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.
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References
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: 456–463
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: 4042–4053
Beatty WW, Butters N, Janowsky DS (1986) Patterns of memory failure after scopolamine treatment: Implications for cholinergic hypothesis of dementia. Behav Neural Biol 45: 196–211
Bejar C, Wang RH, Weinstock M (1999) Effect of of rivastigmine on scopolamine-induced memory impairment in rats. Eur J Pharmacol 383: 231–240
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: 231–237
Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219: 1184–1190
Edwards JG (1995) Drug choice in depression. Selective serotonin reuptake inhibitors or tricyclic antidepressants? CNS Drugs 4: 141–159
Ellman GL, Courtney KD, Anders F, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7: 88–95
Finberg JPM, Lamensdorf I, Commissiong JW, Youdim MBH (1996) Pharmacology and neuroprotective properties of rasagiline. J Neural Transm Suppl 48: 95–101
Finberg JPM, Takeshima T, Johnston JM, Commissiong JW (1998) Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. Neuroreport 9: 703–707
Finberg JPM, Lamensdorf I, Weinstock M, Schwartz M, Youdim MBH (1999) Pharmacology of rasagiline (N-propargyl-1R-aminoindan). Adv Neurol 80: 495–499
Freedman M, Rewilak D, Xerri T, et al (1998) L-deprenyl in Alzheimer’s disease: cognitive and behavioral effects. Neurology 50: 660–668
Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence for neuronal oxidative damage in Alzheimer’s disease. Am J Pathol 149: 21–28
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: 203
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: 127–135
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: 55–64
Kitada Y, Miyauchi T, Satoh A, Satoh S (1981) Effects of antidepressants in the rat forced swim test. Eur J Pharmacol 72: 145–152
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: 5821–5828
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: 1883–1887
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: 260–267
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, 405–432
Morris RGM (1984) Development of a water maze procedure for studying spatial learning in the rat. J Neurosci Meth 11: 47–60
Newman SC (1999) The prevalence of depression in Alzheimer’s disease and vascular dementia in a population sample. J Affect Disord 52: 169–176
Palmer AM, Stratman GC, Procter AW, Bowen DM (1988) Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 23: 616–620
Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioral despair in rats: A new model sensitive to antidepressant treatments. Eur J Pharmacol 47: 379–391
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: 15–30
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: 4752
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, 393–403
Weinstock M (1999) Selectivity of cholinesterase inhibition: Clinical implications for the treatment of Alzheimer’s disease. CNS Drugs 12: 307–323
Youdim MBH, Wadia JS, Tatton WG (1999a) Neuroprotective properties of the antiparkinson drug rasagiline and its optical S-isomer. Neurosci Lett Suppl 54: S45
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: S45
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: 482–489
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© 2000 Springer-Verlag Wien
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Weinstock, M. et al. (2000). TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease. In: Riederer, P., et al. Advances in Research on Neurodegeneration. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6301-6_10
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DOI: https://doi.org/10.1007/978-3-7091-6301-6_10
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