Advertisement

TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease

  • M. Weinstock
  • C. Bejar
  • R.-H. Wang
  • T. Poltyrev
  • A. Gross
  • J. P. M. Finberg
  • M. B. H. Youdim
Conference paper

Summary

TV3326, [(N-propargyl-(3R) aminoindan-5-y1)-ethyl methyl carbamate] is a novel aminoindan derivative of the selective irreversible monoamine oxidase (MAO)-B inhibitor, rasagiline (N-propargyl-(1R)aminoindan), possessing both cholinesterase (ChE) and MAO-inhibitory activity. In doses of 35-100 µmoles/kg administered orally to rats, it inhibits ChE by 25-40% and antagonises scopolamine-induced impairments in spatial memory. After daily administration of 75 µmoles/kg for 2 weeks, TV3326 does not show any motor stimulant effects but significantly reduces immobility in the forced swim test, an action consistent with that of known antidepressants. This could result from more than 70% inhibition of both MAO-A and B in the brain that occurs under these conditions, since it is not shared by the S-isomer, TV3279, which does not block MAO. TV3326 also shows selectivity for brain MAO, even after 2 months of daily administration, with little or no effect on the enzyme in the intestinal tract and liver. This reduces the likelihood of it producing the “cheese effect” if administered with tyramine-containing foods or beverages. TV3326 and TV3279 protect against ischemia-induced cytotoxicity in PC12 cells and reduce the oedema, deficits in motor function and memory after closed head injury in mice. These neuroprotective effects do not result from MAO inhibition. The pharmacological actions of TV3326 could be of clinical importance for the treatment of AD, and the drug is currently in development for this purpose.

Keywords

PC12 Cell Monoamine Oxidase Open Field Test Escape Latency Passive Avoidance Test 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abu-Raya S, Blaugrund E, Trembovler V, Shilderman-Bloch E, Shohami E, et al (1999) Rasagiline, a monoamine oxidase-B inhibitor, protects NGF-differentiated PC12 cells against oxygen-glucose deprivation. J Neurosci Res 58: 456–463PubMedCrossRefGoogle Scholar
  2. Ansari KS, Yu PH, Kruck TPA, Tatton WG (1993) Rescue of axotomized immature rat motorneurons by R (-) deprenyl: Stereospecificity and independence from monoamine oxidase inhibition. J Neurosci 13: 4042–4053PubMedGoogle Scholar
  3. Beatty WW, Butters N, Janowsky DS (1986) Patterns of memory failure after scopolamine treatment: Implications for cholinergic hypothesis of dementia. Behav Neural Biol 45: 196–211PubMedCrossRefGoogle Scholar
  4. Bejar C, Wang RH, Weinstock M (1999) Effect of of rivastigmine on scopolamine-induced memory impairment in rats. Eur J Pharmacol 383: 231–240PubMedCrossRefGoogle Scholar
  5. Chen Y, Shohami E, Constantini S, Weinstock M (1998) Rivastigmine, a brain-selective acetylcholinesterase inhibitor, ameliorates cognitive and motor deficits induced by closed-head injury in the mouse. J Neurotrauma 15: 231–237PubMedCrossRefGoogle Scholar
  6. Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219: 1184–1190PubMedCrossRefGoogle Scholar
  7. Edwards JG (1995) Drug choice in depression. Selective serotonin reuptake inhibitors or tricyclic antidepressants? CNS Drugs 4: 141–159CrossRefGoogle Scholar
  8. Ellman GL, Courtney KD, Anders F, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7: 88–95PubMedCrossRefGoogle Scholar
  9. Finberg JPM, Lamensdorf I, Commissiong JW, Youdim MBH (1996) Pharmacology and neuroprotective properties of rasagiline. J Neural Transm Suppl 48: 95–101PubMedGoogle Scholar
  10. Finberg JPM, Takeshima T, Johnston JM, Commissiong JW (1998) Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. Neuroreport 9: 703–707PubMedCrossRefGoogle Scholar
  11. Finberg JPM, Lamensdorf I, Weinstock M, Schwartz M, Youdim MBH (1999) Pharmacology of rasagiline (N-propargyl-1R-aminoindan). Adv Neurol 80: 495–499PubMedGoogle Scholar
  12. Freedman M, Rewilak D, Xerri T, et al (1998) L-deprenyl in Alzheimer’s disease: cognitive and behavioral effects. Neurology 50: 660–668PubMedCrossRefGoogle Scholar
  13. Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence for neuronal oxidative damage in Alzheimer’s disease. Am J Pathol 149: 21–28PubMedGoogle Scholar
  14. Gorman LK, Fu K, Hovda DA, Becker DP, Katayama Y (1989) Analysis of acetylcholine release following concussive brain injury in the rat. J Neurotrauma 6: 203Google Scholar
  15. Huang W, Chen Y, Shohami E, Weinstock M (1999) Neuroprotective effect of rasagiline, a selective MAO-B inhibitor, against closed head injury in the mouse. Eur J Pharmacol 366: 127–135PubMedCrossRefGoogle Scholar
  16. Kalir A, Sabbagh A, Youdim MBH (1981) Selective acetylenic suicide and reversible inhibitors of monoamine oxidase type A and type B. Br J Pharmacol 73: 55–64PubMedCrossRefGoogle Scholar
  17. Kitada Y, Miyauchi T, Satoh A, Satoh S (1981) Effects of antidepressants in the rat forced swim test. Eur J Pharmacol 72: 145–152PubMedCrossRefGoogle Scholar
  18. Kragten E, Lalande I, Zimmerman K, et al (1998) Glyceraldehyde-3-phosphate dehydrogenate, the putative target of the anti-apoptotic compounds CGP 3466 and R-(—)deprenyl. J Biol Chem 273: 5821–5828PubMedCrossRefGoogle Scholar
  19. Knollema S, Aukema W, Horn H, Korf J, Horst GJT (1995) L-Deprenyl reduces brain damage in rats exposed to transient hypoxia-ischemia. Stroke 26: 1883–1887PubMedCrossRefGoogle Scholar
  20. Lahtinen H, Koistinaho J, Kauppinen R, et al (1997) Selegiline treatment after transient global ischemia in gerbils enhances the survival of CA1 pyramidal cells in the hippocampus. Brain Res 75: 260–267CrossRefGoogle Scholar
  21. Morris RGM (1983) An attempt to dissociate “spatial-mapping” and “working memory” theories of hippocampal function. In: Siefert W (ed), The neurobiology of the hippocampus. Academic Press, London, 405–432Google Scholar
  22. Morris RGM (1984) Development of a water maze procedure for studying spatial learning in the rat. J Neurosci Meth 11: 47–60CrossRefGoogle Scholar
  23. Newman SC (1999) The prevalence of depression in Alzheimer’s disease and vascular dementia in a population sample. J Affect Disord 52: 169–176PubMedCrossRefGoogle Scholar
  24. Palmer AM, Stratman GC, Procter AW, Bowen DM (1988) Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 23: 616–620PubMedCrossRefGoogle Scholar
  25. Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioral despair in rats: A new model sensitive to antidepressant treatments. Eur J Pharmacol 47: 379–391PubMedCrossRefGoogle Scholar
  26. Saura J, Luque JM, Cesura AM, et al (1994) Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative radio-autography. Neuroscience 62: 15–30PubMedCrossRefGoogle Scholar
  27. Strolin-Benedetti M, Boucher T, Carlsson A, Fowler CJ (1983) Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat. Biochem Pharmacol 32: 4752Google Scholar
  28. Tipton KF, Youdim MBH (1976) Assay of monoamine oxidase. In: Wolstenholme GEW, Knight J (eds) Monoamine oxidase and its inhibition. Ciba Foundation Symposium, No 39. Elsevier, Amsterdam, 393–403Google Scholar
  29. Weinstock M (1999) Selectivity of cholinesterase inhibition: Clinical implications for the treatment of Alzheimer’s disease. CNS Drugs 12: 307–323CrossRefGoogle Scholar
  30. Youdim MBH, Wadia JS, Tatton WG (1999a) Neuroprotective properties of the antiparkinson drug rasagiline and its optical S-isomer. Neurosci Lett Suppl 54: S45Google Scholar
  31. Youdim MBH, Finberg JPM, Gross A, Tatton WG, Sterling J, Herzig Y, Chorev M, Weinstock M (1999b) Novels drugs possessing both cholinesterase and monoamine oxidase inhibitory activities. Neurosci Lett Suppl 54: S45Google Scholar
  32. Zhang X, Zuo D-M, Davis BA, Boulton AA, Yu PH (1996) Immunocytochemical evidence of neuroprotection by R(—)-deprenyl and N-(2-hexyl)-Nmethylpropargylamine on DSP-4-induced degeneration of rat brain noradrenergic axons and terminals. J Neurosci Res 43: 482–489PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • M. Weinstock
    • 1
  • C. Bejar
    • 1
  • R.-H. Wang
    • 1
  • T. Poltyrev
    • 1
  • A. Gross
    • 2
  • J. P. M. Finberg
    • 2
  • M. B. H. Youdim
    • 2
    • 3
  1. 1.Department of PharmacologyHebrew University Hadassah School of MedicineJerusalemIsrael
  2. 2.Department of PharmacologyTechnion Faculty of MedicineHaifaIsrael
  3. 3.Eve Topf and NPF Centers of Neurodegenerative Diseases I.I.T.HaifaIsrael

Personalised recommendations