Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression

Psychopharmacology (Berl). 2002 Mar;160(3):318-24. doi: 10.1007/s00213-001-0978-x. Epub 2002 Jan 24.

Abstract

Rationale: 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.

Objectives: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / drug therapy*
  • Anxiety / enzymology
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use*
  • Cholinesterases / metabolism
  • Depression / drug therapy*
  • Depression / enzymology
  • Drug Evaluation, Preclinical / methods
  • Drug Evaluation, Preclinical / statistics & numerical data
  • Indans / pharmacology
  • Indans / therapeutic use*
  • Male
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / pharmacology
  • Monoamine Oxidase Inhibitors / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism

Substances

  • (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate
  • Cholinesterase Inhibitors
  • Indans
  • Monoamine Oxidase Inhibitors
  • Monoamine Oxidase
  • Cholinesterases