Mono-substituted sodium salts of 5-fluoro-, 5-chloro-, 5-bromo-, and 5-iodouracil were synthesized. The toxicity and effect of the synthesized compounds on the DNA-binding activity of transcription factors CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF1á were studied. It was found that the sodium salts of 5-chloro-, 5-bromo-, and 5-iodouracil did not exhibit cytotoxicity comparable with that of the sodium salt of 5-fluorouracil.

Test systems for monitoring activities and the search for substances activating or inhibiting transcription factors as biological targets have been designed on the basis of luciferase constructs containing binding sites for transcription factors CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF1α. An assessment of the functional activity of reporter constructs has been carried out using their transient transfection into HEK293 cells followed by treatment with specific inducers. The functional activity of all reporter constructs was observed based on the increased luciferase expression. In order to evaluate the efficiency of the suggested test systems, aspirin was used. Incubation of cells transfected with the above-mentioned constructs treated with aspirin was accompanied by the suppression of NF-κB, HIF1α, GAS, VDR, and HSF binding activity. The findings revealed for NF-κB, NFAT, and STAT1 confirm the published data concerning the mechanisms of aspirin action. The detected effects of this drug on the HIF1α, GAS, VDR, and CREB activity have been demonstrated for the first time.

На основе репортерных люциферазных конструкций, содержащих сайты связывания транскрипционных факторов CREB, NFAT, NF-кB, p53, STAT1, GAS, VDR, HSF1 и HIF1 , получены тест-системы для мониторинга активности и поиска веществ – активаторов или ингибиторов биомишеней – транскрипционных факторов. Оценку функциональной активности репортерных конструкций проводили путем их транзиентной трансфекции в клетки линии HEK293 с последующей обработкой специфическими индукторами. Показана функциональная активность всех репортерных конструкций, о чем судили по увеличению экспрессии люциферазы. Для доказательства работоспособности предложенных тест-систем использовали аспирин. Показано, что инкубация трансфецированных репортерными конструкциями клеток в присутствии аспирина сопровождается подавлением связывающей активности NF- B, HIF1 , GAS, VDR и HSF. Полученные нами данные в отношении NF- B, NFAT и STAT1 подтверждают литературные сведения о механизмах действия аспирина. Выявленные эффекты препарата на активность HIF1 , GAS, VDR, CREB и HSF показаны впервые.

A library of derivatives of the quinolizidine alkaloid (–)-cytisine with amine, amide, and thio- and carboxamides in the 3-, 5-, and 12-positions were synthesized. Their activity with respect to NFAT transcription factor was studied. It was shown that NFAT modulation activity was a function of the nature of the substituent.

Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. In this study, we investigated the neuroprotective action of noopept on cellular model of AD, Aβ25–35-induced toxicity in PC12 cells and revealed the underlying mechanisms.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The neuropharmacological activity of two (–)-cytisine derivatives with adamantyl fragments was studied. It was shown that N-1-adamantylcytisine-12-thiocarbamide exhibited in tests in vivo a pronounced mnestic effect, increased the lifespan of laboratory animals under hypoxic conditions, and also enhanced in vitro binding of transcription factors NFAT and NF-κB to the DNA sequences corresponding to them.

We studied the effects of single treatment with ladasten (50 mg/kg) on the content of effector kinases of the mitogen-activated cascade (ERK1/ERK2), pERK1/ERK2 activity (Thr202/Tyr204), and expression of genes for neurotrophic factors BDND and NGF in the striatum, hypothalamus, and hippocampus of rats.

We studied the effects of single intragastric administration of ladasten in a dose of 50 mg/kg on the time course of histone deacetylase 1 (HDAC1) and levels of acetylated histones H3 (Lys9) and H4 (Lys8) in the striatum, hippocampus, and hypothalamus. Ladasten reduced HDAC1 level in rat striatum and hippocampus and modified H3acK9 and H4acK8 levels in various structures of rat brain.

Two-dimensional electrophoresis and mass spectrometry detection were used to evaluate the range of proteins in rat brain after single treatment with ladasten (50 mg/kg). We identified 13 proteins with various levels of expression.

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111)--a drug combining the nootrope and neuroprotector properties--on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased. In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest thatthis drug hasaspecific activity withrespect to some pathogenetic mechanisms involved in the Alzheimer disease.

Streptozotocin-intracerebroventricularly treated rats are proposed as an experimental model of sporadic Alzheimer disease (AD). Diabetogenic toxin streptozotocin (STZ) administered in both cerebral ventricles in a dose of 3 mg/kg decreases the expression of NGF and BDNF mainly in the hippocampus and increases the content of malonic dialdehyde (MDA)--a product of lipid peroxidation--in the brain tissues. These metabolic changes are accompanied by a pronounced cognitive deficiency, which is manifested by long-term memory deterioration in the passive avoidance test. These manifestations of pathology are not accompanied by hyperglycemia in the case of intraventricular STZ administration, in contrast to the systemic (in particular, intraperitoneal) route of introduction that causes a pronounced increase in the blood glucose level. These results are consistent with the existing notions that (i) STZ administered intraventricularly provokes a complex of changes imitating the sporadic AD and (ii) this disease can be considered as a manifestation of type-III diabetes. The new original cognition enhancing and neuroprotective dipeptide noopept decreases the aforementioned metabolic changes and the accompanying long-term deterioration of the memory. Previously, this systemically active dipeptide was shown to be capable of increasing expression of NGF and BDNF in the hippocampus, stimulating the antibody production to beta-amyloid, inhibiting the lipid peroxidation, activating the endogenous antioxidant systems, and decreasing the rate of glutamate release (cholinopositive effect). Taken together, these data indicate that noopept can be considered as a multipotent substance acting upon several important pathogenic chainsof the sporadic AD.

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) - a drug combining the nootrope and neuroprotector properties - on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased. In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest that this drug has a specific activity with respect to some pathogenetic mechanisms involved in the Alzheimer disease.

We studied the effects of single administration of ladasten (50 mg/kg) on the level of transcriptional factor CREB (cyclic AMP response binding element protein) phosphorylated by Ser133 in rat striatum, hypothalamus, and hippocampus. Transcriptional factors with affected DNA-binding activity were identified in brain cells.

A new phytoecdysteroid, 24(241)[Z]-dehydroamarasterone B, has been isolated from seeds of Leuzea (Rhaponticum) carthamoides. It has been unambiguously identified by CIMS, 13C NMR and 1H NMR spectroscopy. The biological activity of the ecdysteroid has been determined in the Drosophila melanogaster BII bioassay. The ED50 (5.2 × 10−7 M) is 70-fold higher than that for 20-hydroxyecdysone (7.5 × 10−9 M). © 1997 Elsevier Science Ltd. All rights reserved

The effect of ladasten (50 mg/kg) on the activity of protein kinase C (PKC) in rat brain was studied depending on the duration of drug action. In the initial stage of the drug action, the PKC activity in the cytosol fraction of rat brain proteins exhibits a more than twofold increase. The effect is independent of the presence of exogenous Ca2+ and is inhibited by cinnarizine and nifedipine. The optimum Ca2+ concentration is maintained due to the activation of Ca2+ ATPase. It is concluded that the pharmacological activity of ladasten is related to activation of Ca2+ phospholipid-dependent protein kinases.

The effects of ladasten on the activation-induced expression of Fas-receptor on T-lymphocytes, their sensitivity to Fas-induced apoptosis, and the expression of mitogen-activated ERKI/ERK2 protein kinases have been studied. In the range of concentrations 0.1-10 microM, ladasten exhibited a comitogenic effect on the TCR-mediated stimulation of T-lymhocytes ion the peripheral human blood, which was accompanied by an increase in the level of phosphorylated form of ERK-2. At the same time, ladasten virtually did not change the activation-induced expression of Fas-receptor on T-lymphocytes, but reduced the rate of the Fas-induced apoptosis. It was concluded that the immunoprotective effect of ladasten is probably based on a decrease in the rate of Fas-induced apoptosis.

The effect of ladasten (50 mg/kg) on the activity of cAMP-dependent protein kinases (represented by protein kinase A (PKA)) in the soluble protein fraction of rat brain was studied. Changes in the PKA activity were monitored in the initial period of drug action (1-12 h). In this stage, ladasten increased the PKA activity, and the level of phosphorylation of one isoform of the main protein myelin (14 kD) and of the proteolipid protein (30 kD). It is concluded that the pharmacological activity of ladasten is related to both cAMP-dependent and cAMP-independent signaling systems.