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I M Neelov,
A Janaszewska,
N B Klajnert,
M Bryszewska,
N Z Makova,
D Hicks,
H A Pearson,
G P Vlasov,
M Yu Ilyash,
D S Vasilev, N M Dubrovskaya,
N L Tumanova,
I A Zhuravin,
A J Turner,
N N Nalivaeva
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ABSTRACT: Prevention of amyloidosis by chemical compounds is a potential therapeutic strategy in Alzheimer's, prion and other neurodegenerative diseases. Regularly branched dendrimers and less regular hyperbranched polymers have been suggested as promising inhibitors of amyloid aggregation. As demonstrated in our previous studies, some widely used dendrimers (PAMAM, PPI) could not only inhibit amyloid aggregation in solution but also dissolve mature fibrils. In this study we have performed computer simulation of polylysine dendrimers of 3rd and 5th generations (D3 and D5) and analysed the effect of these dendrimers and some hyperbranched polymers on a lysine base (HpbK) on aggregation of amyloid peptide in solution. The effects of dendrimers on cell viability and their protective action against Aβ-induced cytotoxicity and alteration of K+channels was also analysed using human neuroblastoma SH-SY5Y cells. In addition, using fluorescence microscopy, we analysed uptake of FITC-conjugated D3 by SH-SY5Y cells and its distribution in the brain after intraventricular injections to rats. Our results demonstrated that dendrimers D3 and D5 inhibited amyloid aggregation in solution while HpbK enhanced amyloid aggregation. Cell viability and patch-clamp studies have shown that D3 can protect cells against Aβ-induced cytotoxicity and K+channel modulation. In contrast, HpbK had no protective effect against Aβ. Fluorescence microscopy studies demonstrated that FITC-D3 accumulates in the vacuolar compartments of the cells and can be detected in various brain structures and populations of cells after injections to the brain. As such, polylysine dendrimers D3 and D5 can be proposed as compounds for developing anti-amyloidogenic drugs.
Current Medicinal Chemistry 10/2012; · 4.86 Impact Factor
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ABSTRACT: In old male Wistar rats (older than 12 months), or adult males (3-4 months) subjected to prenatal hypoxia (7% O(2), 3 h, E14), a disruption of short-term memory was observed. Prenatal hypoxia also led to a decrease in the brain cortex of the levels of expression of the metallopeptidases neprilysin (NEP) and endothelinconverting enzyme (ECE-1) which regulate some neuropeptides and are the main amyloid-beta (Αβ)-degrading enzymes. Moreover we have demonstrated a significant decrease (by 2.7 times) of NEP activity in the sensorimotor cortex of old rats and of adult rats subjected to prenatal hypoxia (by 1.7 times). To confirm possible involvement of these enzymes in memory we have performed an analysis of the effect of microinjections of phosphoramidon - an inhibitor of NEP and ECE-1, and thiorphan - an inhibitor of NEP - into the rat sensorimotor cortex. Using a two-level radial maze test, disruption of short-term memory was observed 60 and 120 min after i.c. injections of phosphoramidon (10(-2) M) and 30 and 60 min after i.c. injections of thiorphan (10(-2) M). Thus, involvement of NEP and ECE-1 in short-term memory observed in this study allows us to suggest that one of the main factors in disruption of cognitive functions after prenatal hypoxia or in the process of ageing could be a decrease in the level of expression and activity of metallopeptidases participating in metabolism of Αβ and other neuropeptides.
Neuroscience and Behavioral Physiology 10/2010;
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ABSTRACT: Physiological development, motor activity, and cognitive functions were studied in rats subjected to acute normobaric hypoxic hypoxia (3 h at an O2 concentration of 7%) at different stages of embryogenesis (days E14 or E18). Prenatal hypoxia was found to lead to delays in physiological development and the establishment of motor behavior during the first month of postnatal ontogenesis. These changes were more marked in rats subjected to hypoxia on day 14 of intrauterine development and disappeared with age. In adult rats, regardless of the timing of exposure to hypoxia (E14 or E18), learning ability was degraded and long-term and short-term memory were impaired. These results suggest that exposure to the pathogenic factor during the main period of neuroblast generation and migration (E14) was significant both for physiological development and the establishment of motor behavior in the animals and for the execution of the cognitive functions of the brain, while exposure during the period at which maturation and differentiation processes dominate in the brain (E18) was more significant in relation to the execution of cognitive functions.
Neuroscience and Behavioral Physiology 02/2010; 40(2):231-8.
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International Journal of Psychophysiology - INT J PSYCHOPHYSIOL. 01/2008; 69(3):156-156.
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ABSTRACT: Using light microscopy (Nissl and Golgi techniques), electron microscopy and immunohistochemistry, formation of structure
of the brain striatum dorsolateral part from birth to three month of age was studied in rats submitted to acute hypoxia at
the period of embryogenesis. Hypoxia at the 13.5th day of pregnancy (E 13.5) was found to lead to a delay of neuronogenesis
for the first two weeks of postnatal development as compared with control animals, and the majority of large neurons for this
period were degenerated by the type of chromatolysis with swelling of the cell body and processes and lysis of cytoplasmic
organelles. By the end of the third week, shrunken hyperchromic or pycnomorphic neurons with the electron-dense cytoplasm
and enlarged tubules of endoplasmic reticulum and Golgi complex were also observed. An increased number of swollen processes
of glial cells was found in neuropil around the degenerating neurons. By the 30th day as well as in adult animals, destruction
of mitochondrial apparatus, an increased number of lysosomes, and blade-shaped nuclei, which are characteristics of the apoptotic
cell death, were observed. This is also confirmed by an increased expression of proapoptotic protein (p53) and its co-localization
with caspase-3 in a part of neurons. Morphometric analysis showed a decrease of the cell distribution density in striatum
and a change of ratio of different cell types in hypoxia-exposed rats as compared with control group. The most pronounced
decrease (42.3% at the 5th day, 14.2% at the 10th day, p < 0.01) of the number of large neurons (larger than 80 μm2) was revealed at early stages of postnatal ontogenesis. After 3 postnatal weeks, the number of middle-sized neurons (30–95
μm2) decreased (by 11.8–19.2% as compared with control, p < 0.05). The obtained data have shown that changes of embryogenesis conditions (hypoxia) at the period of the most intensive
proliferation of telencephalon neuroblasts lead to impairment of the process of striatal nervous tissue formation. This might
be the cause of delay of development and disturbances of behavior and learning, which are observed in rats exposed to prenatal
hypoxia.
Journal of Evolutionary Biochemistry and Physiology 03/2007; 43(2):229-239. · 0.24 Impact Factor
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ABSTRACT: Intracortical administration of 10(-4) M batimastat, a specific inhibitor of alpha-secretase (a metalloproteinase which cleaves the amyloid peptide precursor), decreased the number of correct runs in a single-level eight-arm maze to 92.78 +/- 1.03% compared with baseline (p < 0.01) within 60 min. However, injection of batimastat into the cerebral cortex of animals during the early postnatal period (days 5 and 7 of life) led to impaired orientation in the simple single-level maze when these adults reached adulthood (90.92 +/- 2.21% correct runs, p < 0.001) as compared with controls. The data obtained here provide evidence for the important role of alpha-secretase in memory processes. The possible role of alpha-secretase in memory processes and the pathogenesis of Alzheimer's disease is discussed.
Neuroscience and Behavioral Physiology 11/2006; 36(9):911-3.
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ABSTRACT: Light (Nissl and Golgi methods) and electron microscopy methods were used to study the formation of the structure of the striatum during the first two weeks after birth in rats subjected to acute hypoxia at different times of embryogenesis. The dynamics of the physiological development of the same population of rats were studied in parallel. Hypoxia at day 13.5 of embryogenesis was found to lead to delayed neurogenesis (delayed establishment of elements of the neuropil and differentiation of cells) and abnormalities in the structure of the striatum (degeneration, particularly chromatolysis, of neurons and the appearance of glial nodes). Morphometric analysis demonstrated a decrease in the total number of cells in the striatum; small changes in large neurons were seen. Hypoxia at day 18.5 of embryogenesis produced no significant changes. Structural abnormalities were accompanied by changes in the process of the animals' physiological development. The data obtained here show that changes in the conditions of embryogenesis (hypoxia) during the period of the most intense proliferation of neuroblasts in the forebrain lead to impairment of the process of formation of striatal nervous tissue and the body as a whole in the period of early postnatal ontogenesis.
Neuroscience and Behavioral Physiology 07/2006; 36(5):473-8.
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ABSTRACT: Light (Nissl and Golgi methods) and electron microscopy methods were used to study the formation of the structure of the striatum
during the first two weeks after birth in rats subjected to acute hypoxia at different times of embryogenesis. The dynamics
of the physiological development of the same population of rats were studied in parallel. Hypoxia at day 13.5 of embryogenesis
was found to lead to delayed neurogenesis (delayed establishment of elements of the neuropil and differentiation of cells)
and abnormalities in the structure of the striatum (degeneration, particularly chromatolysis, of neurons and the appearance
of glial nodes). Morphometric analysis demonstrated a decrease in the total number of cells in the striatum; small changes
in large neurons were seen. Hypoxia at day 18.5 of embryogenesis produced no significant changes. Structural abnormalities
were accompanied by changes in the process of the animals’ physiological development. The data obtained here show that changes
in the conditions of embryogenesis (hypoxia) during the period of the most intense proliferation of neuroblasts in the forebrain
lead to impairment of the process of formation of striatal nervous tissue and the body as a whole in the period of early postnatal
ontogenesis.
Neuroscience and Behavioral Physiology 05/2006; 36(5):473-478.
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ABSTRACT: The aim of the present work was to identify the characteristics of the physiological development of the brain and the formation of behavior in rats subjected to hypoxia on day 13.5 of embryogenesis. These animals showed delayed development and changes in nerve tissue structure in the sensorimotor cortex, along with disturbances to the processes forming normal movement responses during the first month after birth. These changes were partially compensated with age, though adult animals subjected to acute prenatal hypoxia were less able to learn new complex manipulatory movements. Alterations in nerve tissue structure and changes in the neuronal composition of the sensorimotor cortex correlated with the times of appearance of behavioral impairments at different stages of ontogenesis. Thus, changes in the conditions in which the body is formed during a defined period of embryogenesis lead to abnormalities in the process of ontogenetic development and the ability to learn new movements.
Neuroscience and Behavioral Physiology 11/2004; 34(8):809-16.
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ABSTRACT: Using a model of acute hypoxia during pregnancy of rats, changes in the development of old (hippocampus) and new (sensorimotor) cortex associated with disturbance of neuronogenesis have been revealed in the studied brain structures at the period of action of a pathological factor. It was found that in rats submitted to hypoxia at the 13–14th days of embryogenesis, the number of degenerating neurons (including the pyramidal ones) at various levels of chromatolysis increased since the 5th day after birth; the increase was present for the entire first month of postnatal development. In the cortex of rat pups submitted to prenatal hypoxia there were observed deformation of neuronal bodies, vacuoles in the cytoplasm, shrinkage of apical dendrites of pyramidal neurons and delayed development of the structure (time of the appearance of spikes, formation of structural elements and the size of the cells) of the nervous tissue of the brain of the rat pups exposed to prenatal hypoxia. The columnar structure of the cortex was disturbed. In hippocampus, the process of degeneration of neurons started by 2–3 days later than in the cortex; by two weeks of postnatal development a massive degeneration and death of a part of neurons were also revealed. The morphometrical analysis showed a decrease in the number of neurons and their total area in the sensorimotor cortex (the layer V) and an increase in the number of glial elements at the 10–17th days after birth. In the hippocampus a decrease in the area occupied by neurons and in their size was detected in adult animals. The adult rats submitted to prenatal hypoxia were found to have disturbances of memory and learning. A correlation was shown between the disturbances of the conditions of embryonic development and the changes in the ability of learning and storage of new skills in the offspring.
Journal of Evolutionary Biochemistry and Physiology 10/2003; 39(6):752-763. · 0.24 Impact Factor
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ABSTRACT: The role of the striatal adenylyl cyclase (AC) and cholinergic systems in the learning and expression of new forepaw movements (reaching with prolonged pushing on a fixed piston) was studied in male Wistar rats. Motor learning processes, prenatal hypoxia, and cholinergic drugs changed the properties of the AC system in the striatum. After learning, the striatal basal AC activity was decreased compared to untrained control rats. In addition, the AC activity was more decreased in animals with a good ability to learn compared to poor learners (up to 31 % and 51 %, correspondingly; p<0.01). Rats subjected to prenatal hypoxia (13-14th days of embryogenesis) had a lower ability to learn the new movements requiring tactile control and the striatal AC activity in these rats was 1.8 times higher (p<0.001) than controls. In vitro application of the cholinergic agonist carbachol (CARB) 10-5 M (corresponding to approximately 0.3 microg), as well as the antagonist scopolomine (SCOP) 10(-5) M (approximately 0.3 microg) decreased AC activity in the synaptosomal fraction of the striatum. In vivo injections of CARB (0.3-3 microg/1microl) or SCOP (0.3-3 microg/1microl) into the ventral striatum (nucleus accumbens) modified the newly learned sensorimotor skill. After CARB injections the rats performed slower movements with more prolonged pushing. After SCOP the rats could not retain the learned pushing movement. These in vivo and in vitro data suggest that the cholinergic mediator system of the striatum is involved in learning sensory-controlled forepaw movements as well as the regulation of new motor skills by modulating the AC signal transduction process in the striatum. The data confirmed that modification of the striatal AC system resulted in the modulation of reaching behavior and better expression of the learned reflex.
Physiological research / Academia Scientiarum Bohemoslovaca 01/2002; 51 Suppl 1:S67-76. · 1.55 Impact Factor
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ABSTRACT: The experiments were performed on adult Wistar male rats trained to push with the forepaw on a fixed piston inside a narrow tube. It was found that after localized intracerebral injection of a cholinergic antagonist into the dorso-lateral (but not medial) neostriatum (i.e., the caudato-putamen) the behavioral performance requiring brief innate movements remained unchanged, but the performance requiring a prolonged pushing movement (> 50 msec) became disrupted. Micoinjection of carbacholine (0.03-3 mu g/l microliters) did not affect the performance of the acquired movements, whereas scopolamine (3 mu g/l microliters) led to the significant decrease in pushing time. We conclude that changes in the state of the dorso-lateral neostriatal cholinergic system result only in disturbances of the sensory-controlled component of a complex instrumental movement.
Integrative Physiological and Behavioral Science 04/1995; 30(2):127-37. · 2.43 Impact Factor
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ABSTRACT: The role of the cholinergic system of the sensorimotor cortex of the Wistar rat brain in controlling various types of movements was assessed by studying the effects of microinjections of carbachol and scopolamine into the representation area of the forelimb on the performance of two types of fore-limb food-procuring movements--with and without pressure on an obstacle--as well as on the animals' locomotion. These studies showed that administration of the cholinergic agonist carbachol (0.03-3 microg) leads to slowing of both types of procuring movements and acceleration of locomotor activity in an open field. Injections of the cholinergic antagonist scopolamine (0.3-3 microg) into the same area accelerated procuring movements, while the animals' locomotor activity remained unaltered. These data indicate that the cholinergic system of the sensorimotor cortex has different regulatory influences on movement activity (locomotion) and the performance of learned movements requiring forelimb muscle tone to be maintained for different periods of time (the usual rapid movements used for extracting food from a narrow horizontal tube versus slow movements with additional tactile and tonic components).
Neuroscience and Behavioral Physiology 31(2):145-51.
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ABSTRACT: Adenylate cyclase (AC) and 5'-nucleotidase (NT) activities were measured in the limbic (amygdala, hippocampus) and sensorimotor (cortex, striatum) structures of the brain in three groups of rats: untrained rats and rats which were good and poor learners in training to perform movements involving pushing against an obstruction. After training, AC activity decreased in all structures studied. Activity decreased in the cortex and striatum to a greater extent in good learners, and in the amygdala in poor learners. NT activity decreased in all brain structures apart from the striatum, to a greater extent in rats which were less able to learn to produce movements involving prolonged pushing. The striatum was the only structure in which increases in NT activity occurred, from the lowest initial level in the control group. 1.0 +/- 0.04 microgram P(i)/mg protein/min, to 1.3 +/- 0.1 micrograms P(i)/mg protein/min in poor learners and to 2.0 +/- 0.1 micrograms P(i)/mg protein/min in good learners. Interhemisphere asymmetries in AC activity in the cortex and hippocampus were seen, along with an interhemisphere difference in NT activity in the amygdala. Thus, the activity of enzymes involved in adenine and cAMP biosynthesis changed in different ways in the limbic and sensorimotor structures of the brain, depending on the ability of rats to learn. The increase in NT activity after training of rats, which was limited to the striatum, may reflect a special role for the purinergic system in these structures in mediating sensation-regulated movements.
Neuroscience and Behavioral Physiology 26(6):552-7.
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ABSTRACT: The participation of the cholinergic system of the neostriatum in the regulation of sensorily-monitored movements and the differentiation of sensory signals were investigated in 12 Wistar rats, 27 Sprague-Dawley rats, and 6 mongrel dogs, using the following models: 1) the maintenance of learned extension of the forelimb for a specified time (rats); 2) prolonged conditioned reflex flexion of the hind limb (dogs); and 3) active avoidance in a T-maze (rats). It was demonstrated that the injection of carbacholine (0.03 microgram) into the dorsolateral division of the caudate nucleus of the rats does not bring about significant changes in the performance of movements associated with the maintenance of tonus of the forelimb, whereas the injection of carbacholine (0.05-0.1 microgram) into the same division of the caudate nucleus of the dogs improves the realization of movement associated with the maintenance of tonus of the hind limbs. The injection of a blocker of the cholinergic system (scopolamine in the rats and atropine in the dogs) in both the first and the second instance disturbed the performance of the movement by the animals. Bilateral microinjections of carbacholine (0.03 microgram) into the neostriatum of the rats significantly improves the development of a differentiated active avoidance conditioned reflex in a T-maze on the first three days of testing. The differentiation of acoustic signals by dogs also significantly improved against the background of the injection of carbacholine (0.05-0.1 microgram) into the caudate nucleus. Thus, the data obtained in the various behavioral models and different animals suggest that the cholinergic system of the neostriatum participates in the regulation of both motor and sensory mechanisms in connection with the realization of learned movement.
Neuroscience and Behavioral Physiology 26(2):164-73.
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Doklady Biological Sciences 438:145-8.
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ABSTRACT: Comparative studies were performed of the effects of injections of a cholinergic agonist (carbachol) and antagonist (scopolamine) into the ventral and dorsal striatum on the performance of a learned movement involving prolonged maintenance of extension of the forelimb in rats. Doses of carbachol (0.03-3.00 micrograms) into the ventral striatum were accompanied by increases in the numbers of movements with prolonged maintenance of extension with application of pressure against an obstacle, with a simultaneous decrease in the percentage of rapid nonreinforced movements (by an average of 18.8%). Injections into the dorsal striatum disrupted slow movements which were not reinforced during training, on a background of stable performance of the learned reflex. Doses of scopolamine (0.3-3.0 micrograms) into both the dorsal and ventral parts of the striatum produced increases (by 22.7 +/- 8.2% and 68.9 +/- 14.3%) in the numbers of rapid nonreinforced movements typical of the repertoire of untrained animals. These data led to the suggestion that the cholinergic system of the ventral striatum is involved in the maintenance of forelimb muscle tone in rats during the performance of movements in which pressure is applied to an obstacle. The cholinergic system of the dorsal striatum does not have this property, but plays a significant role in the process of learning new sensory-controlled movements.
Neuroscience and Behavioral Physiology 28(4):386-91.
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ABSTRACT: Indicators of the activity of acetylcholinesterase (ACE), 5'-nucleotidase (NT), adenylate cyclase (AC) in the sensorimotor cortex and the neostriatum (NS) of the right and left cerebral hemispheres of control rats and rats trained to perform a food-procuring movement by pressing against an obstacle with the forelimb. An identical level of the averaged bilateral values of the activity of NT and AC in both of the structures in question and an increased ACE activity in the NS were found in the control animals. After the development of a manipulatory skill, the activity of AC decreased in the cortex and the NS in the presence of unchanged ACE activity, while NT activity decreased in the cortex and increased in the NS. The bilateral values of the activity of the enzymes differed significantly in well and poorly trained rats. At the same time, the activity of the enzymes was similar in character in the dominant and subdominant hemispheres for each group of animals. Overall the neurochemical changes obtained can be regarded as specific correlates of the developed unilateral manipulatory reactions that are characteristic for the structures in question of both cerebral hemispheres.
Neuroscience and Behavioral Physiology 25(2):117-21.
