TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment o
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-i
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Department of Pharmacology, Hebrew Uni versity Hadassah School of Medicine, Jeru salem, Israel 2Department of Pharmacology, Technion Faculty of Medicin e, Haifa , Isra el 3 Eve Topf and NPF Centers of Neurodegenerative Diseases I.I.T ., Haifa, Israel
Summary. TV3326, [(N-propargyl-(3R) aminoindan-5-yl)-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 umoles/kg admini stered orally to rats , it inhibits ChE by 25-40% and antagonises scopolamine-induced impairments in spatial memory. After daily administration of75 umoles/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 injur y 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. Introduction Alzheimer's (AD) and Parkinson's disease are neurodegenerative conditions involving the decay of functionally related populations of neurones, that may result from an age-related decline in the ability to respond to neurotoxins and environmental insults . This phenomenon could result from higher activity of
P. Riederer et al. (eds.), Advances in Research on Neurodegeneration © Springer-Verlag Wien 2000
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MAO-B in association with gliosis, which increases the likelihood of the formation of H 20 2 (Saura et aI., 1994). Oxidative free radicals (ROS) can then be produced as a result of inadequate scavenging by enzymes such as catalase and others. ROS can react with NO to form the peroxynitrite radical, causing nitration of tyrosine residues in proteins (Good et aI., 1996). In AD, cognitive impairment is the most prevalent finding and correlates well with the degree of degeneration of cholinergic neurones arising in the basal forebrain (Whitehouse et aI., 1981). Depressive symptoms also occur in this condition (Newman, 1999) which may be associated with a decrease in serotoninergic and noradrenergic transmission in the limbic system (Palmer et aI., 1988). Cholinesterase (ChE) inhibitors are effective in improving memory in AD,
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