Evaluation of the Hepatoprotective Effect of L-Ascorbate 1-(2-Hydroxyethyl)-4,6-Dimethyl-1,2-Dihydropyrimidine-2-One Upon Exposure to Carbon Tetrachloride.

Hepatoprotective properties of a new pyrimidine derivative - L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropyrimidine-2-one, synthesized on the basis Xymedon, were assessed in white rats exposed to CCl4. The compound under study administered prior to exposure to CCl4 reduced the deviation of biochemical parameters from reference values and severity of structural and morphological changes in liver, when compared to the control. Hepatoprotective properties of the studied compound were more pronounced than those of Xymedon.

New Xymedon Analogues for Stimulation of Posttraumatic Regeneration of the Spinal Cord in Rats.

Effect of systemic administration of synthetic pyrimidine derivatives, xymedon and compounds 29D and 34D, was studied in rats with experimental dosed contusion spinal cord injury. Xymedon promoted recovery of motor function after injury. Compounds 29D and 34D more effectively restored the parameters of open-field and Rotarod tests in comparison with xymedon. Compound 29D more effectively than xymedon maintained the number of Olig2+ oligodendrocytes in the corticospinal tract and NG2 cells in all investigated areas of the white matter. In the group treated with compound 34D, the differences in the number of NG2+ cells were revealed only in the anterior funiculi, where the number of these glial cells was 2-fold higher than in the xymedon-treated group. Obtained results suggest that the studied xymedon analogs, compounds 29D and 34D, can exert their therapeutic action through different molecular and cellular pathways.

Antibacterial and antifungal activity of acyclic and macrocyclic uracil derivatives with quaternized nitrogen atoms in spacers.

The reactions of 1,3-bis(alpha,omega-bromoalkyl)-6-methyluracils with 1,3-bis(alpha,omega-ethylaminoalkyl)-6-methyluracils or 1,3-bis(bromopentyl)thymine with butylamine afforded pyrimidinophanes containing one or two uracil units and nitrogen atoms in bridging polymethylene chains. In some cases individual geometric isomers of pyrimidinophanes differing in the mutual arrangement of the carbonyl and methyl groups at different pyrimidine rings were isolated. Quaternization of the bridging nitrogen atom with o-nitrobenzyl bromide, benzyl bromide, n-decyl bromide gave rise to water-soluble pyrimidinophanes which were evaluated for their antibacterial and antifungal activity. The arrangement of the carbonyl groups in macrocycles doesn't affect the activity. Antibacterial and antifungal activity of pyrimidinophanes increases with the increase of polymethylene N(pyr)-N-chain length and dramatically increases upon the introduction of n-decyl substituent at nitrogen atoms in spacers. Pyrimidinophanes with 5 and 6 methylene groups in N(pyr)-N-chain and n-decyl substituent showed significant bacteriostatic, fungistatic, bactericidal, fungicidal activity which comparable with standard antibacterial and antifungal drugs. Acyclic counterpart demonstrated the highest activity against fungi. Toxicity of more effective pyrimidinophanes was determined for mice and Daphnia magna Straus.

Pirimidine derivatives as hepatoprotective agents.

BACKGROUND: Research and development of effective hepatoprotective medicines is one of the priority areas of research in Russia. Literature data shows that active research and development of hepatoprotectors is carried out both in Russian and other countries [1-6]. Pirimidines are used as hepatoprotective medicines stimulating protein synthesis and reparation of hepatocytes in toxical and infectious liver disorders [7]. In our previous work ee have shown hepatoprotective properties of pyrimidine derivative, named Xymedon [8]. This research, funded by the Russian Science Foundation, is aimed at identifying the most effective hepatoprotectors among pirimidine derivatives. OBJECTIVE: To test hepatoprotective properties of one of the new Xymedon (Xym) derivative - L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydro-pirimidine-2-one (Asc-Xym) on the toxic liver damage model induce by carbon tetrachloride (CTC, CCl4). METHODS: The toxic liver damage in rats was modeled by subcutaneous injection of CTC (CCl4) in vegetable oil (mixed at 1:1 ratio) at a dose of 2 ml per kg. The experiments were carried out under two schemes: 1) oral administration of Xym or Asc-Xym preparations by gavage at the doses of 10 and 20 mg/kg followed by subcutaneous injection of CTC 1 hour after pyrimidine oral administration and continued for 3-4 days; - this was the design of preventive pyrimidine use, 2) liver damage modeling by CTC subcutaneous injections for 3 days followed by oral administration of Xym, Asc-Xym or Thiotriazolin (Thi) preparations at the doses of 20 mg/kg for 5 days; - this was the design of therapeutic scheme. The rats of control groups were injected with CTC according to the same schemes, but did not get any preparations. We looked at some biochemical parameters of blood serum: alanine aminotran-sferase (AlAT), aspartate aminotransferase (AsAT), their ratio (de Rytis coefficient), and the total protein level as the markers of toxic liver damage. We performed statistical data analysis by rank nonparametric Mann-Whitney U-criterion for comparison of two independent groups. We evaluated pathomorphologic characteristics of liver damage on the histological slices colored with hematoxylin and eosin. RESULTS: Carbon tetrachloride (CTC) caused profound changes in the studied biochemical parameters of rats' blood serum. The AlAT activity level in the serum of control animals in the preventive scheme was 116,23 (the median) with the lower quartile and the upper quartile of 76,96 and 211,71 U/l respectively; the AsAT level was 230,08/201,49-290,03 U/l; this was the increase in comparison with the reference values. De Rytis coefficient was 1,76 /1,47-2,67. This was the decrease in comparison with the reference values of intact group (36,37/28,18-43,3 U/l; 132,95 /118,24-164,00 U/l and 4,26/3,03-5,23 respectively). The differences were statistically significant at P < 0,001. In the experimental groups the changes of the biochemical parameters with respect to the reference values were less marked than in Control. The AlAT level was 89,86/87,06-165,15; 103,23/38,19-270,87 U/l; 80,28/6,12-141,82 and 100,33/62,24-144,64 U/l in the groups of rats treated with Xym at the doses of 10 and 20 mg/kg or Asc-Xym at the doses of 10 and 20 mg/kg respectively. Similarly, in the same groups the AsAT level was 211,19/170,20-250,16; 193,61 /181,57-274,69 U/l; 190,91 /65,21-198,65 and 173,25/135,50-210,70 U/l respectively. The differences of the AsAT level were statistically significant at P < 0,05 in comparison with Control in the both groups treated with Asc-Xym.Nnearly 2 times increase of the AlAT level (67,60/1,22-94,60 U/l) (P = 0,00002) was shown in comparison with the reference values in the rats of Control group in the therapeutic scheme. However the AsAT level (163,80/130,1-178,8 U/l) was only slightly higher than reference values. De Rytis coefficient (2,07/1,78-3,48) was significantly lower than the reference values (P = 0,001). The total protein level (59,36/55,17-60,10 g/l) was lower than the reference values (65,06/62,06-68,98 g/l) by 8,4%. The differences of biochemical parameters as compared with the reference values in rats of experimental groups treated with Xym, Thi and Asc-Xym at the doses 20 mg/kg were less than those in the Control groups. They were: AlAT 52,49/44,64-62,30 and 61,42/53,20-96,66 U/l, AsAT 105,00/94,7-142,3 and 235,35/111,7-335,6 U/l, de Rytis coefficient 2,09/1,87-2,28 and 3,24/1,86-4,53, total protein 63,10/62,46-64,27 and 62,46/58,70-64,43 g/l respectively in the groups treated with Xym and Thi. The values of the studied biochemical parameters AlAT (39,04/32,46-44,24 U/l), AsAT (111,9/105,27-155 U/l), de Rytis coefficient (2,87/2,72-3,30), total protein (62,89/61,46-68,14 g/l) of the rats, treated with Asc-Xym, were the most close to the reference values in comparison with other experimental groups.The analysis of histological slices revealed large areas of steatosis and necrosis of hepatocytes in Control groups in both schemes. These were less pronounced in experimental groups than in Control groups and particularly in rats, treated with Asc-Xym. CONCLUSIONS: Hepatoprtotective properties of the new compound L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropirimidine-2-one were established. The hepatoprotective efficacy of the compound is higher than that of Xymedon and Thiotriazolin.

6-Methyluracil derivatives as acetylcholinesterase inhibitors for treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Aß production and clearance, resulting in increased amount of Aß in various forms [2]. Reduction of Aß production and increasing clearance of Aß pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to increase lifetime of cerebral acetylcholine [3]. It is important to emphasize that AChE itself promotes the formation of Aß fibrils in vitro and Aß plaques in the cerebral cortex of transgenic mouse models of AD [4]. This property of AChE results from interaction between Aß and the peripheral anionic site of the enzyme (PAS) [5]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Aß-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited. OBJECTIVE: To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer's disease. METHODS: In vitro studies. Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7]. The ability of compound to block in vitro AChE-induced Aß1-40 aggregation was studied using a thioflavin T (ThT) fluorescent probe [8].In vivo biological assays. For in vivo blood-brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman.Scopolamine and transgenic models of AD were used to evaluate the influence of compound 35 on spatial memory performance.Water solution of scopolamine was injected to mice (ip) 20 minutes before starting memory test during 14 days [9]. Mice were assigned to 7 groups, including 4 groups receiving injection (ip) of compound in different dosages, donepezil-treated mice (donepezil is conventionally used to treat Alzheimer's disease), positive and negative control groups. Double transgenic (APP/PS1) mice expressing a chimeric mouse/human amyloid precursor protein and a mutant of human presenilin-1 [10] were assigned to 4 groups, including transgenic animals injected (ip) with compound 35 or donepezil solution, positive (transgenes injected with water) and negative (wild-type mice) controls.To evaluate spatial memory performance, mice were trained on a reward alternation task using a conventional T-maze [11]. The criterion for a mouse having learned the rewarded alternation task was 3 consecutive days of at least 5 correct responses out of the 6 free trials.For ß-amyloid peptide load was evaluated quantitatively as a number and summary area of Thioflavine S fluorescent spots in cerebral cortex and hippocampal images using Image J program. Statistical analyses were performed using the Mann-Whitney test. RESULTS: We evaluated the acute toxicity of the most active compounds. The most potent AChE inhibitor compound 35 (IC50 (AChE) = 5 ± 0.5 nM) exhibited the lowest LD50 values (51 mg/kg) and inhibited brain AChE by more than 71 ± 1%. Compound 35 at 10 nM, exhibited a significant (35 ± 9%) inhibitory activity toward human AChE-induced Aß aggregation.Scopolamine injection induced significant decrease in correct choice percentage in T-maze, as well as decrease in percentage of mice reaching criterion for learning the task by day 14. This memory deficit was relieved to some extent either by compound 35 (5 mg/kg) or donepezil (reference compound) treatment (0.75 mg/kg). Interestingly, higher doses of compound 35 (10 and 15 mg/kg) produced less therapeutic effect on spatial memory deficit.Group of APP/PS1 mice showed 3 times lower percentage of reaching behavioral criterion and lower percentage of correct choice in T-maze alternation task comparing to WT mice, whereas compound 35 (5 mg/kg) or Donepezil treatment effectively improved these parameters in APP/PS1 mice.Compound 35 treatment (5 mg/kg) during 14 days significantly reduced percentage of summary area and number of ß-amyloid peptide (ßAP) deposits visualized in sections of cerebral cortex, dentate gyrus, and hippocampal CA3 area in APP/PS1 mice. The most prominent reduction of ßAP load by compound 35 treatment was found in CA3 area and cerebral cortex. Meanwhile, Donepezil treatment (1 mg/kg) during 14 days significantly reduced ßAP load in cerebral cortex but not in dentate gyrus and CA3 area. CONCLUSIONS: Experiments showed that the most potent AChE inhibitor compound 35 (6-methyluracil derivative) permeated the blood-brain barrier, improved working memory in the APP/PS1 transgenic mice and significantly reduced the number and area of Aß plaques in the brain. Thus, compound 35 is a promising candidate as a bi-functional inhibitor of AChE for treatment of AD.

Statistical theory for incoherent light propagation in nonlinear media.

A statistical approach based on the Wigner transform is proposed for the description of partially incoherent optical wave dynamics in nonlinear media. An evolution equation for the Wigner transform is derived from a nonlinear Schrödinger equation with arbitrary nonlinearity. It is shown that random phase fluctuations of an incoherent plane wave lead to a Landau-like damping effect, which can stabilize the modulational instability. In the limit of the geometrical optics approximation, incoherent, localized, and stationary wave fields are shown to exist for a wide class of nonlinear media.

[The development and introduction of a rational system for the protection of the personnel in a large enterprise against attack by blood-sucking arthropods in western Siberia]. / Razrabotka i vnedrenie ratsional'noi sistemy zashchity personala krupnogo predpriiatiia ot napadeniia krovososushchikh chlenistonogikh v Zapadnoi Sibiri.

In the middle Ob River Valley (north and moderate taiga), a large number of bloodsucking dipterans (mosquitoes, blackflies, biting midges, horseflies) are recorded during 90-100 days; the activity of Ixodes persulcatus and their attack on humans are notified during 90-115 days. A package of measures that protect petroleum industrial workers from the attacks of bloodsucking insects and ticks includes the use of protective suits, the treatment of premises with insecticides, the use of repellents, and health education. Protective means for workers should be the items included into the list of expenses on safety measures. Work is done on a cost-accounting principle. The introduced system annually shows a high efficiency (95-98%) in protecting large groups of workers in their working places.

Amphiphilic macrocycles bearing biofragment: molecular design as factor controlling self-assembly.

Two novel macrocyclic 6-methyluracilic amphiphiles (uracilophanes) with four (UP1) and two (UP2) uracil moieties and ammonium groups have been synthesized. Tetracationic multi-uracilophane is composed of two macrocyclic units bridged each other with an external methylene spacer, while in the cryptand-like dicationic uracilophane pyrimidinic moieties are connected with an internal methylene spacer. This internal spacer provided a conformational rigidity to the macrocycle. The self-assembly of the uracilophanes is studied and compared with a reference dicationic uracilophane (UP3) with no spacer fragment. Compounds UP1 and UP3 are capable of aggregating, which is characterized by the analogous critical micelle concentration of 1mM, although the former has four decyl tails versus two decyl tails in UP3 molecule. NMR self-diffusion, fluorimetry and DLS techniques revealed that bimodal size distribution occurs in the UP1 solution, with small (≤2nm) and large (ca. 30-50 nm) aggregates contributed. Unexpectedly, the cryptand-like uracilophane UP2 with the same hydrophobicity as UP3 does not form aggregates. The balance of the geometry and energetic factors was analyzed and compared with those contributing to the aggregation of the reference compound UP3. It was established that it is the geometry that controls the packing of the cryptand-like uracilophanes upon aggregation, while hydrophobic effect plays a minor role. In contrast, both factors control the aggregation of oligomeric macrocycle, with energetic factor prevailing. These findings are of importance for (i) the understanding the diverse structural behavior of bioamphiphiles that have very similar chemical structure, but different conformations; and (ii) the design of amphiphiles with controlled model of self-assembly. Supramolecular systems studied can be recommended for biotechnological applications.

Experimental electron energy distribution function investigation at initial stage of electron cyclotron resonance discharge.

Experimental investigation is undertaken to study formation of electron energy distribution function (EEDF) at the initial stage of electron cyclotron resonance (ECR) discharge inside magnetic mirror trap. In experiment, where discharge was initiated by high power radiation of gyrotron operated in the mm-wavelength range, electrons were revealed to leave the trap having EEDF be quite different from Maxwellian one. Specifically, the EEDF was found to decrease slowly with energy up to 400-500 keV and drops abruptly further. The possible physical mechanisms are discussed to explain losses of high energy electrons from the trap and a limitation of their energy.

Algorithm of invariant image description by the use of a modified Gabor transform.

A scale-invariant algorithm of image description that is derived from the investigations of the neural structure of striate complex modules is proposed. First an image is preprocessed by difference-of-Gaussians functions, then the Gabor expansion in modules of different scales is used, and a group of the most excited modules is looked for with the help of scale weighting functions (SWF's). Finally, the image code is calculated as a linear combination of the output signals from the Gabor modules. The coefficients of this linear combination correspond to the SWF selected in the previous step. The scales of Gabor modules are chosen to be a logarithmic sequence with a half-octave step. Because of the SWF method, the described algorithm takes into account all the image sizes on a continuum between the minimum and the maximum scales of the Gabor modules.