Institute of General Pathology and Pathophysiology RAMS

Moscow, Russia

Institute of General Pathology and Pathophysiology RAMS

Moscow, Russia
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Gruden M.A.,Pk Anokhin Institute Of Normal Physiology Rams | Davidova T.V.,Institute of General Pathology and Pathophysiology RAMS | Yanamandra K.,Umeå University | Kucheryanu V.G.,Institute of General Pathology and Pathophysiology RAMS | And 3 more authors.
Behavioural Brain Research | Year: 2013

Animal models of Parkinson's disease (PD) have been widely used to investigate the pathogenesis of this neurodegenerative disorder which is typically associated with the specific and largely disordered protein α-synuclein (α-syn). In the current study, the nasal vector was used to deliver α-syn aggregates to the brain. Both α-syn oligomers and its fibrils were firstly characterized using atomic force microscopy and the thioflavin T binding assay. The toxic oligomers alone (0.48. mg/kg) or their 50:50 combination with fibrils (in a total dose of 0.48. mg/kg) were then given intranasally for ten days in mice and PD-mimetic symptoms as well as humoral immunity to these species and dopamine (DA) were evaluated simultaneously. Open-field behavioral deficits indicated by rigidity and reduced locomotor activity were induced by the dual administration of α-syn oligomers plus fibrils but not the oligomers by themselves under the 10-day dosing regimen. In contrast, using ELISA, high levels of serum autoantibodies to α-syn monomeric, oligomeric and fibrillar conformers as well as DA were observed in both treatment groups reflecting immune system activation and this substantiates previous clinical studies in Parkinson's disease patients. Thus, nasal administration of α-syn amyloidogenic species may be a potential experimental PD model which results not only in motor deficits but also incitement of humoral protection to mimic the disease. Such a paradigm may be exploitable in the quest for potential therapeutic strategies and further studies are warranted. © 2013 Elsevier B.V.


Gruden M.A.,P K Anokhin Institute Of Normal Physiology Rams | Davydova T.V.,Institute of General Pathology and Pathophysiology RAMS | Narkevich V.B.,Institute of Pharmacology RAMS | Fomina V.G.,Institute of General Pathology and Pathophysiology RAMS | And 4 more authors.
Behavioural Brain Research | Year: 2015

Alpha-synuclein (α-syn) toxic aggregates delivered by the nasal vector have been shown to modify the neurochemistry of dopamine (DA) which is associated with parkinsonian-like motor symptoms. The aim was therefore to study the intranasal effects of α-syn oligomers, fibrils or their combination on the motor behavior of aged mice in relation to possible noradrenergic and serotonergic correlates. In vitro generated α-syn oligomers and fibrils were verified using atomic force microscopy and the thioflavin T binding assay. Levels of noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected using HPLC with electrochemical detection in the substantia nigra (SN) and striatum. The oligomers or fibrils administered alone or in a 50:50 combination (total dose of 0.48. mg/kg) were given intranasally for 14 days and "open-field" behaviour was tested on days 0, 15 and 28 of the protocol, at which time brain structures were sampled. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e. 14 days after treatment completion) induced hypokinesia and immobility whilst the aggregate combination additionally produced rigidity. The α-Syn oligomer/fibril mixture also instigated PD-like motor symptoms which correlated heterochronically with elevated NA levels in the striatum but then later in the SN while intranasal fibrils alone augmented 5-HT and 5-HIAA nigral concentrations throughout the protocol. In contrast, α-syn oligomers displayed a delayed serotonin upsurge in the SN. Neurodegenerative and/or actions on neurotransmitter transporters (such as NET, SERT and VMAT2) are discussed as being implicated in these α-syn amyloid induced neurochemical and motoric disturbances. © 2014 Elsevier B.V.


Kolikova J.,University of Helsinki | Afzalov R.,University of Helsinki | Surin A.,University of Helsinki | Surin A.,Institute of General Pathology and Pathophysiology RAMS | And 3 more authors.
Cell Calcium | Year: 2011

Neuronal ceroid lipofuscinoses (NCLs) are a group of genetic childhood-onset progressive brain diseases characterized by a decline in mental and motor capacities, epilepsy, visual loss and premature death. Using patch clamp, fluorescence imaging and caged Ca 2+ photolysis, we evaluated the mechanisms of neuronal Ca 2+ clearance in Cln8 mnd mice, a model of the human NCL caused by mutations in the CLN8 gene. In Cln8 mnd hippocampal slices, Ca 2+ clearance efficiency in interneurons and, to some extent, principal neurons declined with age. In cultured Cln8 mnd hippocampal neurons, clearance of large Ca 2+ loads was inefficient due to impaired mitochondrial Ca 2+ uptake. In contrast, neither Ca 2+ uptake by sarco/endoplasmic reticulum Ca 2+ ATPase, nor Ca 2+ extrusion through plasma membrane was affected by the Cln8 mutation. Excitotoxic glutamate challenge caused Ca 2+ deregulation more readily in Cln8 mnd than in wt neurons. We propose that neurodegeneration in human CLN8 disorders is primarily caused by reduced mitochondrial Ca 2+ buffering capacity. © 2011 Elsevier Ltd.


Mironova G.D.,Pushchino State University | Shigaeva M.I.,Russian Academy of Sciences | Gritsenko E.N.,Russian Academy of Sciences | Murzaeva S.V.,Russian Academy of Sciences | And 3 more authors.
Journal of Bioenergetics and Biomembranes | Year: 2010

The mechanism of tissue protection from ischemic damage by activation of the mitochondrial ATP-dependent K + channel (mitoK ATP) remains unexplored. In this work, we have measured, using various approaches, the ATP-dependent mitochondrial K + transport in rats that differed in their resistance to hypoxia. The transport was found to be faster in the hypoxia-resistant rats as compared to that in the hypoxia-sensitive animals. Adaptation of animals to the intermittent normobaric hypoxia increased the rate of transport. At the same time, the intramitochondrial concentration of K + in the hypoxia-sensitive rats was higher than that in the resistant and adapted animals. This indicates that adaptation to hypoxia stimulates not only the influx of potassium into mitochondria, but also K +/H + exchange. When mitoK ATP was blocked, the rate of the mitochondrial H 2O 2 production was found to be significantly higher in the hypoxia-resistant rats than that in the hypoxia-sensitive animals. The natural flavonoid-containing adaptogen Extralife, which has an evident antihypoxic effect, increased the rate of the mitochondrial ATP-dependent K + transport in vitro and increased the in vivo tolerance of hypoxia-sensitive rats to acute hypoxia 5-fold. The involvement of the mitochondrial K + transport in the mechanism of cell adaptation to hypoxia is discussed. © 2010 Springer Science+Business Media, LLC.


Goncharov N.V.,RAS Sechenov Institute of Evolutionary Physiology and Biochemistry | Avdonin P.V.,Russian Academy of Sciences | Nadeev A.D.,Russian Academy of Sciences | Zharkikh I.L.,Institute of General Pathology and Pathophysiology RAMS | Jenkins R.O.,De Montfort University
Current Pharmaceutical Design | Year: 2015

The volume of publications on the role of reactive oxygen species (ROS) in biological processes has been increasing exponentially over the last decades. ROS in large amounts clearly have detrimental effects on cell physiology, whereas low concentrations of ROS are permanently produced in cells and play a role as signaling molecules. An imbalance in ROS production and defense mechanisms can lead to pathological vascular remodeling, atherosclerosis being among them. The aim of this review is to examine different sources of ROS from the point of view of their participation in pathogenesis of atherosclerosis and related cardiovascular risk. Among the possible sources of ROS discussed here are mitochondria, NADPH-oxidases, xanthine oxidase, peroxidases, NO-synthases, cytochrome P450, cyclooxygenases, lipoxygenases, and hemoglobin of red blood cells. A great challenge for future research is to establish interrelations, feedback and feed-forward regulation mechanisms of various sources of ROS in development of atherosclerosis and other vascular pathologies. © 2015 Bentham Science Publishers.


Makarenko A.N.,Institute of General Pathology and Pathophysiology RAMS
Patologicheskaia fiziologiia i èksperimental'naia terapiia | Year: 2013

The processes of developed in CNS the complicated stroke and developments of fittings for their pharmaceutical therapy were developed and offering by standardized method of the experimental secondary stroke in rats, suitable for the use in sharp and chronic researches. Variant of repeated hemorrhagic stroke consist of autohemorrhagic right hemisphere stroke by the mechanical damage of brain tissue after 10-daily occlusion of right common carotid artery was studied. A model is comfortable for reproducing of the repeated standardized local damage of brain, is more adequate form of design of transient and chronic cerebrovascular pathology, than the independent use of local hemorrhage of autoblood in the brain of animals. The morphological description of model approaches the clinical variants of development and flow of sharp hemorrhagic stroke after a previous chronic cerebral insufficiency on an ischemic type.


Merkulov Y.A.,Institute of General Pathology and Pathophysiology RAMS
Patologicheskaia fiziologiia i èksperimental'naia terapiia | Year: 2013

Work with night shift is an obligate necessity of modem industrial urban society. In developed countries in the work on the night shift use up to 20%. These categories of workers are definitely the locomotive drivers. The consequence of a regular work with night shifts is a violation of human circadian rhythms, which, through dysregulation of the autonomic nervous system, is reflected in a greater risk of disease and transport accidents. The need to find ways and criteria of preventive monitoring dysregulatory changes in the human body is an urgent and challenging issue in terms of the health of the working population, disease prevention, and transportation security.


Nikoforov N.G.,Institute of General Pathology and Pathophysiology RAMS
Patologicheskaia fiziologiia i èksperimental'naia terapiia | Year: 2013

In the present review we focus on the major cellular and molecular processes leading to the formation and accumulation of foamy cells: increased transmigration of monocytes into sub-endothelial sites of inflammation, activation of macrophages, modifications of lipoproteins, different types of uptake of native and associated lipoproteins (endocytosis, phagocytosis, and less-investigated--patocytosis), as well as participation of different molecular systems in the reverse cholesterol transport in macrophages. Special attention is given to the recent data indicating that scavenger receptors participate not only in the uptake of modified lipoproteins, but also in the reverse cholesterol transport. In conclusion, we discuss most relevant open questions in our understanding of the mechanism and functional consequences of macrophage/lipoprotein interactions: which receptor systems are used for the recognition and internalisation of aggregated lipoproteins, what are the mechanisms of intracellular processing of associated lipoproteins, and how associated lipoproteins affect functional programming of macrophages.


Menzikov S.A.,Institute of General Pathology and Pathophysiology RAMS
Patologicheskaia fiziologiia i èksperimental'naia terapiia | Year: 2013

Effect of the glucose and Mg(2+)-ATP on the coupled with CABA(A)-receptor Cl-,HCO3(-)-activated Mg(2+)-ATPase of the plasma membranes from rat brain involving from "basal" Mg(2+)-ATPase which it is activated by Cl-,HCO3(-) ions it was investigated. The glucose (1-10 mM) decreased the "basal" Mg(2+)-ATPase activity on 17% and completely eliminated the enzyme activation by 10 mM Cl(-)+2 mM HCO3(-) ions. The variety effect of the glucose and Mg(2+)-ATP on the activation of the '"basal" Mg(2+)-ATPase by variety concentrations of anions it was established. So it was found that in the presence Mg(2+)-ATP in the incubation medium > 1 mM the enzyme activation by 10 mM Cl- + 2 mM HCO ions not appear. However, in the presence of the glucose (10 mM) the inhibiting effect of the Mg(2+)-ATP on the enzyme is disappears and Cl-,HCO3(-)-ATPase activity is restored. While, in the presence of the high concentrations 40 mM Cl- + 8 mM HCO3(-) in the incubation medium the inhibiting effect of the glucose and Mg(2+)-ATP it was negligible (-20%). It was conclusion about direct involvement of the glucose and Mg(2+)-ATP in the regulation of the coupled with CABA(A)-receptor Cl-,HCO3(-)-ATPase activity of the neuronal membrane under different concentration anions in the incubation medium.


Rebrov I.G.,Institute of General Pathology and Pathophysiology RAMS
Patologicheskaia fiziologiia i èksperimental'naia terapiia | Year: 2013

Functional activity of the CGABA(A)-receptor/Cl(-) ionophore complex was investigated the muscimol-stimulated entry of the radioactive isotope 36Cl(-) in synaptoneurosomes in changing the structure and permeability of neuronal membranes. Integrity of the membranes was damaged by removal of Ca(+2) and Mg(+2) from the incubation medium and by the method of freezing-thawing synaptoneurosomes. In both cases, an increase in basal 36Cl(-) entry into synaptoneurosomes, indicating increased nonspecific permeability of neuronal membranes, and decreased activity the CABA(A)-receptor/Cl(-) ionophore complex. The conclusion about the relationship of processes damage neuronal membranes and reducing the inhibitory processes in the epileptic focus.

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