Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil.

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.

Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo.

We have recently shown that the anti-Parkinson-propargyl-containing monoamine oxidase B (MAO-B) inhibitor drug, rasagiline [N-propargyl-(1R)-aminoindan], and its cholinesterase inhibitor derivatives TV3326 and TV3279, regulate amyloid precursor protein (APP) processing by a protein kinase C (PKC)-dependent mechanism in SH-SY5Y neuroblastoma and PC12 cells. In the present study, we investigated the effect of rasagiline and its derivatives on the regulation of the PKC-dependent mechanism and APP processing under in vivo conditions. Administration of rasagiline (0.

The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent amyloid precursor protein processing.

Rasagiline [N-propargyl-(1R)-aminoindan] a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor exerts neuroprotective and antiapoptotic effects against a variety of insults in cell cultures and in vivo and has finished its phase III clinical trials for Parkinson's disease. In the present study, we show that rasagiline (1 and 10 microM) significantly protected rat PC12 cells against beta-amyloid (Abeta1-42) toxicity. In addition, rasagiline significantly increased (approximately threefold) the secretion of the nonamyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) from SH-SY5Y neuroblastoma and PC12 cells.

Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline.

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined.