A A Boldyrev

Russian Academy of Medical Sciences, Moskva, Moscow, Russia

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Publications (257)347.54 Total impact

  • L V Karpova · E E Akkuratov · O M Brodskaia · A A Boldyrev
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    ABSTRACT: The main properties of Na+ /K(+)-ATPase as a natural receptor for cardiotonic steroids have been discusses. Primary attention is focused on structural and functional differences between the alpha-subunit isoforms of Na+/K(+)-ATPase in different tissues. General information on the role of the Na pump in signaling cascades in kidney epithelial cells, cardiomyocytes and neurons is presented. The data obtained indicate that, in neurons, several alpha-isoforms of Na+/K(+)-ATPase possessing different sensitivity to ouabain may have different signaling functions.
    No preview · Article · Nov 2010 · Biofizika
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    ABSTRACT: This study investigated the effect of antioxidants, i.e., carnosine and its Trolox- (water-soluble analog of alpha-tocopherol) acylated derivatives (S,S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-beta-alanyl-L-histidine (S,S-Trolox-carnosine, STC) and (R,S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-beta-alanyl-L-histidine (R,S-Trolox-carnosine, RTC) on the life span of the fruit fly Drosophila melanogaster. Adding carnosine to foodstuff was accompanied and followed by a 20% increase in the average life span of males, but it did not influence the average life span of females. At the same time, adding STC to foodstuff prolonged average longevity both in males (by 16%) and females (by 36%), but the addition of RTC to foodstuff had no influence upon the average life span of insects of either gender. The compounds studied have previously been shown to protect neurons of the rat brain from oxidative stress in the descending order of efficiency: RTC > STC > carnosine. The finding obtained in the present study suggests another order of efficacy regarding the effect on life span in male insects: STC > carnosine > RTC (inefficient). No correlation between antioxidant protection of rat neurons and the effect on life span of the fruit fly makes it possible to suppose the presence of additional cellular targets to be acted upon by exposure of D. melanogaster to these compounds.
    No preview · Article · Aug 2010 · Rejuvenation Research
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    ABSTRACT: N-methyl-d-aspartate (NMDA) receptors are ligand-gated nonselective cation channels mediating fast neuronal transmission and long-term potentiation in the central nervous system. These channels have a 10-fold higher permeability for Ca(2+) compared with Na(+) or K(+) and binding of the agonists (glutamate, homocysteine, homocysteic acid, NMDA) triggers Ca(2+) uptake. The present study demonstrates the presence of NMDA receptors in rat erythrocytes. The receptors are most abundant in both erythroid precursor cells and immature red blood cells, reticulocytes. Treatment of erythrocytes with NMDA receptor agonists leads to a rapid increase in intracellular Ca(2+) resulting in a transient shrinkage via Gardos channel activation. Additionally, the exposure of erythrocytes to NMDA receptor agonists causes activation of the nitric oxide (NO) synthase facilitating either NO production in l-arginine-containing medium or superoxide anion (O(2)(.-)) generation in the absence of l-arginine. Conversely, treatment with an NMDA receptor antagonist MK-80, or the removal of Ca(2+) from the incubation medium causes suppression of Ca(2+) accumulation and prevents attendant changes in cell volume and NO/O(2)(.-) production. These results suggest that the NMDA receptor activity in circulating erythrocytes is regulated by the plasma concentrations of homocysteine and homocysteic acid. Moreover, receptor hyperactivation may contribute to an increased incidence of thrombosis during hyperhomocysteinemia.
    Full-text · Article · Jun 2010 · AJP Cell Physiology
  • Anna P Mashkina · Dasha Cizkova · Ivo Vanicky · Alexander A Boldyrev
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    ABSTRACT: There is increasing evidence showing that the interplay between neuronal and immune systems may be regulated by neuromediators. However, little is known about the involvement of glutamatergic system in such neuro-immune relations. In the present study, we have shown that some intact lymphocytes express N-methyl-D: -aspartate activated receptors (NMDA receptors), an important constituent of glutamatergic system. The activation of lymphocytes with phytohemagglutinin (PHA) induces a time-dependent increase in the amount of NMDA receptor presenting cells, and NMDA stimulates this process. Immune response of such lymphocytes is suppressed and the amount of cells producing interferon gamma (IFN-gamma) in vitro is decreased to the level corresponding to intact (non-activated) cells. Furthermore, lymphocytes in the region of inflammation, induced by spinal cord injury (SCI), are also NMDA-positive. We suggest that expression of NMDA receptors in lymphocytes is regulated by central nervous system, which controls the inflammation process.
    No preview · Article · Apr 2010 · Cellular and Molecular Neurobiology
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    ABSTRACT: Using SK-N-AS human neuroblastoma cells, which co-express the alpha1 and alpha3 isoforms of the sodium pump alpha subunit, we selectively silenced either the alpha1 or alpha3 subunit by means of transfection with small interfering RNA, and investigated cell survival and the cellular response to ouabain. We found that both of the alpha subunits are essential for cell survival, indicating that substitution of one subunit for the other is not sufficient. In the presence of both alpha subunits, ouabain causes sustained activation of extracellular signal-regulated kinases 1 and 2 (Erk1/2). This activation is not affected when the alpha1 subunit is silenced. However, when alpha3 expression is silenced, ouabain-induced activation of Erk1/2 does not occur, even at a high concentration of ouabain (1 microM). Thus, ouabain-induced Erk1/2 activation is mediated in SK-N-AS cells by alpha3 only, and alpha1 does not participate in this event. This is a clear demonstration of selective involvement of a specific sodium pump alpha subunit isoform in ouabain-induced signaling.
    Preview · Article · Mar 2010 · FEBS Journal
  • Larisa V Karpova · Elena R Bulygina · Alexander A Boldyrev
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    ABSTRACT: Inhibition of rat neuronal Na(+)/K(+)-ATPase alpha3 isoform at low (100 nM) ouabain concentration led to activation of MAP kinase cascade via PKC and PIP(3) kinase. In contrast to ouabain-sensitive alpha3 isoform of Na(+)/K(+)-ATPase, an ouabain-resistant alpha1 isoform (inhibition with 1 mM of ouabain) of Na(+)/K(+)-ATPase regulates MAP kinase via Src kinase dependent reactions. Using of Annexin V-FITC apoptotic test to determine the cells with early apoptotic features allows to conclude that alpha3 isoform stimulates and alpha1 suppresses apoptotic process in cerebellum neurons. These data are the first demonstration showing participation of ouabain-resistant (alpha1) and ouabain-sensitive (alpha3) Na(+)/K(+)-ATPase isoforms in diverse signaling pathways in neuronal cells.
    No preview · Article · Mar 2010 · Cell Biochemistry and Function
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    ABSTRACT: In our investigation, we describe the complex model of brain oxidative stress consisted of combination of experimental brain ischemia and energy metabolism violation induced by irreversible inhibitor of mitochondrial succi-nate dehydrogenase, 3-nitropropionate (3-NPA). 3-NPA causes selective degeneration of striatum neurons, which is extremely sensitive to energy deficit. This complex model allows revealing not only biochemical but also neurological symptoms in experimental animals that permits proper estimation of protective effect of different drugs on animal status. Combination of global ischemia induced by 3-vessel occlusion of major arteries supplys rat brain and subsequent 5-day reperfusion with intraperitoneal injection of 3-nitropropionic acid induces vigorous oxidative stress in brain tissues accompanied by evident neurological symptoms in Wistar rats. Such a combination of damaging factors may be considered as a new complex experimental model of brain oxidative stress permitting the evaluation of neuroprotective effect of potential therapeutic agents. Using this model, protective effect of neuropeptide carnosine was demonstrated which is in agreement with previous data.
    Full-text · Article · Jan 2010 · International Journal of Clinical and Experimental Medicine
  • A.A. Boldyrev · S.L. Stvolinsky · T.N. Fedorova · Z.A. Suslina
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    ABSTRACT: Carnosine is a neuroprotective dipeptide consisting of beta-alanine and L-histidine. It demonstrates a number of useful features, including stimulation of brain and muscle microcirculation and a rejuvenating effect on cultured cells. Its activity is based on its antioxidant and antiglycating action that, in addition to heavy metal chelation and pH-buffering ability, makes carnosine an essential factor for preventing neurodegeneration and accumulation of senile features. Recently, carnosine was successfully used to treat patients after brain stroke or patients with Parkinson disease. We conclude that carnosine can be recommended for patients under oxidative stress as a natural remedy having high efficiency and no side effects.
    No preview · Article · Dec 2009 · Rejuvenation Research
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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.
    No preview · Article · Dec 2009 · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology
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    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.
    No preview · Article · Oct 2009 · Cellular and Molecular Neurobiology
  • AA 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.
    No preview · Article · Jul 2009 · Biochemistry (Moscow)
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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.
    Full-text · Article · Jul 2009 · FEBS letters
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    ABSTRACT: Carnosine administration (in a daily dose of 2 g) as an additional therapy for patients with chronic discirculatory encephalopathy (DE) results in an increase in stability of blood plasma lipoproteins toward Fe2+-induced oxidation and stabilization of red blood cells against acidic hemolysis as well as intensification of respiratory burst of periphery blood leucocytes. At the same time, latent period of brain induced potentials, P300, decreases and the proportion of the high-amplitude induced potentials increases. The data presented demonstrate that carnosine enhances the efficiency of basal therapy of DE patients.
    No preview · Article · Mar 2009 · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology
  • E. A. Vladychenskaya · A. A. Boldyrev
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    ABSTRACT: Homocysteine is a risk factor of many neurodegenerative and cardiovascular diseases. The target for its effect was suggested to be brain neurons. Recently, it was found that homocysteine can affect immune competent cells. In this work we have shown that, in neutrophils, homocysteine stimulates the amplitude and initial rate of respiratory burst induced by fMLP. Adenosine receptors of the A1 and A2 types are involved in this process but not the A3 type. Phospholipase C is also involved in the stimulation of the fMLP-induced respiratory burst by homocysteine.
    No preview · Article · Mar 2009 · Neurochemical Journal
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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.
    Full-text · Article · Sep 2008 · Rejuvenation Research
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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.
    No preview · Article · Aug 2008 · Neurochemical Journal
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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).
    Full-text · Article · Jun 2008 · Journal of Neurochemistry
  • L. V. Karpova · E. E. Akkuratov · E. R. Bulygina · A. A. Boldyrev
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    ABSTRACT: Three-hour incubation of rat cerebellar granule cells with 0.1 μM ouabain increases intracellular levels of Ca2+ ions and reactive oxygen species (ROS) resulting in pronounced activation of Mitogen-Activated Protein Kinase (MAPK). Higher concentrations of ouabain induce further increases in MAPK activity. The activating effect of ouabain is attenuated by the NMDA-receptor antagonists MK-801 and D-AP5. The data obtained suggest that similar to NMDA receptors ouabain-sensitive and ouabain-resistant isoforms of Na+,K+-ATPase are actively involved in intracellular signaling cascades controlling proliferative activity of neuronal cells.
    No preview · Article · Jun 2008 · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology
  • 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.
    No preview · Article · Jun 2008 · Neurochemical Journal
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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.
    No preview · Article · May 2008 · Bulletin of Experimental Biology and Medicine

Publication Stats

4k Citations
347.54 Total Impact Points


  • 1995-2014
    • Russian Academy of Medical Sciences
      Moskva, Moscow, Russia
    • Medical University of Ohio at Toledo
      Toledo, Ohio, United States
  • 1986-2014
    • Lomonosov Moscow State University
      • • Department of Biochemistry
      • • Faculty of Biology
      • • Department of Biology
      Moskva, Moscow, Russia
  • 1977-2010
    • Moscow State Forest University
      Mytishi, Moskovskaya, Russia
  • 1994-2007
    • Institute of Neurology
      Moskva, Moscow, Russia
    • King's College London
      Londinium, England, United Kingdom
  • 2004
    • The University of Tokyo
      • Department of Aquatic Bioscience
      Edo, Tōkyō, Japan
  • 2000
    • Albany State University
      Georgia, United States
  • 1996
    • Russian Academy of Sciences
      Moskva, Moscow, Russia
  • 1993
    • University College London
      • Department of Electronic and Electrical Engineering
      Londinium, England, United Kingdom
  • 1990
    • Research Institute for Physico-Chemical Medicine
      Moskva, Moscow, Russia