N K Isaev

Lomonosov Moscow State University, Moskva, Moscow, Russia

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Publications (58)77.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: A single intraperitoneal injection to rats of the mitochondria-targeted plastoquinone antioxidant SkQR1 at dose 1 μmol/kg significantly improved reproduction by the rats of the passive avoidance conditional reflex. In vitro experiments on hippocampal slices showed that a single intraperitoneal injection of SkQR1 24 h before the preparation of the slice significantly increases the synaptic transmission efficiency of the pyramidal neurons of the CA1 field. The findings indicate that SkQR1 has a positive effect on memory processes.
    Biochemistry (Moscow) 05/2015; 80(5):592-595. DOI:10.1134/S0006297915050119 · 1.35 Impact Factor
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    ABSTRACT: Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+.
    Biochemistry (Moscow) 05/2014; 79(5):391-6. DOI:10.1134/S0006297914050022 · 1.35 Impact Factor
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    ABSTRACT: Exposure of cerebellar granule neurons in culture to the inhibitor of the plasma membrane Na+/H+ exchanger 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) for 24 h resulted in intense death of neurons. Menadione and the antioxidant trolox prevented the neurocytotoxic effect of EIPA. We previously reported that menadione protected a culture of cerebellar granule neurons from death induced by inhibition of complex I of the mitochondrial respiratory chain [11]. Blockade of complex I is probably the main cause of neuronal death induced by EIPA. Moreover, lipid peroxidation may also be involved in the neurodestructive effect of EIPA.
    Neurochemical Journal 04/2014; 8(2):121-124. DOI:10.1134/S181971241402010X · 0.19 Impact Factor
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    ABSTRACT: The mitochondrial matrix is the only intracellular compartment that is negatively charged compared to the cytosol. This is why any cation penetrating the mitochondrial membrane must be accumulated inside mitochondria. This principle was used to construct mitochondria-targeted antioxidants (mtAOX) composed of an antioxidant moiety and a penetrating cation with delocalized positive charge. The mtAOX most active in various in vitro tests are MitoQ and SkQ, cationic derivatives of mitochondrial ubiquinone and chloroplast plastoquinone, respectively. Their high activities are due to the fact that the reduced (active) form of MitoQ and SkQ can be regenerated by the mitochondrial respiratory chain from their oxidized forms produced as a result of the antioxidant action of these quinones. An additional important advantage of SkQ is that the “window” between anti- and prooxidant activities of this compound is very much wider than that of MitoQ. Both MitoQ and SkQ have already been tested on animals to treat various diseases that seem to be caused by reactive oxygen species (ROS) produced by mitochondria. In several cases, the use of SkQ was more successful than MitoQ. In particular, it was found that SkQ prolongs the life span of various organisms (from fungi to mammals) and retards (sometimes even reverses) a group of traits typical for aging. Clinical trials of drops of an aqueous solution of SkQ as a medicine have already given a positive result in the case of the age-related disease “dry-eye syndrome.” The SkQ1-containing drops of Visomitin are now available in Russian drugstores.
    Systems Biology of Free Radicals and Antioxidants, 01/2014: pages 323-354; , ISBN: 978-3-642-30017-2
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    ABSTRACT: Bivalent metal cations are key components in the reaction of DNA synthesis. They are necessary for all DNA polymerases, being involved as cofactors in catalytic mechanisms of nucleotide polymerization. It is also known that in the presence of Mn2+ the accuracy of DNA synthesis is considerably decreased. The findings of this work show that Cd2+ and Zn2+ selectively inhibit the Mn2+-induced error-prone DNA polymerase activity in extracts of cells from human and mouse tissues. Moreover, these cations in low concentrations also can efficiently inhibit the activity of homogeneous preparations of DNA polymerase iota (Pol ι), which is mainly responsible for the Mn2+-induced error-prone DNA polymerase activity in cell extracts. Using a primary culture of granular cells from postnatal rat cerebellum, we show that low concentrations of Cd2+ significantly increase cell survival in the presence of toxic Mn2+ doses. Thus, we have shown that in some cases low concentrations of Cd2+ can display a positive influence on cells, whereas it is widely acknowledged that this metal is not a necessary microelement and is toxic for organisms.
    Biochemistry (Moscow) 10/2013; 78(10):1137-45. DOI:10.1134/S0006297913100088 · 1.35 Impact Factor
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    ABSTRACT: Mitochondrial medicine was established more than 50 years ago after discovery of the very first pathology caused by impaired mitochondria. Since then, more than 100 mitochondrial pathologies have been discovered. However, the number may be significantly higher if we interpret the term "mitochondrial medicine" more widely and include in these pathologies not only those determined by the genetic apparatus of the nucleus and mitochondria, but also acquired mitochondrial defects of non-genetic nature. Now the main problems of mitochondriology arise from methodology, this being due to studies of mitochondrial activities under different models and conditions that are far from the functioning of mitochondria in a cell, organ, or organism. Controversial behavior of mitochondria ("friends and foes") to some extent might be explained by their bacterial origin with possible preservation of "egoistic" features peculiar to bacteria. Apparently, for normal mitochondrial functioning it is essential to maintain homeostasis of a number of mitochondrial elements such as mitochondrial DNA structure, membrane potential, and the system of mitochondrial quality control. Abrogation of these elements can cause a number of pathologies that have become subjects of mitochondrial medicine. Some approaches to therapy of mitochondrial pathologies are discussed.
    Biochemistry (Moscow) 09/2013; 78(9):979-990. DOI:10.1134/S0006297913090034 · 1.35 Impact Factor
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    ABSTRACT: Normal brain aging leads to decrease in cognitive functions, shrink in brain volume, loss of nerve fibers and degenerating myelin, reduction in length and branching of dendrites, partial loss of synapses, and reduction in expression of genes that play central roles in synaptic plasticity, vesicular transport, and mitochondrial functioning. Impaired mitochondrial functions and mitochondrial reactive oxygen species can contribute to the damage of these genes in aging cerebral cortex. This review discusses the possibility of using mitochondria-targeted antioxidants to slow the processes of brain aging.
    Biochemistry (Moscow) 03/2013; 78(3):295-300. DOI:10.1134/S0006297913030127 · 1.35 Impact Factor
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    ABSTRACT: A protective effect of a mitochondria-targeted antioxidant, a cationic rhodamine derivative linked to a plastoquinone molecule (10-(6'-plastoquinonyl)decylrhodamine-19, SkQR1) was studied in the model of open focal trauma of rat brain sensorimotor cortex. It was found that daily intraperitoneal injections of SkQR1 (100 nmol/kg) for 4 days after the trauma improved performance in a test characterizing neurological deficit and decreased the volume of the damaged cortical area. Our results suggest that SkQR1 exhibits profound neuroprotective effect, which may be explained by its antioxidative activity.
    Biochemistry (Moscow) 09/2012; 77(9):996-9. DOI:10.1134/S0006297912090052 · 1.35 Impact Factor
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    ABSTRACT: It is generally accepted that mitochondrial production of reactive oxygen species is nonlinearly related to the value of the mitochondrial membrane potential with significant increment at values exceeding 150 mV. Due to this, high values of the membrane potential are highly dangerous, specifically under pathological conditions associated with oxidative stress. Mild uncoupling of oxidative phosphorylation is an approach to preventing hyperpolarization of the mitochondrial membrane. We confirmed data obtained earlier in our group that dodecylrhodamine 19 (C(12)R1) (a penetrating cation from SkQ family not possessing a plastoquinone group) has uncoupling properties, this fact making it highly potent for use in prevention of pathologies associated with oxidative stress induced by mitochondrial hyperpolarization. Further experiments showed that C(12)R1 provided nephroprotection under ischemia/reperfusion of the kidney as well as under rhabdomyolysis through diminishing of renal dysfunction manifested by elevated level of blood creatinine and urea. Similar nephroprotective properties were observed for low doses (275 nmol/kg) of the conventional uncoupler 2,4-dinitrophenol. Another penetrating cation that did not demonstrate protonophorous activity (SkQR4) had no effect on renal dysfunction. In experiments with induced ischemic stroke, C(12)R1 did not have any effect on the area of ischemic damage, but it significantly lowered neurological deficit. We conclude that beneficial effects of penetrating cation derivatives of rhodamine 19 in renal pathologies and brain ischemia may be at least partially explained by uncoupling of oxidation and phosphorylation.
    Biochemistry (Moscow) 09/2012; 77(9):1029-37. DOI:10.1134/S0006297912090106 · 1.35 Impact Factor
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    ABSTRACT: Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems - the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism's death.
    Biochemistry (Moscow) 07/2012; 77(7):742-53. DOI:10.1134/S0006297912070073 · 1.35 Impact Factor
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    ABSTRACT: Addition of 200 nM β-amyloid 1-42 (Abeta) to a rat hippocampal slice impairs the induction of a long-term post-tetanic potentiation (LTP) of population spike (PS) in pyramidal neurons of the CA1 field of hippocampus. Intraperitoneal injection into the rat of the mitochondria-targeted plastoquinone derivative SkQR1 (1 µmol/kg of weight given 24 h before the slices were made) abolishes the deleterious effect of Abeta on LTP. These data demonstrate that SkQR1 therapy is able to compensate the Abeta-induced impairments of long-term synaptic plasticity in the hippocampus, which are the main cause of loss of memory and other cognitive functions associated with Alzheimer's disease.
    Biochemistry (Moscow) 12/2011; 76(12):1367-70. DOI:10.1134/S0006297911120108 · 1.35 Impact Factor
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    ABSTRACT: Magnetic resonance tomography, staining with triphenyltetrazolium chloride, and tests for evaluation of functional disturbances "cylinder" and "limb stimulation" showed that daily intraperitoneal injection of dipeptide mimetic of nerve growth factor GK-2 (1 mg/kg) for 6 days to rats with experimental focal ischemia provoked by unilateral intravascular occlusion of a branch of the middle cerebral artery significantly improved neurological deficit and decreased the infarction area.
    Bulletin of Experimental Biology and Medicine 09/2011; 151(5):584-7. DOI:10.1007/s10517-011-1388-7 · 0.37 Impact Factor
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    ABSTRACT: In this review, we discuss the role of glutamine in the nervous system as a precursor of the excitatory neuromediator glutamate, on one hand, and as an energy substrate for mitochondria in nerve and glial cells during normal and pathological processes, on the other hand. Particular attention is devoted to the functioning of the glutamine-glutamate cycle enzymes during brain ischemia and hypoglycemia and to processes of neuromediator regeneration in neurons. We thoroughly discuss the role of glutamine synthetase in mechanisms of ammonium detoxification and the role of glutamine as a possible factor in astrocyte damage. The analyzed data suggest that the constant maintenance of optimal concentrations and ratio of glutamine to glutamate in nerve tissue is not only critically important for the normal functioning of nervous system, but is also necessary for neuron and astrocyte viability.
    The International journal of neuroscience 05/2011; 121(8):415-22. DOI:10.3109/00207454.2011.570464 · 1.53 Impact Factor
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    ABSTRACT: The specific aim of this study was to elucidate the role of mitochondria in a neuronal death caused by different metabolic effectors and possible role of intracellular calcium ions ([Ca(2+)](i)) and glutamine in mitochondria- and non-mitochondria-mediated cell death. Inhibition of mitochondrial complex I by rotenone was found to cause intensive death of cultured cerebellar granule neurons (CGNs) that was preceded by an increase in intracellular calcium concentration ([Ca(2+)](i)). The neuronal death induced by rotenone was significantly potentiated by glutamine. In addition, inhibition of Na/K-ATPase by ouabain also caused [Ca(2+)](i) increase, but it induced neuronal cell death only in the absence of glucose. Treatment with glutamine prevented the toxic effect of ouabain and decreased [Ca(2+)](i). Blockade of ionotropic glutamate receptors prevented neuronal death and significantly decreased [Ca(2+)](i), demonstrating that toxicity of rotenone and ouabain was at least partially mediated by activation of these receptors. Activation of glutamate receptors by NMDA increased [Ca(2+)](i) and decreased mitochondrial membrane potential leading to markedly decreased neuronal survival under glucose deprivation. Glutamine treatment under these conditions prevented cell death and significantly decreased the disturbances of [Ca(2+)](i) and changes in mitochondrial membrane potential caused by NMDA during hypoglycemia. Our results indicate that glutamine stimulates glutamate-dependent neuronal damage when mitochondrial respiration is impaired. However, when mitochondria are functionally active, glutamine can be used by mitochondria as an alternative substrate to maintain cellular energy levels and promote cell survival.
    Neuroscience Letters 09/2010; 482(2):151-5. DOI:10.1016/j.neulet.2010.07.022 · 2.06 Impact Factor
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    ABSTRACT: Using a specific fluorescent probe of mitochondrial membrane potential (tetramethylrhodamine ethyl ester), we have shown that glucose deprivation (GD) of cultured cerebellar granule neurons (CGN) for 3 h lowers mitochondrial membrane potential in these cells. Longer glucose starvation (24 h) causes CGN death that is not prevented by blockers of ionotropic glutamate receptors (MK-801 (10 µM) and NBQX (10 µM)). Glutamine or pyruvate (2 mM) maintain membrane potential of mitochondria and decrease CGN death under GD conditions. In the presence of glucose the mitochondrial respiratory chain blocker rotenone induces neuron death potentiated by glutamine. The potentiation effect is completely prevented by blockers of ionotropic glutamate receptors. These results show that glutamine under conditions of GD can be utilized by mitochondria as substrate, but at the same time, in the case of mitochondrial function deterioration, metabolism of this amino acid results in glutamate accumulation to toxic level.
    Biochemistry (Moscow) 08/2010; 75(8):1039-44. DOI:10.1134/S0006297910080134 · 1.35 Impact Factor
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics 07/2010; 1797:82-82. DOI:10.1016/j.bbabio.2010.04.247 · 4.83 Impact Factor
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    ABSTRACT: A mitochondria-targeted chimeric compound consisting of a rhodamine derivative linked to a plastoquinone molecule (10-(6'-plastoquinonyl)decylrhodamine, SkQR1) was studied under conditions of acute brain or kidney damage. A protective effect of this compound was demonstrated in a model of focal brain ischemia, rat kidney ischemia/reperfusion, myoglobinuria (rhabdomyolysis, or crush syndrome), and pyelonephritis. We found that a single intraperitoneal injection of SkQR1 diminishes the size of the ischemic zone in the brain and improves performance of a test characterizing neurological deficit in ischemic animals. Control substance not containing plastoquinone appeared to be not neuroprotective. The data show that SkQR1 is a nephroprotectant and neuroprotectant, which can be due to the antioxidative action of this Skulachev cation.
    Biochemistry (Moscow) 02/2010; 75(2):145-50. DOI:10.1134/S0006297910020045 · 1.35 Impact Factor
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    ABSTRACT: Effects of 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) and 10-(6'-plastoquinonyl) decylrhodamine 19 (SkQR1) on rat models of H2O2- and ischemia-induced heart arrhythmia, heart infarction, kidney ischemia, and stroke have been studied ex vivo and in vivo. In all the models listed, SkQ1 and/or SkQR1 showed pronounced protective effect. Supplementation of food with extremely low SkQ1 amount (down to 0.02 nmol SkQ1/kg per day for 3 weeks) was found to abolish the steady heart arrhythmia caused by perfusion of isolated rat heart with H2O2 or by ischemia/reperfusion. Higher SkQ1 (125-250 nmol/kg per day for 2-3 weeks) was found to decrease the heart infarction region induced by an in vivo ischemia/reperfusion and lowered the blood levels of lactate dehydrogenase and creatine kinase increasing as a result of ischemia/reperfusion. In single-kidney rats, ischemia/reperfusion of the kidney was shown to kill the majority of the animals in 2-4 days, whereas one injection of SkQ1 or SkQR1 (1 micromol/kg a day before ischemia) saved lives of almost all treated rats. Effect of SkQR1 was accompanied by decrease in ROS (reactive oxygen species) level in kidney cells as well as by partial or complete normalization of blood creatinine and of some other kidney-controlled parameters. On the other hand, this amount of SkQ1 (a SkQ derivative of lower membrane-penetrating ability than SkQR1) saved the life but failed to normalize ROS and creatinine levels. Such an effect indicates that death under conditions of partial kidney dysfunction is mediated by an organ of vital importance other than kidney, the organ in question being an SkQ1 target. In a model of compression brain ischemia/reperfusion, a single intraperitoneal injection of SkQR1 to a rat (1 micromol/kg a day before operation) effectively decreased the damaged brain area. SkQ1 was ineffective, most probably due to lower permeability of the blood-brain barrier to this compound.
    Biochemistry (Moscow) 12/2009; 73(12):1288-99. DOI:10.1134/S000629790812002X · 1.35 Impact Factor
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    ABSTRACT: The addition of glutamate (Glu) to culture medium for 24 hours induced the dose-dependent death of rat cortical neurons cultured for 9–10 days and did not affect neurons cultured for 4–5 days; this suggests that the later neurons are neurochemically immature. In mature cultures, glucose deprivation (GD) enhanced the toxic effect of low Glu concentrations by 15% and did not influence the toxicity of high concentrations of this neuromediator. In immature cultures, GD potentiated the Glu effect independent of the concentration of this neuromediator. Inhibition of Na+/K+ -ATPase induced the death of some of the neurons. In the presence of a normal level of glucose, ouabain decreased the viability of mature and immature neurons to 67 ± 4 % and 79 ± 5%, respectively, and its presence during GD diminished viability to 28 ± 4 % and 56 ± 3%, respectively. The toxicity of ouabain was substantially attenuated when ionotropic glutamate receptors were blocked by MK-801. GD alone caused no significant increase in the death of these cells, even after a 3-hour incubation. Thus, GD strongly increases the susceptibility of neurons to the toxicity mediated by the activation of the NMDA subtype of ionotropic Glu receptors, even in the case of neurochemically immature neurons.
    Neurochemical Journal 09/2009; 3(3):202-206. DOI:10.1134/S1819712409030088 · 0.19 Impact Factor
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    ABSTRACT: The volumes of foci of injuries, evaluated by T2-suspended MRT images and analysis of histological sections stained by triphenyltetrazoleum chloride, were compared on a model of unilateral intravascular blocking of the middle cerebral artery branch. The two methods for evaluation of foci of lesions gave close results, correlating with the severity of neurological deficiency in animals subjected to ischemia, manifesting in behavioral tests.
    Bulletin of Experimental Biology and Medicine 03/2009; 147(2):269-72. DOI:10.1007/s10517-009-0489-z · 0.37 Impact Factor

Publication Stats

981 Citations
77.18 Total Impact Points

Institutions

  • 1995–2014
    • Lomonosov Moscow State University
      • Faculty of Bioengineering and Bioinformatics
      Moskva, Moscow, Russia
  • 1998–2011
    • Moscow State Forest University
      Mytishi, Moskovskaya, Russia
  • 1996–2011
    • Russian Academy of Medical Sciences
      • Institute of General Pathology and Pathophysiology
      Moskva, Moscow, Russia
  • 2002
    • Humboldt-Universität zu Berlin
      • Microbiology, Molecular Biology, and Biochemistry Section
      Berlín, Berlin, Germany
  • 2000
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany