Antiapoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor.

Abstract The anti Parkinson drug, rasagiline [R-(þ)-N-propargyl-1-aminoindan], an inhibitor of type B monoamine oxidase, has been shown to suppress apoptosis induced by neurotoxins and oxidative stress. A series of novel propargylaminoindans with a carbamate moiety to inhibit cholinesterase were developed from phamacophore of rasagiline to protect or rescue deteriorated neurons in Alzheimer's and Lewy Body disease and provide a beneficial effect on the cognitive deficits. Rasagiline analogues were found to protect dopaminergic SH-SY5Y cells against apoptosis induced by peroxynitrite donor. -(3R)-aminoindan-5-yl]-ethyl methyl carbamate, was as effective as rasagiline in preventing apoptosis, followed by its S-enantiomer, TV3279. The anti-apoptotic-neuroprotective activity was shown to reside in the propargylamine and not the carbamate moiety. This resulted in stabilization of the mitochondrial membrane potential, the collapse of which initiates the apoptotic cascade. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Propargylamines; Anti-apoptotic activity; Mitochondrial membrane potential; Monoamine oxidase inhibitor; Cholinesterase inhibitor; Parkinson's disease; Alzheimer's disease; Lewy Body disease; Peroxynitrite; Rasagiline; TV3326 Neurodegenerative disorders, such as Parkinson's (PD) and Alzheimer's disease (AD), are characterized by progressive cell death of selective neurons in the brain. Apoptosis is considered to be a common type of neuronal cell death in neurodegenerative diseases that may be induced by various environmental and genetic factors. The apoptotic cascade is activated by tightly controlled step-wise processes and has been proposed to be a target of neurorescue or neuroprotective strategies A series of analogues were synthesized with a carbamate cholinesterase inhibitory moiety in the aminoindan structure of rasagiline with the purpose of preserving its neuroprotective activity Rasagiline and derivatives ( SH-SY5Y cells were incubated with 0.01 -10 mM of propargylamine derivatives for 20 min, then cultured for 18 h in the presence of 250 mM SIN-1, and the morphological changes in the cells were observed by phase-contrast and fluorescence microscopy after staining with PI and Hoechst 33342 The effects of SIN-1 with and without propargylamines were examined on mitochondrial permeability transition pore by measurement of DCm, as reported previously The chemical structures of rasagiline and its derivatives, TV3326, TV3279, TV3218 a (3SR)-aminoindan-5-yl]-ethyl methyl carbamate, without the propargyl moiety and TV 3294 (6-hydroxy-rasagiline), a propargylaminoindan metabolite of TV3326 without a carbamate moiety are shown in The effects of TV3326 and rasagiline on DCm were examined by measurement of the reduction in Rhodamin 123 fluorescence. SIN-1 (250 mM) reduced the fluorescence to 28.3% of control, and the pre-treatment with TV3326 or rasagiline (0.1 -10 mM) prevented the fluorescence reduction, as summarized in The present study on the structure-activity relationship among propargylamines studied shows that the propargyl moiety is responsible for the anti-apoptotic activity. The presence of the carbamate moiety in TV3326 and TV3279, did not affect the antiapoptotic function associated with rasagilin

The New Inhibitor of Monoamine Oxidase, M30, has a Neuroprotective Effect Against Dexamethasone-Induced Brain Cell Apoptosis

Stress detrimentally affects the brain and body and can lead to or be accompanied by depression. Although stress and depression may contribute to each other, the exact molecular mechanism underlying the effects is unclear. However, there is a correlation between stress and an increase in glucocorticoid secretion which causes a subsequent increase in monoamine oxidase (MAO) activity during stress. Consequently, MAO inhibitors have been used as traditional antidepressant drugs. Cellular treatment with the synthetic glucocorticoid, dexamethasone (a cellular stressor), has been reported to markedly increase both MAO A and MAO B catalytic activities, as well as apoptosis. This study compares the neuroprotective abilities of M30 (a new generation inhibitor of both MAO A and MAO B) with rasagiline (Azilect®, another new MAO B inhibitor) and selegiline (Deprenyl®, a traditional MAO B inhibitor) in the prevention of dexamethasone-induced brain cell death and MAO activity in human neuroblastoma cells, SH-SY5Y. M30 demonstrated the highest inhibitory effect on MAO A; however, M30 showed the lowest inhibitory effect on MAO B enzymatic activity in comparison to rasagiline and selegiline. Although, M30 exhibited the greatest neuroprotective effect by decreasing cell death rates and apoptotic DNA damage compared to rasagiline and selegiline, these neuroprotective effects of M30 were, overall, similar to rasagiline. Summarily, M30 has a generally greater impact on neuroprotection than the MAO B inhibitors, selegiline and rasagiline. Our results suggest that M30 may have great potential in alleviating disorders involving increases in both MAO A and MAO B, such as stress-induced disorders

Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease

HIGHLIGHTS Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept®) but with limited therapeutic success. This might be due to the complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N -benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N -propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy

The effect of heat, inhibitors and riboflavin deficiency on monoamine oxidase.

Classification of the amine oxidase is at best beset with difficulties and it is important to define monoamine oxidase in such a manner that misunderstandings are reduced to a minimum. [...

A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson’s disease

The current novel therapeutic approach suggests that multi-targeted compounds, with diverse biological activities but a single set of bioavailability and pharmacokinetics, will be significantly more advantageous in the treatment of the complex pathology of Parkinson’s diseases (PD) than traditional therapies. This review introduces a novel cholinesterase (ChE)-monoamine oxidase (MAO) inhibitor, namely MT-031, which was designed by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor and neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the methylamino position of the ChE inhibitor anti-AD drug, rivastigmine. MT-031 possesses neuroprotective, cognition enhancing, anti-depressant, and anti-inflammatory properties both in vitro and in vivo. Altogether, these findings suggest that MT-031 may be a potential treatment for combating PD and associated dementia and depression