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.