A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease

Abstract

Degeneration of cholinergic cortical neurons is one of the main reasons for the cognitive deficit in dementia of the Alzheimer type (AD) and in dementia with Lewy bodies (DLB). Many subjects with AD and DLB have extrapyramidal dysfunction and depression resulting from degeneration of dopaminergic, noradrenergic and serotoninergic neurons. We prepared a novel drug, TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), with both cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity, as potential treatment of AD and DLB. TV-3326 inhibits brain acetyl and butyrylcholinesterase (BuChE) in rats after oral doses of 10-100 mg/kg. After chronic but not acute treatment, it inhibits MAO-A and -B in the brain by more than 70% but has almost no effect on these enzymes in the small intestine in rats and rabbits. The brain selectivity results in minimal potentiation of the pressor response to oral tyramine. TV-3326 acts like other antidepressants in the forced swim test in rats, indicating a potential for antidepressant activity. Chronic treatment of mice with TV-3326 (26 mg/kg) prevents the destruction of nigrostriatal neurons by the neurotoxin MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In addition to ChE and MAO inhibition, the propargylamine moiety of TV-3326 confers neuroprotective activity against cytotoxicity induced by ischemia and peroxynitrite in cultured neuronal cells that results from prevention of the fall in mitochondrial membrane potential and antiapoptotic activity. These unique multiple actions of TV-3326 make it a potentially useful drug for the treatment of dementia with Parkinsonian-like symptoms and depression.