Antioxidant action of the hexahydropyridoindole SMe1EC2 in the cellular system of isolated red blood cells<i>in vitro</i>

Štefek, Milan; Milackova, Ivana; Juskova-Karasova, Maria; Snirc, Vladimir

doi:10.1179/1351000213y.0000000043

Cited by 14 publications

(15 citation statements)

References 22 publications

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“…In membranes, however, the relative reactivities may be different since they are determined also by additional factors such as location of the antioxidant and radicals, ruled predominantly by their actual distribution ratios between water and lipid compartments. As we reported earlier (Stefek et al , 2013 ), SMe1EC2 and stobadine have similar lipophilicities, characterized by the corresponding log P values of 1.95 and 1.79, respectively. Yet their actual distribution ratios at pH 7.4 were shown to differ profoundly (calculated log D SMe1EC2 =1.78 vs. calculated log D stobadine =–0.05) as a result of basicity variance of SMe1EC2 vs. stobadine, characterized by respective pKa values, –3.7 vs. 8.5.…”

Section: Discussionsupporting

confidence: 83%

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Antioxidant action of SMe1EC2, the low-basicity derivative of the pyridoindole stobadine, in cell free chemical models and at cellular level

Balcerczyk

Bartosz

Drzewińska

et al. 2014

Interdisciplinary Toxicology

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The aim of the study was to evaluate the antioxidant action of SMe1EC2, the structural analogue of the hexahydropyridoindole antioxidant stobadine. The antiradical activity of SMe1EC2 was found to be higher when compared to stobadine, as determined both in cell-free model systems of AAPH-induced oxidation of dihydrorhodamine 123 and 2′,7′-dichloro-dihydrofluorescein diacetate, and in the cellular system of stimulated macrophages RAW264.7. Analysis of proliferation of HUVEC and HUVEC-ST cells revealed absence of cytotoxic effect of SMe1EC2 at concentrations below 100 µM. The antioxidant activity of SMe1EC2, superior to the parent drug stobadine, is accounted for by both the higher intrinsic free radical scavenging action and by the better bioavailability of the low-basicity SMe1EC2 relative to the high-basicity stobadine.

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Section: Discussionsupporting

confidence: 83%

“…In our previous study (Stefek et al , 2013 ), on applying a DPPH test, we reported efficient free radical scavenging activity of SMe1EC2, comparable with that of the standard trolox. In the cellular system of isolated erythrocytes, SMe1EC2 protected red blood cells against free-radical-initiated hemolysis.…”

Section: Introductionmentioning

confidence: 57%

Antioxidant action of SMe1EC2, the low-basicity derivative of the pyridoindole stobadine, in cell free chemical models and at cellular level

Balcerczyk

Bartosz

Drzewińska

et al. 2014

Interdisciplinary Toxicology

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“…Anti-infl ammatory and anti-oxidative effects with high free radicals scavenging activity is also known for SMe1EC2 (38,39). Both atorvastatin and SMe1EC2 can thus protect the heart from excessive oxidative damage following ischemia/reperfusion injury.…”

Section: Tab 3 Occurrence Of Ventricular Arrhythmia In Animals Amonmentioning

confidence: 99%

Anti-arrhythmic and cardio-protective effects of atorvastatin and a potent pyridoindole derivative on isolated hearts from rats with metabolic syndrome

Lipták¹,

Knézl²,

Gaspárová³

2019

BLL

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OBJECTIVES: Aims of this study were to investigate the anti-arrhythmic and cardio-protective effect of atorvastatin and of a new pyridoindole derivative (SMe1EC2) on isolated and perfused hearts while following the Langendorff principles. BACKGROUND: Metabolic syndrome is a widely distributed condition progressing to cardiovascular disease. Many of the metabolic syndrome patients take (HMG)-co-enzyme A (CoA) reductase inhibitors with potential cardioprotective effects. SMe1EC2 is a promising new drug, exerting many positive effects in experimental settings. METHODS: Rats with induced metabolic syndrome were treated with atorvastatin (25 mg/kg) and SMe1EC2 (25 mg/kg and 0.5 mg/kg, respectively) daily for 3 weeks. After the treatment, the hearts were isolated and perfused according to Langendorff. RESULTS: Both atorvastatin and SMe1EC2 improved cardiac function by elevating the left ventricular developed pressure (VLDP) and cardiac contractility. Both SMe1EC2-treated groups improved LVDP during reperfusion, signifi cantly increased-dP/dt, and moderately elevated +dP/dt values. The treatment with both atorvastatin and SMe1EC2 (25 mg/kg) signifi cantly reduced malignant arrhythmia in comparison to control group and group treated with SMe1EC2 0.5 mg/kg. CONCLUSIONS: Owing to its anti-arrhythmic and cardio-protective effects, atorvastatin and SMe1EC2 could be of benefi t to patients suffering from metabolic syndrome (Tab.

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“…SMe1EC2 had high intrinsic scavenging activity as measured with 1,1TM-diphenyl-2-picrylhydrazyl (DPPH) (Stefek et al, 2013 ). The initial velocity of DPPH decolorization by 50 μM SMe1EC2 (0.507 ± 0.003 optical density(OD)/min) was comparable with that of equimolar trolox (0.494 ± 0.009 OD/min).…”

Section: Antioxidant Properties In An Example Mtdlmentioning

confidence: 99%

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

et al. 2016

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HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases.Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to “dirty drugs” for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress toward strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent met...

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Antioxidant action of the hexahydropyridoindole SMe1EC2 in the cellular system of isolated red blood cellsin vitro

Cited by 14 publications

References 22 publications

Antioxidant action of SMe1EC2, the low-basicity derivative of the pyridoindole stobadine, in cell free chemical models and at cellular level

Antioxidant action of SMe1EC2, the low-basicity derivative of the pyridoindole stobadine, in cell free chemical models and at cellular level

Anti-arrhythmic and cardio-protective effects of atorvastatin and a potent pyridoindole derivative on isolated hearts from rats with metabolic syndrome

Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration

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