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

Abstract

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.

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

“…Pharmacological studies have demonstrated that MAO inhibitors exert neuroprotective effects in patients with AD (21,52,53) through the following mechanisms: Improvement of cognitive impairment (50,54,55); antioxidant and enhancement of iron chelating activities (56-59); regulation of APP and Aβ expression processing (56,60), involving the activation of certain signaling pathways, including the p42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways (61); and inhibition of cholinesterase (ChE) activity (62-64).…”

“…It has been established that MAO, a marker of oxidative stress, is linked to the production of reactive oxygen species and other molecules that cause oxidative stress, which results in neuronal damage and neurodegeneration, including AD, indicating that excessive MAO activity contributes to neurodegeneration in AD (62,(111)(112)(113). Molecular biology studies have shown the critical role of Aβ generation through the modulation of APP processing by MAO (60,61,114,115) (Fig. 2).…”

“…The main neuroprotective mechanisms of MAO inhibitors in AD include the following: i) Improvement of cognitive impairment (50,54,55), where MAO inhibitors correct chemical imbalances in the brain; ii) antioxidant activities and enhancement of iron-chelating activities (56)(57)(58)(59), where chelators can modulate Aβ accumulation, protect against tau hyperphosphorylation and block metal-associated oxidative stress, thereby holding considerable promise as effective anti-AD drugs (145,146); iii) regulation of APP and Aβ expression processing (56,60), for example ladostigil (TV3326), a selective MAO-B inhibitor, which regulates APP translation and processing (114); iv) the selective MAO inhibitors selegiline and rasagiline have been proven to possess neuroprotective activities in cell cultures and animal models of neurodegenerative diseases through the activation of certain signaling pathways, including p42/44 MAPK and PKC (61); v) inhibition of ChE activity by the MAO inhibitor rasagiline (62)(63)(64), with MAO inhibitors also affecting other chemicals throughout the body and acting by correcting chemical imbalances in the brain.…”

Multifunctional Receptor-Directed Drugs for Disorders of the Central Nervous System

“…Ladostigil also has been reported to enhance soluble amyloid precursor protein (APP)-␣ secretion via the protein kinase C-MAP kinasedependent pathway, and to decrease the levels of holo-APP (i.e., actions that favor cell viability). [13][14][15] Thus, ladostigil represents a new drug class that is potentially suitable for the treatment of Alzheimer's disease (AD). Patients with AD require therapies that will delay the progression of the disease, and they may suffer from impaired attention, impaired memory, extrapyramidal disorders, and depression.…”

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment

“…31 The MTDL approach has been employed by many research groups [32][33][34][35] and has shown success, for example in the case of the compound ladostigil 36 which has reached clinical trials. 37 Exploiting the advantage of conjunctive approach, we designed a series of compounds combining known scaffolds of MAO and ABAD inhibitors to introduce MAO inhibitory activity into frentizole moiety and explore structural inhibitory features of both MAO and ABAD scaffolds. Xie et al observed that the FDA approved drug, frentizole ( Fig.…”