A A Boldyrev

Russian Academy of Medical Sciences, Moskva, Moscow, Russia

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Publications (243)273.22 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Two novel derivatives of carnosine--(S)-trolox-L-carnosine (STC) and (R)-trolox-L-carnosine (RTC) are characterized in terms of their antioxidant and membrane-stabilizing activities as well as their resistance to serum carnosinase. STC and RTC were synthesized by N-acylation of L-carnosine with (S)- and (R)-trolox, respectively. STC and RTC were found to react more efficiently with 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and protect serum lipoproteins from Fe(2+)-induced oxidation more successfully than carnosine and trolox. At the same time, STC, RTC and trolox suppressed oxidative hemolysis of red blood cells (RBC) less efficiently than carnosine taken in the same concentration. When oxidative stress was induced in suspension of cerebellum granule cells by their incubation with N-methyl-D-aspartate (NMDA), or hydrogen peroxide (H(2)O(2)), both STC and RTC more efficiently decreased accumulation of reactive oxygen species (ROS) than carnosine and trolox. Both STC and RTC were resistant toward hydrolytic degradation by human serum carnosinase. STC and RTC were concluded to demonstrate higher antioxidant capacity and better ability to prevent cerebellar neurons from ROS accumulation than their precursors, carnosine and trolox.
    Cellular and Molecular Neurobiology 10/2009; 30(3):395-404. · 2.29 Impact Factor
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    ABSTRACT: The validity of the free radical theory of aging has been recently questioned. Our aim was to test whether there is oxidative stress in tissues critically involved in accelerated aging (senescence-accelerated mice, SAM) and whether this correlates with lower glucose consumption in vivo and behavioural tests. Positron emission tomography shows that brains of old SAM-prone animals consume less glucose than young ones. Behavioural characteristics, mitochondrial peroxide production, and damage in both the central nervous system and bone marrow stem cells also indicate that SAM-prone animals age faster than SAM-resistant ones. Our results support the role of the free radical theory of aging in critical tissues involved in aging and that this correlates with glucose consumption.
    FEBS letters 07/2009; 583(13):2287-93. · 3.54 Impact Factor
  • A A Boldyrev
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    ABSTRACT: Hyperhomocysteinemia is a risk factor for a number of cardiovascular and neurodegenerative processes as well as a complicating factor in normal pregnancy. Toxic effects of homocysteine and the product of its spontaneous oxidation, homocysteic acid, are based on their ability to activate NMDA receptors, increasing intracellular levels of ionized calcium and reactive oxygen species. Even a short-term exposure of cells to homocysteic acid at concentrations characteristic of hyperhomocysteinemia induces their apoptotic transformation. The discovery of NMDA receptors both in neuronal tissue and in several other tissues and organs (including immunocompetent cells) makes them a target for toxic action of homocysteine. The neuropeptide carnosine was found to protect the organism from homocysteine toxicity. Treatment of pregnant rats with carnosine under conditions of alimentary hyperhomocysteinemia increases viability and functional activity of their progeny.
    Biochemistry (Moscow) 07/2009; 74(6):589-98. · 1.15 Impact Factor
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    ABSTRACT: Effects of N-methyl-D-aspartate (NMDA), aluminum and amyloid-β (Aβ) on mouse cerebellar granule cells were studied. In the presence of all three compounds, reactive oxygen species levels and cell necrosis were increased dramatically. Mg2+ ions and D-AP5, which are known to prevent ligand binding to NMDA-activated glutamate receptors, were effective in attenuating the neurotoxic effect induced by the presence of all three compounds. All substances tested induced activation of p42/44 MAPK (mitogen activated protein kinase) with no cumulative effects between them. We conclude that neurotoxicity induced by aluminum and Aβ appears at outer cell membranes and NMDA receptors take part in this process. Increase in excitotoxic effect of glutamate in the presence of aluminum and Aβ is suggested to be a factor which provokes Alzheimer’s disease in brain neurons.
    Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology 01/2009; 3(4):425-430.
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    ABSTRACT: The addition of the neuropeptide carnosine (beta-alanyl-L-histidine) as a food additive to the basic protocol of Parkinson's disease treatment results in significant improvement of neurological symptoms, along with increase in red blood cell Cu/Zn-SOD and decrease in blood plasma protein carbonyls and lipid hydroperoxides, with no noticeable change in platelets MAO B activity. The combination of carnosine with basic therapy may be a useful way to increase efficiency of PD treatment.
    Rejuvenation Research 09/2008; 11(4):821-7. · 2.92 Impact Factor
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    ABSTRACT: Prenatal hyperhomocysteinemia induced in rats by overloading of dietary methionine (1 g/kg body mass daily) results in systemic disordering in progeny related to an increase in the excitotoxic feature of NMDA-receptors in cerebellar neurons and memory suppression. Administration of carnosine (100 mg/kg body mass daily) in the diet of pregnant rats with hyperhomocysteinemia prevents both cognitive function in pups and protects cerebellar neurons from oxidative stress. The effect of carnosine is accompanied by with the restoration of superoxide dismutase in rat brain, which is decreased during hyperhomocysteinemia from 2.07 units (control) to 1.54 units.
    Neurochemical Journal 08/2008; 2(3):202-208. · 0.24 Impact Factor
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    ABSTRACT: We evaluated possible therapeutic effect of multipotent mesenchymal stromal cells from human adipose tissue differentiated to neuronal phenotype with retinoic acid on Wistar rats subjected to toxic effect of 3-nitropropionic acid. Transplantation of mesenchymal stromal cells from human adipose tissue considerably decreased neurological symptoms, normalized exploratory activity (open field test) and long-term memory (Morris test), which correlated with normalization of pathomorphological manifestations in the brain. Destructive changes in the caudate nucleus caused by treatment with 3-nitropropionic acid (reduced size of neurons, changes in their shape, and cell edema) tended to decrease under the effect of multipotent mesenchymal stromal cells: the area of neurons increased 2-fold, the cells acquired typical round shape, cell edema decreased.
    Bulletin of Experimental Biology and Medicine 05/2008; 145(4):514-9. · 0.34 Impact Factor
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    ABSTRACT: The cardioprotective effect of cardioplegic solution based on histidine-containing dipeptides was evaluated on isolated rat heart under conditions of hyporthermia and long ischemia. The use of natural dipeptides in cardioplegic solutions promoted an increase in the buffer capacity of myocardial cells and creation of an additional anti-ischemic effect under conditions of long ischemia and hypothermia.
    Bulletin of Experimental Biology and Medicine 04/2008; 145(3):323-7. · 0.34 Impact Factor
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    ABSTRACT: In this work, we demonstrate that homocysteic acid provokes oxidative stress in erythrocytes and decreases their hemolytic resistance, whereas the natural antioxidant carnosine [9] protects erythrocytes from its toxic effect. The discovered property can be used for development of new methods for protecting erythrocytes in hyperhomocysteinemia. Homocysteine and homocysteic acid (HCA), the product of spontaneous homocysteine oxidation, are important risk factors for neurodegenerative and cardiovascular diseases [1]. These compounds induce oxidative stress in brain neurons [2, 3] and lymphocytes [4], resulting from their toxic effect on the nervous and immune systems. The prooxidant effect of homocysteine and homocysteic acid on cell structures can be realized via both the glutamate receptors [3, 4] and the activation of NO synthase or inhibition of Na/KATPase, as was demonstrated for the vascular endothelium [5, 6]. It is known that erythrocytes are capable of accumulating homocysteine and excreting it into the extracellular medium [7, 8]. Erythrocytes constitute the main part of blood cells; correspondingly, the toxic effect of homocysteine and HCA may cover these cells as well. However, the effect of these compounds on the erythrocyte stability has not been studied. The goal of this work was to analyze the effect of HCA on human erythrocytes and to assess the effect of carnosine on the oxidative stress in erythrocytes caused by HCA. Various factors can cause erythrocyte hemolysis, including a decreased ambient osmotic pressure, decreased pH, and oxidants [10‐12]. The resistance of erythrocytes to hemolytic action is an integral parameter characterizing their integrity and viability as well as a criterion of their physiologically native state. Two models of hemolysis were used in this work, namely, the osmotic hemolysis and the hemolysis caused by hydrochloric acid. The former takes place with a decrease in the tonicity of medium produced by diluting cell suspension with distilled water. In this process, cells swell with subsequent disruption of the cell membrane. The latter is induced by supplementing cell suspension with hydrochloric acid, which leads to a decrease in the pH in the cytoplasm, impairments in the cytoskeleton structure, and, eventually, cell swelling and destruction [13].
    Doklady Biochemistry and Biophysics 01/2008; 418:44-6. · 0.32 Impact Factor
  • E. E. Akkuratov, L. V. Karpova, A. A. Boldyrev
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    ABSTRACT: Activity of Na/K-ATPase isolated from bovine brain and kidney decreases during incubation with hydrogen peroxide proportionally to the incubation time and the concentration of the oxidant. Activity suppression is accompanied by a proportional decrease in the level of free SH-groups. Incubation of the oxidized enzyme with dithiothreitol restores the enzyme activity. Na-conformation of the enzyme is more resistant to oxidation, whereas its conversion to the K-form increases its sensitivity to H2O2. Involvement of different conformational states of the enzyme in intracellular signaling, which occurs with the participation of active forms of oxygen, is discussed.
    Neurochemical Journal 01/2008; 2(1):127-130. · 0.24 Impact Factor
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    ABSTRACT: Known experimental models of Parkinson's Disease (PD) are limited by nonsimultaneous expression of physiological and biochemical features. We described a novel PD model consisting of N-methyl,4-phenyl-tetrahydropyridine (MPTP) treatment of Senescence Accelerated Mice (SAM) characteristic of increased level of reactive oxygen species aggravated by deficiency of antioxidant defense system. MPTP treatment was found to suppress locomotion and enhance the nonmotivated behavior (grooming); short-term tremor and apparent rigidity were also noted. MPTP effect was accompanied with increased level of protein carbonyls and lipid hydroperoxides indicating numerous disorders in antioxidant defense system. The brain of MPTP treated animals demonstrated higher MAO B activity and low level of SOD. Brain of control animals treated with MPTP was demonstrated by unchanged MAO B and two times decreased SOD activity; behavioral alterations in these mice being less manifested than that of SAM animals. The data presented showed that MPTP treated SAM animals are perspective model for Parkinson's disease study.Acknowledgements: The work is supported by RFBR (## 99-04-49420; 00-04-48767).
    Journal of Neurochemistry 01/2008; 81:60-63. · 3.97 Impact Factor
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    ABSTRACT: Adjustment of the Na/K ATPase activity to changes in oxygen availability is a matter of survival for neuronal cells. We have used freshly isolated rat cerebellar granule cells to study oxygen sensitivity of the Na/K ATPase function. Along with transport and hydrolytic activity of the enzyme we have monitored alterations in free radical production, cellular reduced glutathione, and ATP levels. Both active K(+) influx and ouabain-sensitive inorganic phosphate production were maximal within the physiological pO(2) range of 3-5 kPa. Transport and hydrolytic activity of the Na/K ATPase was equally suppressed under hypoxic and hyperoxic conditions. The ATPase response to changes in oxygenation was isoform specific and limited to the alpha1-containing isozyme whereas alpha2/3-containing isozymes were oxygen insensitive. Rapid activation of the enzyme within a narrow window of oxygen concentrations did not correlate with alterations in the cellular ATP content or substantial shifts in redox potential but was completely abolished when NO production by the cells was blocked by l-NAME. Taken together our observations suggest that NO and its derivatives are involved in maintenance of high Na/K ATPase activity under physiological conditions.
    The Journal of General Physiology 11/2007; 130(4):389-98. · 4.73 Impact Factor
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    ABSTRACT: The system of NMDA glutamate receptors in human adipose tissue multipotent stromal cells and SH-SY5Y human neuroblastoma cells was used as a model for studies of NMDA receptor expression during neurodifferntiation. Glutamate NMDA receptors were detected in multipotent stromal cells of human adipose tissue. The expression of NRI subunits of NMDA receptors increased significantly after 6-day incubation of multipotent stromal cells of human adipose tissue with 10 microM retinoic acid. Only NR1 subunits of NMDA receptors were expressed in SH-SY5Y neuroblastoma cells. Incubation with retinoic acid did not promote the appearance of mRNA of other subunits (NR2A-D, NR3). The results indicate that expression of NMDA receptors can serve as an indicator of neuronal differentiation of cells and as a marker of the efficiency of neuronal differentiation protocol.
    Bulletin of Experimental Biology and Medicine 10/2007; 144(4):626-9. · 0.34 Impact Factor
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    ABSTRACT: Cardiotonic steroids (CTS) like ouabain are not only specific inhibitors of the sodium pump (Na(+),K(+)-ATPase), they also can influence various cytosolic signaling events in a hormone-like manner. In the neuroblastoma cell line SH-SY5Y ouabain triggers multiple signaling pathways. Within 30 min of incubation with 1 or 10 microM ouabain, SH-SY5Y cells generate reactive oxygen species to a level approximately 50% above control and show a modest but significant elevation in cytosolic [Ca(2+)] of about 25%. After 6 h of exposure, ouabain stimulates a series of anti-apoptotic actions in SH-SY5Y cells, including concentration-dependent phosphorylation of Erk1/2, Akt, and Bad. Nevertheless, at the same time this CTS also induces a series of events that inhibit retinoic acid-induced neuritogenesis and promote cell death. Both of these latter phenomena are possibly associated with the observed ouabain-induced reduction in the abundance of the anti-apoptotic proteins Bcl-XL and Bcl-2. In addition, ouabain treatment results in cytochrome c release into the cytosol and induces activation of caspase 3, events that point towards the stimulation of apoptotic pathways that are probably enhanced by the stimulation of p53 phosphorylation at Ser15 also observed in this study. These pathways may eventually lead to cell death: treatment with 10 nM ouabain results in a 20% decrease in cell number after 4 days of incubation and treatment with 1 microM ouabain decreases cells number by about 75%. The results obtained here emphasize the importance of further research in order to elucidate the various signalling cascades triggered by ouabain and possibly other CTS that are used in the treatment of heart failure and to identify their primary receptor(s).
    Biochimica et Biophysica Acta 08/2007; 1768(7):1691-702. · 4.66 Impact Factor
  • Alexander A Boldyrev, Peter Johnson
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    ABSTRACT: Homocysteine (HC) and its derivatives may be involved in the etiology of Alzheimer's Disease (AD), although the precise mechanisms by which these compounds could cause cellular pathology are still unclear. Because interactions of HC with glutamate receptors have been implicated in AD, receptor-mediated effects of HC and homocysteic acid (HCA) on neurons and lymphocytes have been analyzed. Activation of glutamate receptors by these compounds has been shown to increase intracellular calcium and free radical levels in both types of cells, which may serve as a signal for development of apoptosis. Activation of group III metabotropic glutamate receptors stimulates, whereas activation of group I and group II metabotropic glutamate receptors prevent, the excitotoxic action of HC and HCA. These effects may contribute to the neuronal pathology and immunosenescence that occur in AD. It is proposed that selective agonists of metabotropic glutamate receptors that counter the effects of HC and its derivatives may be used for correction of neuronal and immune cell metabolism in vivo under the conditions of hyperhomocysteinemia, which can occur in AD.
    Journal of Alzheimer's disease: JAD 06/2007; 11(2):219-28. · 4.17 Impact Factor
  • A. A. Boldyrev
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    ABSTRACT: The receptor-mediated effects of homocysteine and homocysteic acid on neurons and lymphocytes are described. Activation of glutamate receptors by these ligands was shown to induce an increase in intracellular calcium concentration and the level of active forms of oxygen in both types of cells. This increase may serve as a signal for activation of apoptosis. Metabotropic receptors of group III stimulated the excitotoxic effect of homocysteine and homocysteic acid, while those of group I and II prevented it. It is proposed that selective agonists/antagonists of these metabotropic receptors can be used for correction of neuronal and immune cell metabolism during hyperhomocysteinemia.
    Neurochemical Journal 01/2007; 1(1):14-20. · 0.24 Impact Factor
  • Parkinsonism & Related Disorders - PARKINSONISM RELAT DISORD. 01/2007; 13.
  • S. Stvolinsky, N. Fedorova, A. Boldyrev
    Parkinsonism & Related Disorders - PARKINSONISM RELAT DISORD. 01/2007; 13.
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    ABSTRACT: The results of research of camosine as an antioxidative system corrector in conditions of oxidative stress caused by the action of damaging factors (y-rays, overcooling, hypobaric hypoxia, brain ischemia, neurotoxin impact) are summarized in the present review. The effects of carnosine are characterized not only at the level of the whole organism but also in "in vitro" models with use of a whole series of enzymatic systems. The results of the experiments conducted displayed the ability of carnosine to protect animals from oxidative stress based on the combination of direct antioxidative effects and a modulation of enzymes' activities which participate in controlling of reactive oxygen species level in tissues.
    Uspekhi fiziologicheskikh nauk 01/2007; 38(3):57-71.
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    ABSTRACT: N-Methyl-d-aspartate (NMDA)-activated glutamate receptors are expressed in lymphocytes, but their roles have not yet been defined. We show that incubation of human peripheral blood lymphocytes with NMDA resulted in increased intracellular calcium and reactive oxygen species (ROS) levels through effects on NMDA-activated glutamate receptors. In terms of ROS production, T cells were most affected, followed by NK cells, whereas B cell ROS levels were not increased. In unstimulated T and NK cells, interferon-gamma (IFN-gamma) production was unaffected by NMDA, whereas interleukin-2 stimulation of IFN-gamma production was significantly suppressed by NMDA. Simultaneous incubation of the cells with NMDA and IL-2 resulted in a dramatic increase in the amount of cells expressing the NR1 subunit of the NMDA-activated receptors. We conclude that NMDA-activated glutamate receptor activation, accompanied by the changes in intracellular calcium and ROS levels, may be involved in the modification of immune functions of human T and NK cells.
    Neurochemistry International 01/2007; 51(6-7):356-60. · 2.66 Impact Factor

Publication Stats

2k Citations
273.22 Total Impact Points

Institutions

  • 1997–2012
    • Russian Academy of Medical Sciences
      Moskva, Moscow, Russia
  • 1972–2012
    • Lomonosov Moscow State University
      • • Department of Biochemistry at the Faculty of Chemistry
      • • Department of Biochemistry
      • • International Research Center for Biochemical Technology
      • • Department of Biology
      Moskva, Moscow, Russia
  • 1972–2010
    • Moscow State Textile University
      Moskva, Moscow, Russia
  • 1995–2007
    • Institute of Neurology
      Moskva, Moscow, Russia
    • Medical University of Ohio at Toledo
      Toledo, Ohio, United States
    • University of Pittsburgh
      • Department of Environmental and Occupational Health
      Pittsburgh, PA, United States
    • The Robert Gordon University
      Aberdeen, Scotland, United Kingdom
  • 2000–2006
    • Albany State University
      Georgia, United States
  • 1999–2005
    • Comenius University in Bratislava
      • Jessenius Faculty of Medicine
      Bratislava, Bratislavsky Kraj, Slovakia
  • 1999–2004
    • The University of Tokyo
      • Department of Aquatic Bioscience
      Tokyo, Tokyo-to, Japan
  • 1998
    • Ohio University
      • Department of Chemistry and Biochemistry
      Athens, OH, United States
  • 1994
    • King's College London
      Londinium, England, United Kingdom
  • 1992
    • University of Ljubljana
      Lubliano, Ljubljana, Slovenia
  • 1990
    • Research Institute for Physico-Chemical Medicine
      Moskva, Moscow, Russia
  • 1984
    • Тольяттинский государственный университет ТГУ
      Stawropol, Samara, Russia