deposition and non-motor symptoms in Parkinson disease,” Journal of the Neurological Sciences, vol. 310, no. 1, pp. 107–111, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. D. O. Claassen, K. A. Josephs, J. E. Ahlskog, M. H. Silber, M. Tippmann-Peikert, and B. F. Boeve, “REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century,” Neurology, vol. 75, no. 6, pp. 494–499, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. R. Postuma and J. F. Gagnon, “Cognition and olfaction in Parkinson's disease,” Brain, vol. 133, no. 12, p. e160, 2010, author reply e161. View at Publisher · View at Google Scholar · View at Scopus
  11. M. A. Hely, W. G. J. Reid, M. A. Adena, G. M. Halliday, and J. G. L. Morris, “The Sydney Multicenter Study of Parkinson's disease: the inevitability of dementia at 20 years,” Movement Disorders, vol. 23, no. 6, pp. 837–844, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. W. G. J. Reid, M. A. Hely, J. G. L. Morris et al., “A longitudinal study of Parkinson's disease: clinical and neuropsychological correlates of dementia,” Journal of Clinical Neuroscience, vol. 3, no. 4, pp. 327–333, 1996. View at Google Scholar · View at Scopus
  13. A. Larner, “Cholinesterase inhibitors: beyond Alzheimer's disease,” Expert Review of Neurotherapeutics, vol. 10, no. 11, pp. 1699–1705, 2010. View at Publisher · View at Google Scholar · View at Scopus
  14. J. T. Olin, D. Aarsland, and X. Meng, “Rivastigmine in the treatment of dementia associated with Parkinson's disease: effects on activities of daily living,” Dementia and Geriatric Cognitive Disorders, vol. 29, no. 6, pp. 510–515, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. F. A. Schmitt, D. Aarsland, K. S. Brønnick, Xiangyi Meng, S. Tekin, and J. T. Olin, “Evaluating rivastigmine in mild-to-moderate Parkinsons disease dementia using ADAS-cog items,” American Journal of Alzheimer's Disease and other Dementias, vol. 25, no. 5, pp. 407–413, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. F. A. Schmitt, M. R. Farlow, X. Meng, S. Tekin, and J. T. Olin, “Efficacy of rivastigmine on executive function in patients with parkinson's disease dementia,” CNS Neuroscience & Therapeutics, vol. 16, no. 6, pp. 330–336, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. D. J. Burn, “The treatment of cognitive impairment associated with parkinson's disease,” Brain Pathology, vol. 20, no. 3, pp. 672–678, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. J. T. Greenamyre and T. G. Hastings, “Parkinson's—divergent causes convergent mechanisms,” Science, vol. 304, no. 5674, pp. 1120–1122, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. K. Gwinn-Hardy, “Genetics of parkinsonism,” Movement Disorders, vol. 17, no. 4, pp. 645–656, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. D. F. Clayton and J. M. George, “The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease,” Trends in Neurosciences, vol. 21, no. 6, pp. 249–254, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. M. H. Polymeropoulos, C. Lavedan, E. Leroy et al., “Mutation in the α-synuclein gene identified in families with Parkinson's disease,” Science, vol. 276, no. 5321, pp. 2045–2047, 1997. View at Publisher · View at Google Scholar · View at Scopus
  22. M. H. Polymeropoulos, “Autosomal dominant Parkinson's disease and alpha-synuclein,” Annals of Neurology, vol. 44, no. 3, supplement 1, pp. S63–S64, 1998. View at Google Scholar
  23. H. Braak, K. Del Tredici, U. Rüb, R. A. I. De Vos, E. N. H. Jansen Steur, and E. Braak, “Staging of brain pathology related to sporadic Parkinson's disease,” Neurobiology of Aging, vol. 24, no. 2, pp. 197–211, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. C. M. Cahill and J. T. Rogers, “Interleukin (IL) 1β induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IκB kinase α pathway targeting activator protein-1,” Journal of Biological Chemistry, vol. 283, no. 38, pp. 25900–25912, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. B. Wolozin and N. Golts, “Iron and Parkinson's disease,” Neuroscientist, vol. 8, no. 1, pp. 22–32, 2002. View at Google Scholar · View at Scopus
  26. S. Gal, M. Fridkin, T. Amit, H. Zheng, and M. B. H. Youdim, “M30, a novel multifunctional neuroprotective drug with potent iron chelating and brain selective monoamine oxidase-ab inhibitory activity for Parkinson's disease,” Journal of Neural Transmission, Supplement, no. 70, pp. 447–456, 2006. View at Google Scholar · View at Scopus
  27. C. M. Cahill, D. K. Lahiri, X. Huang, and J. T. Rogers, “Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases,” Biochimica et Biophysica Acta, vol. 1790, no. 7, pp. 615–628, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. J. P. Taylor, I. F. Mata, and M. J. Farrer, “LRRK2: a common pathway for parkinsonism, pathogenesis and prevention?” Trends in Molecular Medicine, vol. 12, no. 2, pp. 76–82, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. A. E. Oakley, J. F. Collingwood, J. Dobson et al., “Individual dopaminergic neurons show raised iron levels in Parkinson disease,” Neurology, vol. 68, no. 21, pp. 1820–1825, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. O. Weinreb, T. Amit, S. Mandel, and M. B. H. Youdim, “Neuroprotective molecular mechanisms of (-)-epigallocatechin-3-gallate: a reflective outcome of its antioxidant, iron chelating and neuritogenic properties,” Genes & Nutrition, vol. 4, no. 4, pp. 283–296, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. I. Cantuti-Castelvetri, J. Klucken, M. Ingelsson et al., “Alpha-synuclein and chaperones in dementia with Lewy bodies,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 12, pp. 1058–1066, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. L. Reznichenko, T. Amit, H. Zheng et al., “Reduction of iron-regulated amyloid precursor protein and β-amyloid peptide by (-)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer's disease,” Journal of Neurochemistry, vol. 97, no. 2, pp. 527–536, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. A. L. Friedlich, R. E. Tanzi, and J. T. Rogers, “The 5′-untranslated region of Parkinson's disease α-synuclein messengerRNA contains a predicted iron responsive element [1],” Molecular Psychiatry, vol. 12, no. 3, pp. 222–223, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. J. T. Rogers, S. Mikkilineni, I. Cantuti-Castelvetri et al., “The alpha-synuclein 5′untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen,” Journal of Neural Transmission, vol. 118, no. 3, pp. 493–507, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. D. Olivares, X. Huang, L. Branden, N. H. Greig, and J. T. Rogers, “Physiological and pathological role of alpha-synuclein in parkinson's disease through iron mediated oxidative stress; the role of a putative iron-responsive element,” International Journal of Molecular Sciences, vol. 10, no. 3, pp. 1226–1260, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. K. Ueda, H. Fukushima, E. Masliah et al., “Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 23, pp. 11282–11286, 1993. View at Publisher · View at Google Scholar · View at Scopus
  37. V. M. Y. Lee, B. I. Giasson, and J. Q. Trojanowski, “More than just two peas in a pod: common amyloidogenic properties of tau and α-synuclein in neurodegenerative diseases,” Trends in Neurosciences, vol. 27, no. 3, pp. 129–134, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. P. H. Jensen, P. Hojrup, H. Hager et al., “Binding of Abeta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC,” Biochemical Journal, vol. 323, no. 2, pp. 539–546, 1997. View at Google Scholar · View at Scopus
  39. K. A. Conway, J. D. Harper, and P. T. Lansbury, “Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease,” Nature Medicine, vol. 4, no. 11, pp. 1318–1320, 1998. View at Publisher · View at Google Scholar · View at Scopus
  40. Han Hogyu, P. H. Weinreb, and P. T. Lansbury Jr., “The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease?” Chemistry & Biology, vol. 2, no. 3, pp. 163–169, 1995. View at Publisher · View at Google Scholar · View at Scopus
  41. J. Q. Trojanowski and V. M. Y. Lee, “Parkinson's disease and related neurodegenerative synucleinopathies linked to progressive accumulations of synuclein aggregates in brain,” Parkinsonism & Related Disorders, vol. 7, no. 3, pp. 247–251, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. J. T. Rogers, J. D. Randall, C. M. Cahill et al., “An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript,” Journal of Biological Chemistry, vol. 277, no. 47, pp. 45518–45528, 2002. View at Publisher · View at Google Scholar · View at Scopus
  43. J. A. Duce, A. Tsatsanis, M. A. Cater et al., “Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein is Inhibited by Zinc in Alzheimer's Disease,” Cell, vol. 142, no. 6, pp. 857–867, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. P. Davies, D. Moualla, and D. R. Brown, “Alpha-synuclein is a cellular ferrireductase,” PLoS ONE, vol. 6, no. 1, Article ID e15814, 2011. View at Publisher · View at Google Scholar · View at Scopus
  45. P. Davies, X. Wang, C. J. Sarell et al., “The synucleins are a family of redox-active copper binding proteins,” Biochemistry, vol. 50, no. 1, pp. 37–47, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. D. K. Lahiri, D. Chen, B. Maloney et al., “The experimental Alzheimer's Disease drug posiphen [(+)-phenserine] lowers amyloid-β peptide levels in cell culture and mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 320, no. 1, pp. 386–396, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. I. Nakano and A. Hirano, “Parkinson's disease: neuron loss in the nucleus basalis without concomitant Alzheimer's disease,” Annals of Neurology, vol. 15, no. 5, pp. 415–418, 1984. View at Google Scholar · View at Scopus
  48. Y. M. Kuo, Z. Li, Y. Jiao et al., “Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes,” Human Molecular Genetics, vol. 19, no. 9, Article ID ddq038, pp. 1633–1650, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. B. Ray, J. A. Bailey, S. Sarkar, and D. K. Lahiri, “Molecular and immunocytochemical characterization of primary neuronal cultures from adult rat brain: differential expression of neuronal and glial protein markers,” Journal of Neuroscience Methods, vol. 184, no. 2, pp. 294–302, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. H. H. Cho, C. M. Cahill, C. R. Vanderburg et al., “Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1,” Journal of Biological Chemistry, vol. 285, no. 41, pp. 31217–31232, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Bandyopadhyay, X. Huang, H. Cho, N. H. Greig, M. B. Youdim, and J. T. Rogers, “Metal specificity of an iron-responsive element in Alzheimer's APP mRNA 5′untranslated region, tolerance of SH-SY5Y and H4 neural cells to desferrioxamine, clioquinol, VK-28, and a piperazine chelator,” Journal of Neural Transmission, Supplement, no. 71, pp. 237–247, 2006. View at Google Scholar · View at Scopus
  52. M. Maccecchini, “Posiphen’s pharmacokinetics and mecha-883nism of action in mild cognitive impaired patients,” Alzheimer’s & Dementia, vol. 6, no. 4, supplement 1, p. e54, 2010. View at Google Scholar
  53. B. Winblad, E. Giacobini, L. Frölich et al., “Phenserine efficacy in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1201–1208, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. N. H. Greig, K. Sambamurti, Q. S. Yu, A. Brossi, G. B. Bruinsma, and D. K. Lahiri, “An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer's disease,” Current Alzheimer Research, vol. 2, no. 3, pp. 281–290, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. J. Klein, “Phenserine,” Expert Opinion on Investigational Drugs, vol. 16, no. 7, pp. 1087–1097, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. K. T. Y. Shaw, T. Utsuki, J. Rogers et al., “Phenserine regulates translation of β-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 13, pp. 7605–7610, 2001. View at Publisher · View at Google Scholar · View at Scopus
  57. A. Venti, T. Giordano, P. Eder et al., “Integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5′-untranslated region,” Annals of the New York Academy of Sciences, vol. 1035, pp. 34–48, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. Y. Xia, T. Saitoh, K. Uéda et al., “Characterization of the human α-synuclein gene: genomic structure, transcription start site, promoter region and polymorphisms,” Journal of Alzheimer's Disease, vol. 3, no. 5, pp. 485–494, 2001. View at Google Scholar · View at Scopus
  59. J. B. Goforth, S. A. Anderson, C. P. Nizzi, and R. S. Eisenstein, “Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy,” RNA, vol. 16, no. 1, pp. 154–169, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. W. Luo, Q. S. Yu, M. Zhan et al., “Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine,” Journal of Medicinal Chemistry, vol. 48, no. 4, pp. 986–994, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. Q. S. Yu, X. F. Pei, H. W. Holloway, N. H. Greig, and A. Brossi, “Total syntheses and anticholinesterase activities of (3aS)-N(8)- norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers, and other N(8)-substituted analogues,” Journal of Medicinal Chemistry, vol. 40, no. 18, pp. 2895–2901, 1997. View at Publisher · View at Google Scholar · View at Scopus
  62. Q. S. Yu, N. H. Greig, H. W. Holloway, and A. Brossi, “Syntheses and anticholinesterase activities of (3aS)-N1,N8- bisnorphenserine, (3aS)-N1,N8-bisnorphysostigmine, their antipodal isomers, and other potential metabolites of phenserine,” Journal of Medicinal Chemistry, vol. 41, no. 13, pp. 2371–2379, 1998. View at Publisher · View at Google Scholar · View at Scopus