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Neurotoxic beta-amyloid peptide plays an important role in the pathology of Alzheimer's disease. In aggregated form it binds to several proteins on the surface of the brain cells leading to their death. p75 receptor in- volved in supporting of cell balance is one of the targets for toxic beta-amyloid. We proposed that induction of antibodies against potential binding sites of p75 with beta-amyloid can be a promising approach towards new drug development for Alzheimer's disease therapy. Four potentially immunoactive fragments of p75 were chosen and chemically synthesized. Investigation of immunoprotective effect of the peptide fragments carried out in mice with experimentally induced form of Alzheimer's disease helped to reveal two fragments effectively preserving murine memory from impairment. Results obtained by ELISA biochemical analysis showed that only immunization with fragment p75 155-164 led to significant decrease in beta-amyloid level in the brain of the experimental mice. Thus, immunization with both fragments of p75 receptor is believed to be an effective tool for the development of new drugs against Alzheimer's disease.

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The effect of immunization with the synthetic fragments of the alpha7 subunit of the acetylcholine nicotine receptor on the spatial memory of mice subjected to olfactory bulbectomy, which causes the development of the neuro-degenetrative disease of Alzheimer's type, was studied. Mice of the NMRI line were immunized with the KLH conjugates of two peptide fragments of the N-terminal fragment of the alpha7 subunit extraxcellular fragment, subjected to olfactory bulbectomy to cause the development of the neurodegenetrative disease of Alzheimer's type, and then the state of the spartial memory was evaluated. It was shown that 20% of bulbectomized mice immunized with the N-terminal 1-23 fragment exhibited good spatial memory after training. Immunization with the peptide construct (159-167)-(179-188) consisting of two hydrophilic exposed regions of alpha7-subunit induced good spatial memory in 50% of bulbectomized mice, while in the control group, which received only KLH, none of the animals were educated. Thus, the development of immunotherapy with peptide (159-167)-(179-188) seems to be a promising approach to prophylaxis and treatment of Alzheimer's disease.

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Olfactory bulbs removal (bulbectomy) induced neurodegeneration in the brain of mice and guinea pigs which, according to its morphological, biochemical and behavioral features was simular to manifestations of Alzheimer's disease. In the present work long-term effects of bulbectomy were examined in rats. It was shown that 1 year after the operation bulbectomized animals (BEA) could be divided into two subgroups: animals with good results of testing spatial memory(BEA-GM), and with poor memory (BEA-PM). The quantitative analysis of neurons morpho-functional state has shown more expressed pathological changes (an increase in the number of cells with pyknosis, karyolysis, cytolysis, and vacuolization) in neurons of temporal cortex and hippocampus in BEA-PM as compared to those in BEA-GM. In both animal groups the reduction of cellular density was marked in the cortex. According to the content of brain beta-amyloid the groups of experimental animals were distributed in the following order: BEA-PM>BEA-GM>control group of sham-operated rats. The results indicate the long-term changes of morpho-functional state of neurons in the brain of BEA, which correlated with the level of their spatial memory.

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The effects of the novel proline-containing nootropic and neuroprotective dipeptide noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were studied on NMRI mice upon olfactory bulbectomy, which had been previously shown to imitate the main morphological and biochemical signs of Alzheimer's disease (AD). The spatial memory was assessed using the Morris (water maze) test; the immunological status was characterized by ELISA with antibodies to prefibrillar beta-amyloid(25-35), S100b protein, and protofilaments of equine lysozyme, which are the molecular factors involved in the pathogenesis of AD. The control (sham-operated) animals during the Morris test preferred a sector where the safety platform was placed during the learning session. Bulbectomized animals treated with saline failed to recognize this sector, while bulbectomized animals treated with noopept (0.01 mg/kg for 21 days) restored this predominance, thus demonstrating the improvement of the spatial memory. These animals also demonstrated an increase in the level of antibodies to beta-amyloid(25-35)--the effect, which was more pronounced in the sham-operated than in bulbectomized mice. The latter demonstrated a profound decrease of immunological reactivity in a large number of tests. Noopept, stimulating the production of antibodies to beta-amyloid(25-35), can attenuate the well-known neurotoxic effects of beta-amyloid. The obtained data on the mnemotropic and immunostimulant effects noopept are indicative of good prospects for the clinical usage of this drug in the therapy of patients with neurodegenerative diseases.

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We studied the immune response in lymphoid cells of mice subjected to bilateral olfactory bulbectomy in comparison with sham-operated animals 1.5 and 13 months after surgery. The concentration of tumor necrosis factor decreased threefold in the peripheral blood of bulbectomized mice 1.5 months after surgery. Signs of immunodepression were also observed 13 months after surgery: suppression of mitogen-stimulated proliferation of T and B lymphocytes in the spleen, inhibition of synthesis of tumor necrosis factor in peritoneal macrophages and splenocytes, and decreased macrophage NO production. According to the immune status indices and our previous data on behavioral, biochemical, and morphological changes induced in bulbectomized mice, they have common symptoms with the Alzheimer's disease. This allows us to consider such animals as a model of sporadic form of this disease rather than of a depression.

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The effect of antioxidant mixture of mineralascorbates (MA) on the status of neurons of brain temporal cortex and behavior of mice after olfactory bulbectomy (BE) was studied, as it was previously shown by us that these animals were characterized by a deficit of spatial memory and development of neurodegenerative process in brain structures, which are affected by Alzheimer disease. Disorganization of cytoarchitectonics of temporal cortex with the deletion of its layers as a result of dystrophy of pyramidal neurons and foci of their complete disappearance were shown 1 month after BE. The increased number of neurons with the phenomena of karyopyknosis, karyolysis and vacuolysis was observed with a concomitant reduction in neuronal density. Addition of MA to the diet for three weeks prevented the development of deterioration of spatial memory in mice after BE and protected the neurons of brain temporal cortex from the degenerative changes. The results obtained suggest the possibility of realization of prophylaxis aimed at the prevention of the development of Alzheimer-type neurodestructive processes.

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The results of the study of the mnemotropic activity of the ergot alkaloid agroclavine are presented. Effects of this substance administered in doses of 1, 10, 25, 50, and 200 micrograms/kg on learning and spatial memory were studied in a Morris water maze. Agroclavine had no effect on learning but sharply impaired the retention. This memory impairment persisted for 48 h after the agroclavine administration. Agroclavine treatment did not affect the ability of mice to learn and retain a new skill. Possible mechanisms of the agroclavine effect on memory are discussed.

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The effects of ultra low power pulse-width + modulation electromagnetic radiation (EMR, power density 10 mc/Wt/cm2, carrying frequency 915 MHz, modulating pulses with frequency 4, 6, 16 and 20 Hz, duration 10 min) on the rat emotional behavior and motor activity in the elevated plus-maze were studied. It was established that EMR (frequency of modulation 4 and 6 Hz) significantly decreased the emotionally negative reactions of anxiety and fear by a factor of 3.7 (p < 0.01) and 4.5 (p < 0.01) correspondingly and increased by a factor of 1.9-2.2 (p < 0.05) exploratory activity. On the contrary EMR (frequency of modulation 20 Hz) significantly increased by a factor of (p < 0.05) emotionally negative reactions of anxiety and fear and decreased by a factor of 1.8 (p < 0.05) the exploratory activity in rats.

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Effects of balis-2 on exploratory activity in the open field and elevated plus-maze, attention to sensory stimuli of different modalities, elaboration and retention of conditioned reflexes with food reinforcement, were studied in rats under stress. Prolonged treatment of rats with balis-2 seems to normalise integrative activity and metabolism of serotonine and dopamine in the animal brain.

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The effects of low level chronic ionising irradiation (12.9 cGy/day on the sensory attention to the stimuli of different modalities (somatosensory, visual, odor) of Wistar rats were studied. Analysis of animals behaviour was made after they had received the different doses of irradiation: 4, 6, 8, 10, 15 and 20 Gy. It was founded, that the attention and exploratory activity of rats is significantly decreased up to 20-30% after 4-6 Gy. The irradiation doses 8 Gy did not change animal behaviour as compared to control animals, but doses 10, 15 and 20 Gy decreased the exploratory activity as well as sensory attention of rats to 3-5-times as compared to previous dose. Such a wave-like way of behaviour reflects the functioning of an adaptive mechanism. Biochemical data indicated that after 5 months of the irradiation (dose 20 Gy) the level of phospholipids, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylcholine, cholesterol were decreased.

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The HCK8 was found to inhibit the field search behaviour in rats. Administration of the peptide impairs formation and reproduction of a habit within 1 hour and 24 hrs. The data obtained suggest an important role of the brain monoaminergic systems in the mechanisms of the HCK8 effect upon learning and memory.

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The effect of taftcine (Thr-Lys-Pro-Arg) and its analog TP-7 (Thr-Lys-Pro-Arg-Pro-Gly-Pro) on rat behavior and serotonin brain exchange was studied in 95 adult male Wistar rats neonatally administered with 5,7-dihydroxytriptamine. Intracutaneous administration of both peptides (300 micrograms/kg) was found to result in weakening perception of stress situations; an increase in stability of investigation behavior and normalization of serotonin level in the brain of rats with chronic deprivation of serotoninergic system activity. Anxiolytic and psychostimulant activities of TP-7 are more pronounced than those of tafcine.

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