Monoamine oxidase A upregulated by chronic intermittent hypoxia activates indoleamine 2,3-dioxygenase and neurodegeneration

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M30 Antagonizes Indoleamine 2,3-Dioxygenase Activation and Neurodegeneration Induced by Corticosterone in the Hippocampus

Monoamine oxidases (MAO), downstream targets of glucocorticoid, maintain the turnover and homeostasis of monoamine neurotransmitters; yet, its pathophysiological role in monoamine deficiency, oxidative stress and neuroinflammation remains controversial. Protective effects of M30, a brain selective MAO inhibitor with iron-chelating antioxidant properties, have been shown in models of neurodegenerative diseases. This study aims to examine the neuroprotective mechanism of M30 against depressive-like behavior induced by corticosterone (CORT). Sprague-Dawley rats were given CORT subcutaneous injections with or without concomitant M30 administration for two weeks. CORT-treated rats exhibited depressive-like behavior with significant elevated levels of MAO activities, serotonin turnover, oxidative stress, neuroinflammation and apoptosis in the hippocampus with significant losses of synaptic proteins when compared to the control. The expression and activity of cytokine-responsive indoleamine 2,3-dioxygenase (IDO-1), a catabolic enzyme of serotonin and tryptophan, was significantly increased in the CORT-treated group with lowered levels of serotonin. Besides, CORT markedly reduced dendritic length and spine density. Remarkably, M30 administration neutralized the aberrant changes in the hippocampus and prevented the induction of depressive-like behavior induced by CORT. Our results suggest that M30 is neuroprotective against CORT-induced depression targeting elevated MAO activities that cause oxidative stress and neuroinflammation, resulting in IDO-1 activation, serotonin deficiency and neurodegeneration.published_or_final_versio

A Novel Antioxidant Multitarget Iron Chelator M30 Protects Hepatocytes against Ethanol-Induced Injury

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Physiological and pathological aspects of Aβ in iron homeostasis via 5'UTR in the APP mRNA and the therapeutic use of iron-chelators

Many studies have highlighted the pathological involvement of iron accumulation and iron-related oxidative stress (OS) in Alzheimer's disease (AD). Iron was further demonstrated to modulate expression of the Alzheimer's amyloid precursor holo-protein (APP) by a mechanism similar to that of regulation of ferritin-L and -H mRNA translation through an iron-responsive element (IRE) in their 5' untranslated regions (UTRs). Here, we discuss two aspects of the link between iron and AD, in relation to the recently discovered IRE in the 5'UTR of APP mRNA. The first is the physiological aspect: a compensatory neuroprotective response of amyloid-β protein (Aβ) in reducing iron-induced neurotoxicity. Thus, given that Aβ possesses iron chelation sites, it is hypothesized that OS-induced intracellular iron may stimulate APP holo-protein translation (via the APP 5'UTR) and subsequently the generation of its cleavage product, Aβ, as a compensatory response that eventually reduces OS. The second is the pathological aspect: iron chelating compounds target the APP 5'UTR and possess the capacity to reduce APP translation, and subsequently Aβ levels, and thus represent molecules with high potential in the development of drugs for the treatment of AD

The iron-chelating drug M30 down-regulates carbon tetrachloride (CCI4)-induced hepatic oxidative stress, inflammation and apoptosis in vitro

Topic: 2 Acute Liver FailureThis journal suppl. entitled: APASL Liver Week 2013BACKGROUND/AIMS: The novel multifunctional brain permeable ironchelator M30 possesses neuroprotective activities against several insults applicable to various neurodegenerative diseases. However, the effect of M30 on CCl4 induced acute liver damage is still unknown. The aim of this study is to investigate whether the multifunctional drug M30 could ameliorate CCl4 induced hepatic injury in human HepG2 cell line. METHODS: HepG2 cells were grown in DMEM supplemented with ...postprin

Monoamine oxidase A expression is vital for embryonic brain development by modulating developmental apoptosis

Monoamine oxidases (MAO-A, MAO-B) metabolize biogenic amines and have been implicated in neuronal apoptosis. Although apoptosis is an important process in embryo development, the role of MAO isoenzymes has not been investigated in detail. We found that expression of MAO-A and MAO-B can be detected early on during embryo development. Expression levels remained constant until around midgestation but then dropped to almost undetectable levels toward birth. Similar expression kinetics were observed in the brain. Isoform-specific expression silencing of MAO-A mediated by siRNA during in vitro embryogenesis induced developmental defects, as indicated by a reduction of the crown rump length and impaired cerebral development. These alterations were paralleled by elevated serotonin levels. Similar abnormalities were observed when embryos were cultured in the presence of the MAO-A inhibitor clorgyline or when the transcriptional inhibitor of MAO-A expression Rl was overexpressed. In contrast, no such alterations were detected when expression of MAO-B was knocked down. To explore the underlying mechanisms for the developmental abnormalities in MAO-A knockdown embryos, we quantified the degree of developmental apoptosis in the developing brain. MAO-A knockdown reduced the number of apoptotic cells in the neuroepithelium, which coincided with impaired activation of caspases 3 and 9. Moreover, we observed reduced cyclin Dl levels as an indicator of impaired cell proliferation in MAO-A knockdown embryos. This data highlights MAO-A as a vital regulator of embryonic brain development

Why Do We Need Multifunctional Neuroprotective and Neurorestorative Drugs for Parkinson's and Alzheimer's Diseases as Disease Modifying Agents

Parkinson's disease (PD) and Alzheimer's Disease (AD) are severe neurodegenerative disorders, with no drugs that are currently approved to prevent the neuronal cell loss characteristic in brains of patients suffering from PD and AD and all drug treatment are synptomactic. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events that results in neuronal death and predisposition to depression and eventual dementia and etiology of these disorders, an innovative approach towards neuroprotection or neurorestoration (neurorescue) may be the development and use of multifunctional pharmaceuticals. Such drugs target an array of pathological pathways, each of which is believed to contribute to the cascades that ultimately lead to neuronal cell death. In this short review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorestorative therapeutics in PD and AD. The compounds discussed originate from synthetic chemistry as well as from natural sources

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

Selegiline : a molecule with innovative potential

Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on-off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson's disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors

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