The recent therapeutic approach in which
drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of several multifunction drugs. These include
ladostigil (
TV3326) [(
N-propargyl-(3R) aminoindan-5yl)-ethyl
methyl carbamate], which combines the pharmacophore-
neuroprotective effects of
rasagiline, a selective
monoamine oxidase (
MAO)-B inhibitor, with the
cholinesterase (ChE) inhibitory activity of
rivastigmine or
iron chelating moiety such as M30. In the case of M30 the pharmacophore of brain permeable
iron chelator VK-28 plus the
MAO inhibitor-neuroprotective
propargylamine moiety of
rasagiline are combined in a single molecule as a potential treatment for
Alzheimer's disease,
Lewy body disease, and
Parkinson's disease with
dementia. Here, we discuss the activities of
ladostigil in terms of its
cholinesterase cognitive enhancing potential, antiParkinson,
antidepressant, neuroprotection and APP (
amyloid precursor
protein) processing potential. One major attribute of
ladostigil is its neuroprotective activity in neuronal cell cultures and in vivo. Employing an apoptotic model of
neuroblastoma SK-N-SH cells, the molecular mechanism of its neuroprotective activity has been determined. The current studies show that
ladostigil significantly decreased apoptosis via inhibition of the cleavage and prevention of
caspase-3 activation through a mechanism related to regulation of the Bcl-2 family
proteins, resulting in reduced levels of Bad and Bax and induced levels of Bcl-2. In addition,
ladostigil elevated the levels of pPKC(pan). We have also followed the regulation of APP processing and found that
ladostigil markedly decreased apoptotic-induced levels of holo-APP, as well as stimulated the release of the non-amyloidogenic soluble APP (sAPPalpha) into the
conditioned medium via a established
protein kinsae C-MAPkinase dependent pathway. Similar to
ladostigil, its S-isomer,
TV3279, which is a ChE inhibitor lacking
MAO inhibitory activity, exerted similar neuroprotective properties and APP processing, suggesting that the mode of action is independent of
MAO inhibition. These effects were shown to reside in the
propargylamine moiety. These findings indicate that the dual actions of the anti-apoptotic-neuroprotective activity and the ability to modulate APP processing, could make
ladostigil a potentially valuable
drug for the treatment of
Alzheimer's disease.