Degeneration of nigrostriatal dopamine neurons and
cholinergic cortical neurones are the main pathological features of
Parkinson's disease (PD) and for the cognitive deficit in
dementia of the Alzheimer' type (AD) and in
dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have
dementia and depression resulting from possible degeneration of
cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of
iron within the
melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that
iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia
hydrogen peroxide producing
monoamine oxidase (
MAO) activity that can generate of reactive
hydroxyl radical formed from interaction of
iron and
hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson
monoamine oxidase B inhibitor,
rasagiline, by introducing a
carbamate cholinesterase (ChE) inhibitory moiety into it.
Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and
MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with
dementia Being a brain selective
MAO-AB inhibitor it has limited potentiation of the pressor response to oral
tyramine and exhibits
antidepressant activity similar to classical non-selective
MAO inhibitor antidepressants by increasing brain
serotonin and
noradrenaline.
Ladostigil inhibits brain acetyl and
butyrylcholinesterase in rats and antagonizes
scopolamine-induced inhibition of spatial learning.
Ladostigil like
MAO-B inhibitor it prevents
MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of
rasagiline.
Ladostigil,
rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family
proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of
mitochondrial permeability transition pore.
Iron accumulates in brain regions associated with
neurodegenerative diseases of PD, AD,
amyotrophic lateral sclerosis and
Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional
iron chelator from our prototype brain permeable
iron chelators, VK-28, possessing
propargylamine moiety (HLA-20, M30 and M30A) to
iron out
iron from the brain. These compounds have been shown to have
iron chelating and
monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.