Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression.
BACKGROUND
A high incidence of depression is found in subjects with Alzheimer's disease (AD), in whom many antidepressants are contraindicated because they have anticholinergic activity. We have designed a new cholinesterase inhibitor TV3326 [( N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] for the treatment of AD, which has neuroprotective activities and also blocks monoamine oxidase (MAO) A and B in the brain but not in the intestine after chronic administration.


OBJECTIVE
To examine the antidepressant and anxiolytic potential of TV3326 in rats and compare them with those of its R isomer TV3279, which lacks MAO-inhibitory activity, and of amitriptyline and moclobemide.


METHODS
Each of the drugs was administered orally, acutely or once daily for 2 weeks, and its effect was evaluated on the behavior of rats in the forced swim test (FST) and plus maze (EPM) test.


RESULTS
Immobility in the FST was reduced by 56% after acute and chronic administration of amitriptyline (10 mg/kg) and by 42% after acute administration of moclobemide (20 mg/kg) and by 63% when this drug was given chronically. TV3326 (26 mg/kg) only reduced immobility (by 44%) when given chronically and inhibited brain MAO-A and -B by more than 66%. TV3279 had no significant effect in the FST. All the drugs except TV3326 increased anxiogenic activity in rats in EPM, as indicated by a more than 50% decrease in the time in open arms after chronic administration.


CONCLUSIONS
TV3326 has potential antidepressant-like activity when given in a dose regimen that causes significant inhibition of brain MAO-A and -B. Together with its neuroprotective properties, this action could make TV3326 a potentially valuable drug for the treatment of dementia in patients with depression.
Weinstock
Marta
M
Department of Pharmacology, Hebrew University Faculty of Medicine, Jerusalem 91120, Israel. martar@cc.huji.ac.il
Poltyrev
Tatyana
T
Bejar
Corina
C
Youdim
Moussa B H
MB
D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002802:Cholinesterases / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000201:enzymology; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D002800:Cholinesterase Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; D002802:Cholinesterases