Monoamine oxidase inhibitors, and iron chelators in depressive illness and neurodegenerative diseases.

In early 1920s, tyramine oxidase was discovered that metabolized tyramine and in 1933 Blaschko demonstrated that this enzyme also metabolized adrenaline, noradrenaline and dopamine. Zeller gave it the name monoamine oxidase (MAO) to distinguish it from the enzyme that oxidatively deaminated diamines. MAO was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamines (and, later, 5-hydroxytryptamine, as well).

Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.

Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice.

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral β-amyloid plaques.

Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment.

Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity.

Novel therapeutic approach for neurodegenerative pathologies: multitarget iron-chelating drugs regulating hypoxia-inducible factor 1 signal transduction pathway.

Our novel multimodal brain-permeable iron-chelating compounds M30 and HLA20 were demonstrated to possess neuroprotective/neurorescue activities in vitro and in vivo against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent reactive oxygen species generation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron-chelating compounds is associated with their ability to regulate the transcriptional activator hypoxia-inducible factor 1 (HIF-1).

Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain.

The novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the present study, we demonstrate that systemic chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1α protein levels in various brain regions (e.g.

Iron-chelating backbone coupled with monoamine oxidase inhibitory moiety as novel pluripotential therapeutic agents for Alzheimer's disease: a tribute to Moussa Youdim.

It is for these authors a great privilege to dedicate this review article to Moussa Youdim, who is one of the most imperative pharmacologists and pioneer investigators in the search and development of novel therapeutics for neurodegenerative diseases. 40 years ago, Moussa Youdim has started studying brain iron, catecholamine receptor and monoamine oxidase (MAO)-A and -B functions. Although Moussa Youdim succeeded in exploring the novel anti-Parkinsonian, selective MAO-B inhibitor drug, rasagiline (Azilect, Teva Pharmaceutical Co.

Does 1-(R)-aminoindan possess neuroprotective properties against experimental Parkinson's disease?

The anti-Parkinsonian, monoamine oxidase-B inhibitor drug, rasagiline (Azilect®), is primarily metabolized by hepatic cytochrome P450 isoenzyme 1A2-mediated N-dealkylation to form its major metabolite, 1-(R)-aminoindan. The present study was undertaken to further investigate, for the first time, the possible neuroprotective effect of 1-(R)-aminoindan in two rat models of Parkinson's disease, the 6-hydroxydopamine- and lactacystin (a proteasomal inhibitor)-induced nigrostriatal degeneration. 1-(R)-aminoindan reversed behavioral asymmetry and restored striatal catecholamine levels in these two rat models and significantly protected neurons from hydrogen peroxide-induced oxidative stress.

Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein precursor: involvement of MAPK and PKC activation.

The anti-Parkinsonian, irreversible, selective monoamine oxidase (MAO)-B inhibitors, selegiline (deprenyl, (R)-N-methyl-N-(1-phenylpropan-2-yl) prop-2-yn-1-amine) and rasagiline (Azilect, N-propargyl-1(R)-aminoindan), have been proven to possess neuroprotective/neurorestorative activities in cell cultures and animal models of neurodegenerative diseases. Structure-activity studies provide evidence that neuroprotection is associated with some intrinsic pharmacological action of the propargylamine moiety in these drugs. This indication and recent therapeutic approaches, entailing new drug candidates possessing diverse pharmacological properties and acting on multiple targets, have stimulated the development of two multifunctional chimeric propargylamine-derivatives: 1) ladostigil (TV3326, [(N-propargyl-(3R) 1-(R)-aminoindan-5yl)-ethyl methyl carbamate)], which combines the pharmacophore of rasagiline, with the carbamate moiety of the cholinesterase inhibitor rivastigmine, as a potential treatment for Alzheimer's disease and Lewy body disease; and 2) M30 5-[(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], where the propargylamine moiety of rasagiline was embedded onto the backbone of the neuroprotective and brain permeable iron chelator 8-hydroxyquinoline-derivative, VK28 as a potential treatment for various neurodegenerative disorders.

Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration.

Water-soluble iron, and manganese(III) complexes of corroles and porphyrins were examined with regard to their neuroprotective/neurorescue activities by using various neuronal cytotoxic models of oxidative and nitrative stress. The present study demonstrates that the metallocorroles significantly protect human neuroblastoma SH-SY5Y and mouse motor neuron-neuroblastoma fusion NSC-34 cell lines against neurotoxicity induced by either the peroxynitrite donor 3-morpholinosydnonimine or the parkinsonism-related neurotoxin 6-hydroxydopamine. The neuronal survival effect is further reflected by the prevention of 3-morpholinosydnonimine-induced protein nitration, inhibition of caspase 3 activation, as well as attenuation of 6-hydroxydopamine-mediated decrease in growth associated protein-43 levels.

Neuroprotective multifunctional iron chelators: from redox-sensitive process to novel therapeutic opportunities.

Accumulating evidence suggests that many cytotoxic signals occurring in the neurodegenerative brain can initiate neuronal death processes, including oxidative stress, inflammation, and accumulation of iron at the sites of the neuronal deterioration. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent hydroxyl radical formation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron chelators is associated with their ability to upregulate or stabilize the transcriptional activator, hypoxia-inducible factor-1alpha (HIF-1alpha).

Up-regulation of hypoxia-inducible factor (HIF)-1α and HIF-target genes in cortical neurons by the novel multifunctional iron chelator anti-Alzheimer drug, M30.

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelator, M30, possessing the neuroprotective propargylamine moiety of the anti-Parkinsonian drug, rasagiline (Azilect) and antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of our iron chelator, VK28. M30 was recently found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models and regulate the levels and processing of the Alzheimer's amyloid precursor protein and its toxic amyloidogenic derivative, Abeta. Here, we show that M30 activates the hypoxia-inducible factor (HIF)-1alpha signaling pathway, thus promoting HIF-1alpha mRNA and protein expression levels, as well as increasing transcription of HIF-1alpha-dependent genes, including vascular endothelial growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat primary cortical cells.

The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline.

The anti-parkinsonian drug, rasagiline [N-propargyl-1-(R)-aminoindan; Azilect(R)], is a secondary cyclic benzylamine and indane derivative, which provides irreversible, potent monoamine oxidase-B (MAO-B) inhibition and possesses neuroprotective and neurorestorative activities. A prospective clinical trial has shown that rasagiline confers significant symptomatic improvement and demonstrated alterations in Parkinson's disease progression. Rasagiline is primarily metabolized by hepatic cytochrome P-450 to form its major metabolite, 1-(R)-aminoindan, a non-amphetamine, weak reversible MAO-B inhibitor compound.

Genomic and proteomic study to survey the mechanism of action of the anti-Parkinson's disease drug, rasagiline compared with selegiline, in the rat midbrain.

The novel anti-Parkinson's disease (PD) drug, rasagiline (N-propargyl-1-(R)-aminoindan), is a second generation of irreversible selective inhibitor of monoamine oxidase-B follows selegiline. In light of the recent large clinical study (phase III ADAGIO) reporting benefits in PD patients, it has been suggested that rasagiline could be the first PD treatment to receive the label neuroprotective "disease-modifying" drug. Indeed, rasagiline has been shown to have a broad neuroprotective activity against a variety of neurotoxins in preclinical models of neurodegenerative diseases and in cultured neuronal cells.

Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer's disease drugs.

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 the multimodal drugs, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuroprotective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine.

Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus.

While iron deficiency is not perceived as a life threatening disorder, it is the most prevalent nutritional abnormality in the world, and a better understanding of modes and sites of action, can help devise better treatment programs for those who suffer from it. Nowhere is this more important than in infants and children that make up the bulk of iron deficiency in society. Although the effects of iron deficiency have been extensively studied in systemic organs, until very recently little attention was paid to its effects on brain function.

The novel cholinesterase-monoamine oxidase inhibitor and antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells and aged rats.

The current therapeutic advance in which future drugs are designed to possess varied pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326; (N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase (MAO)-A and MAO-B and cholinesterase (ChE) inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy body disease. In the present study, we demonstrate that ladostigil (10(-6)-10 muM) dose-dependently increased cell viability, associated with increased activity of catalase and glutathione reductase and decrease of intracellular reactive oxygen species production in a cytotoxic model of human SH-SY5Y neuroblastoma cells exposed to hydrogen peroxide (H(2)O(2)).

The neuroprotective effect of ladostigil against hydrogen peroxide-mediated cytotoxicity.

The multifunctional, anti-Alzheimer drug, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] combines the neuroprotective effects of the anti-Parkinson drug, rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule. Ladostigil has been shown to possess potent antiapoptotic and neuroprotective activities in various oxidative insults in vitro and in vivo, such as prevention of the fall in mitochondrial membrane potential and regulation of Bcl-2 family proteins. In the present study, we demonstrate that ladostigil (1 microM) increased cell viability, associated with the increase of catalase activity and decrease of intracellular reactive oxygen species (ROS) production in human SH-SY5Y neuroblastoma cells exposed to (hydrogen peroxide) H(2)O(2).

The neuroprotective mechanism of action of the multimodal drug 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 the multimodal drug, ladostigil (TV3326) ((N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase -A and -B and cholinesterase inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease. Preclinical studies show that ladostigil has antidepressant and anti-AD activities and the clinical development is planned for these dementias.

The application of proteomics for studying the neurorescue activity of the polyphenol (-)-epigallocatechin-3-gallate.

Accumulating evidence suggests that oxidative stress resulting in reactive oxygen species generation plays a pivotal role in neurodegenerative diseases, supporting the realization of the use of radical scavengers, metal chelator agents, such as the natural polyphenols for therapy. In this study, we have focused on specific identification of proteins involved in the neurorescue activity of the green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG) in a progressive model of neuronal death, induced by long-term serum deprivation of human neuroblastoma SH-SY5Y cells. The study was designed in attempt to define biomarkers for the mechanism of action of EGCG, associated with its iron chelating properties and its ability to regulate metabolic energy balance and affect cell morphology.

Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative disorders, although there is no drug or therapeutic treatment to demonstrate disease-modifying effects. Previous work has proposed that neurodegeneration is linked to a lack of trophic support in those neurons and brain areas associated with PD and AD. Indeed, previous studies have found that neurotrophic factors (NTFs) support neuronal survival in various cellular and animal models of PD and AD.

A model of MPTP-induced Parkinson's disease in the goldfish.

Parkinson's disease (PD) has been modeled in humans, lower primates, and to a lesser extent in some other vertebrates by the administration of the potent neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). The MPTP model has thus drawn considerable attention during the past 15 years, as a system to search for anti-PD drugs. It has been previously reported that a Parkinsonian syndrome can be elicited in the common goldfish (Carassius auratus) by a single dose of MPTP.

The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases.

Activin is a member of the transforming growth factor-beta superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- [either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1)] induced neuronal death in human SH-SY5Y neuroblastoma cells.

A novel approach of proteomics and transcriptomics to study the mechanism of action of the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin-3-gallate.

Previous findings suggest that the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) may have a neurorescue impact in aging and neurodegenerative diseases to retard or even reverse the accelerated rate of neuronal degeneration. The present study sought a deeper elucidation of the molecular neurorescue activity of EGCG in a progressive neurotoxic model of long-term serum deprivation of human SH-SY5Y neuroblastoma cells. In this model, proteomic analysis revealed that EGCG (0.