The protective effect of (S)-trolox–carnosine on a human neuroblastoma SH-SY5Y cell culture under the impact of heavy metals

Evaluation of the dose-dependent effects of heavy metals on the viability of a human neuroblastoma SH-SY5Y cell culture showed that 50% cell death was observed in the presence of 5 × 10–4 М lead, 5 × 10–6 М cadmium, 5 × 10–5 М cobalt, and 10–5 М molybdenum. The presence of these metals led to an increase in the level of reactive oxygen species (ROS) (from 39% to 74% in the cases of lead and cobalt, respectively). We revealed a cytoprotective effect against toxic heavy metals (HMs) of a new synthetic compound, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-β-alanyl-L-hystidine. This compound is a combination of carnosine with a water-soluble vitamin E analog, trolox (S-trolox–carnosine, S-TC). S-TC efficiently increased the cell viability in the presence of any of the studied metals, which correlated with a decrease in the proportion of necrotic cells and with efficient inhibition of ROS formation. Trolox also had a large cytoprotective effect under toxic conditions caused by lead, cadmium, and cobalt. The protective activity of carnosine under these conditions was significantly lower than the effects of trolox or trolox–carnosine. In general, these results revealed the greater cytoprotective effect of S-trolox–carnosine in the presence of heavy metals as compared to its precursors, trolox and carnosine. © 2016, Pleiades Publishing, Ltd

The protective effect of (S)-trolox–carnosine on a human neuroblastoma SH-SY5Y cell culture under the impact of heavy metals

Evaluation of the dose-dependent effects of heavy metals on the viability of a human neuroblastoma SH-SY5Y cell culture showed that 50% cell death was observed in the presence of 5 × 10–4 М lead, 5 × 10–6 М cadmium, 5 × 10–5 М cobalt, and 10–5 М molybdenum. The presence of these metals led to an increase in the level of reactive oxygen species (ROS) (from 39% to 74% in the cases of lead and cobalt, respectively). We revealed a cytoprotective effect against toxic heavy metals (HMs) of a new synthetic compound, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-β-alanyl-L-hystidine. This compound is a combination of carnosine with a water-soluble vitamin E analog, trolox (S-trolox–carnosine, S-TC). S-TC efficiently increased the cell viability in the presence of any of the studied metals, which correlated with a decrease in the proportion of necrotic cells and with efficient inhibition of ROS formation. Trolox also had a large cytoprotective effect under toxic conditions caused by lead, cadmium, and cobalt. The protective activity of carnosine under these conditions was significantly lower than the effects of trolox or trolox–carnosine. In general, these results revealed the greater cytoprotective effect of S-trolox–carnosine in the presence of heavy metals as compared to its precursors, trolox and carnosine. © 2016, Pleiades Publishing, Ltd

Carnosine prevents the development of oxidative stress under the conditions of toxic action of cadmium

Protective effect of the natural dipeptide carnosine on the antioxidant system of rats under conditions of oxidative stress caused by chronic cadmium administration was investigated. Oxidative status of experimental animals were evaluated based on a number of informative parameters of iron-induced chemiluminescence. It was shown that the introduction of cadmium for 7 days reduces the duration of the latent period of chemiluminescence in the brain, liver, and blood plasma suggesting the depletion of endogenous antioxidant defense. Coexposure to carnosine and cadmium led to significant increase in the level of antioxidant protection in plasma, liver, and brain of animals. Carnosine also prevented the increase of lipid hydroperoxides in the brain and prevented the development of lipid peroxidation content in liver and plasma of animals. Mechanism of the protective effect of carnosine under conditions of oxidative stress induced by cadmium administration was shown on human neuroblastoma SH-SY5Y cell culture. Addition of the cadmium to the incubation medium to a final concentration of 5 μM reduced cell viability of a culture, as was determined by MTT assay; simultaneous addition of carnosine (0.25 mM final concentration) with cadmium resulted in increased cell viability during 24 hours of incubation. Thus, carnosine in a final concentration of 1 mM effectively prevented the development of necrotic lesions of neuroblastoma cells, inhibiting the formation of reactive oxygen species as measured by flow cytometry. The results indicate the ability of carnosine to prevent the development of oxidative stress under the toxic action of cadmium. © 2016, Allerton Press, Inc

Carnosine prevents the development of oxidative stress under the conditions of toxic action of cadmium

Protective effect of the natural dipeptide carnosine on the antioxidant system of rats under conditions of oxidative stress caused by chronic cadmium administration was investigated. Oxidative status of experimental animals were evaluated based on a number of informative parameters of iron-induced chemiluminescence. It was shown that the introduction of cadmium for 7 days reduces the duration of the latent period of chemiluminescence in the brain, liver, and blood plasma suggesting the depletion of endogenous antioxidant defense. Coexposure to carnosine and cadmium led to significant increase in the level of antioxidant protection in plasma, liver, and brain of animals. Carnosine also prevented the increase of lipid hydroperoxides in the brain and prevented the development of lipid peroxidation content in liver and plasma of animals. Mechanism of the protective effect of carnosine under conditions of oxidative stress induced by cadmium administration was shown on human neuroblastoma SH-SY5Y cell culture. Addition of the cadmium to the incubation medium to a final concentration of 5 μM reduced cell viability of a culture, as was determined by MTT assay; simultaneous addition of carnosine (0.25 mM final concentration) with cadmium resulted in increased cell viability during 24 hours of incubation. Thus, carnosine in a final concentration of 1 mM effectively prevented the development of necrotic lesions of neuroblastoma cells, inhibiting the formation of reactive oxygen species as measured by flow cytometry. The results indicate the ability of carnosine to prevent the development of oxidative stress under the toxic action of cadmium. © 2016, Allerton Press, Inc

Neuroprotective effect of the carnosine – α-lipoic acid nanomicellar complex in a model of early-stage Parkinson's disease

In a model of early-stage Parkinson's disease induced by a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to Wistar rats, a neuroprotective effect of a new derivative of carnosine and α-lipoic acid (C/LA nanomicellar complex) was demonstrated. Acute intraperitoneal administration of carnosine, α-lipoic acid and C/LA complex following MPTP administration normalized the total antioxidant activity in the brain tissue. Of all the compounds tested only C/LA complex normalized the metabolism of dopamine (DA) and serotonin (5-HT), while its components did not show similar effects when used separately. C/LA complex effectively restored the level of DA metabolites: the level of DOPAC was increased by 24.7 ± 5.6% compared to the animals that had received MPTP only, and the level of HVA was restored to the values observed in the intact animals. Integral metabolic indices of DA (DOPAC/DA and HVA/DA ratios) and 5-HT turnover (5-HIAA/5-HT ratio) in the striatum tended to increase in case of C/LA complex administration. © 2018 Elsevier Inc

Изучение механизмов токсического действия уабаина на культуру клеток мозжечка крысы

Both endogenous and exogenous cardiotonic steroids (CTS), specific inhibitors of Na,K-ATPase, can evoke different physiological responses in the central nervous system by influencing synaptic transmission and intracellular signal cascades. In addition, they might participate in the development of neurodegenerative processes in the central nervous system. The toxicity of CTS for neurons has been shown earlier, but it has not been sufficiently characterized, and the mechanism of neuronal death has not been described in detail. In the present study it was shown that the viability of the primary cell culture of rat cerebellum under the action of 10 pM ouabain already decreases at 12 h of incubation and does not further decrease after 24 and 48 h of incubation, which suggests that this is a fast process, presumably apoptotic. At 12 h of incubation, the action of both toxic (10 pM) and nontoxic (1 pM) concentrations of ouabain leads to a shift in the ratio of apoptosis regulating proteins of the Bcl-2 family towards proapoptotic ones. At the same time, reducing the time of incubation of cells with 10 pM ouabain, but not with 1 pM ouabain, to 3 hours also leads to a decrease in the ratios of antiapoptotic proteins Bcl-2 and Bcl-xL to proapoptotic Bax and Bak, respectively, which indicates a fast development of apoptotic processes in response to ouabain neurotoxicity. Thus, it can be assumed that the effect of toxic concentrations of ouabain which cause neuronal death, is carried out through the mechanism of the mitochondrial apoptotic pathway.Изучены механизмы нейротоксического действия специфического ингибитора Na, К-АТФазы кардиотонического стероида уабаина. Показано, что уабаин в концентрации более 1 мкМ вызывает снижение жизнеспособности первичной культуры клеток мозжечка крысы при 12 ч инкубации; после 24 ч дальнейшее снижение жизнеспособности не наблюдается. При этом токсичные концентрации уабаина вызывают снижение отношения антиапоптотических белков семейства Bcl-2 к проапоптотическим

Neuroprotective effect of the carnosine – α-lipoic acid nanomicellar complex in a model of early-stage Parkinson's disease

In a model of early-stage Parkinson's disease induced by a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to Wistar rats, a neuroprotective effect of a new derivative of carnosine and α-lipoic acid (C/LA nanomicellar complex) was demonstrated. Acute intraperitoneal administration of carnosine, α-lipoic acid and C/LA complex following MPTP administration normalized the total antioxidant activity in the brain tissue. Of all the compounds tested only C/LA complex normalized the metabolism of dopamine (DA) and serotonin (5-HT), while its components did not show similar effects when used separately. C/LA complex effectively restored the level of DA metabolites: the level of DOPAC was increased by 24.7 ± 5.6% compared to the animals that had received MPTP only, and the level of HVA was restored to the values observed in the intact animals. Integral metabolic indices of DA (DOPAC/DA and HVA/DA ratios) and 5-HT turnover (5-HIAA/5-HT ratio) in the striatum tended to increase in case of C/LA complex administration. © 2018 Elsevier Inc

Carnosine as an effective neuroprotector in brain pathology and potential neuromodulator in normal conditions

Carnosine (b-alanyl-l-histidine) is an endogenous dipeptide widely distributed in excitable tissues, such as muscle and neural tissues—though in minor concentrations in the latter. Multiple benefits have been attributed to carnosine: direct and indirect antioxidant effect, antiglycating, metal-chelating, chaperone and pH-buffering activity. Thus, carnosine turns out to be a multipotent protector against oxidative damage. However, the role of carnosine in the brain remains unclear. The key aspects concerning carnosine in the brain reviewed are as follows: its concentration and bioavailability, mechanisms of action in neuronal and glial cells, beneficial effects in human studies. Recent literature data and the results of our own research are summarized here. This review covers studies of carnosine effects on both in vitro and in vivo models of cerebral damage, such as neurodegenerative disorders and ischemic injuries and the data on its physiological actions on neuronal signaling and cerebral functions. Besides its antioxidant and homeostatic properties, new potential roles of carnosine in the brain are discussed. © 2018, Springer-Verlag GmbH Austria, part of Springer Nature

Lipoylcarnosine: Synthesis, Study of Physico-Chemical and Antioxidant Properties, Biological Activity

Abstract—: Synthesis of lipoylcarnosine (LipС), a conjugated molecule based on two natural antioxidants, carnosine and α-lipoic acid, is described and its physico-chemical, antioxidant properties and biological activity are characterized. According to reversed-phase HPLC with a UV detector, purity of the final product was 89.3%. The individuality of the obtained sodium salt of LipС was confirmed by tandem HPLC-mass spectrometry. LipC demonstrated high resistance to hydrolysis with serum carnosinase. The antioxidant activity of LipC evaluated by the reaction with the formation of thiobarbituric acid reacting substances and kinetic parameters of iron-induced chemiluminescence was higher than that of carnosine and lipoic acid. LipC did not affect viability of SH-SY5Y human neuroblastoma cells, differentiated to the dopaminergic phenotype, at concentrations not exceeding 5 mM. In the concentration range of 0.1–0.25 mM LipC protected neuronal cells against 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity. © 2018, Pleiades Publishing, Ltd

Lipoilcarnosine: Synthesis, study of physico-chemical and antioxidant properties, biological activity

Synthesis of lipoilcarnosine (LipC) - a conjugated molecule based on two natural antioxidants, carnosine and a-lipoic acid, is described. Its physico-chemical, antioxidant properties and biological activity are characterized. According to reversed-phase HPLC with a UV detector, purity of the final product was 89.3%. The individuality of the obtained sodium salt of LipC was confirmed by tandem HPLC-mass spectrometry. High resistance of LipC to hydrolysis with serum carnosinase was demonstrated. The antioxidant activity of LipC measured by reaction with the formation of thiobarbituric acid reacting substances and kinetic parameters of iron-induced chemiluminescence was higher than that of carnosine and lipoic acid. LipC did not affect viability of SH-SY5Y human neuroblastoma culture cells, differentiated towards the dopaminergic type, at concentrations not exceeding 5 mM. At the concentration range of 0.1-0.25 mM LipC protected neuronal cells against 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity. © 2018 Russian Academy of Medical Sciences. All rights reserved