Dimebon, a Russian-made drug, inhibited toxic effects of beta -amyloid on cultured neurons. Excessive accumulation of beta-amyloid in the brain is characteristic of Alzheimer dementias. Antialzheimer preparations tacrine and dimebon improve survival of cerebellar granule cells during long-term incubation with Abeta25-35, the neurotoxic fragment of beta-amyloid. Both preparations can block potential-dependent Ca(2+) entry into neurons by about 20%, which is explained by their selective action on L-type Ca(2+) channels. It was assumed that the neuroprotective effect of dimebon and tacrine against Abeta25-35 partially depends on inhibition of potential-dependent Ca(2+) entry.

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

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A series of Zn, Mn, Fe, Co, and Ni complexes ([MX2L], X = Cl, OAc) of the novel di-(2-picolyl)amine ligand L with an antioxidant 2,6-di-tert-butylphenol pendant were synthesized and characterized by elemental analysis, IR, multinuclear NMR spectroscopy, MALDI-TOF mass spectrometry and the molecular structures of [ZnCl2L] and [MnCl2L] were established by X-ray crystallography. The chemical oxidation of complexes with a 2,6-di-tert-butylphenol fragment to the phenoxyl radicals was studied by means of ESR method. The antioxidant radical scavenging activity of the complexes was measured spectrophotometrically using a DPPH-test and linoleic acid peroxidation. The electron transfer reactions were examined in CUPRAC tests and as the inhibition of an enzymatic reaction involving the generation of a reactive oxygen species (superoxide radical-anion) by xanthine oxidase. The lipoxygenase (LOX) inhibition activity of the studied compounds was evaluated. The in vitro biological experiments were performed by using rat brain homogenates. The role of the phenol fragment and metal was found to be essential in antioxidant activity.

Brucellosis is a major zoonotic infection in Kazakhstan. However, there is limited data on its incidence in humans and animals, and the genetic diversity of prevalent strains is virtually unstudied. Additionally, there is no detailed overview of Kazakhstan brucellosis control and eradication programs. Here, we analyzed brucellosis epidemiological data, and assessed the effectiveness of eradication strategies employed over the past 70 years to counteract this infection. We also conducted multiple loci variable-number tandem repeat analysis (MLVA) of Brucella abortus strains found in Kazakhstan. We analyzed official data on the incidence of animal brucellosis in Kazakhstan. The records span more than 70 years of anti-brucellosis campaigns, and contain a brief description of the applied control strategies, their effectiveness, and their impact on the incidence in humans. The MLVA-16 method was used to type 94 strains of B. abortus and serial passages of B. abortus 82, a strain used in vaccines. MLVA-8 and MLVA-11 analyses clustered strains into a total of four and seven genotypes, respectively; it is the first time that four of these genotypes have been described. MLVA-16 analysis divided strains into 28 distinct genotypes having genetic similarity coefficient that varies from 60 to100% and a Hunter & Gaston diversity index of 0.871. MST analysis reconstruction revealed clustering into "Kazakhstani-Chinese (Central Asian)", "European" and "American" lines. Detection of multiple genotypes in a single outbreak confirms that poorly controlled trade of livestock plays a crucial role in the spread of infection. Notably, the MLVA-16 profile of the B. abortus 82 strain was unique and did not change during 33 serial passages. MLVA genotyping may thus be useful for epidemiological monitoring of brucellosis, and for tracking the source(s) of infection. We suggest that countrywide application of MLVA genotyping would improve the control of brucellosis in Kazakhstan.

We describe the genetic diversity of 1327 Brucella strains from human patients in Kazakhstan using multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA). All strains were assigned to the Brucella melitensis East Mediterranean group and clustered into 16 MLVA11 genotypes, nine of which are reported for the first time. MLVA11 genotype 116 predominates (86.8%) and is present all over Kazakhstan indicating existence and temporary preservation of a “founder effect” among B. melitensis strains circulating in Central Eurasia. The diversity pattern observed in humans is highly similar to the pattern previously reported in animals. The diversity observed by MLVA suggested that the epidemiological status of brucellosis in Kazakhstan is the result of the introduction of a few lineages, which have subsequently diversified at the most unstable tandem repeat loci. This investigation will allow to select the most relevant strains for testing these hypotheses via whole genome sequencing and to subsequently adjust the genotyping scheme to the Kazakhstan epidemiological situation.

The currently available experimental data supports the hypothesis that the neuroprotective effect of dimebon is related to the protection of the brain-mitochondria from neurodegeneration. In this study, the influence of dimebon on mitochondria was investigated to gain a better understanding of the neuroprotective effects of this drug. Here, we demonstrate that dimebon enhances the resistance of the isolated rat brain and liver mitochondria to the induction of mitochondrial permeability transition (MPT) by calcium ions even in the presence of atractyloside, a MPT pore (MPTP) opener, but is ineffective against atractyloside-induced mitochondria swelling. Unlike cyclosporine A (CsA), a MPTP inhibitor, Dimebon does not influence the adenine nucleotide translocase (ANT) conformational changes and is not able to prevent the MPT of de-energized mitochondria. Using three different assays, and using amyloid-β peptide for inducing mitochondrial toxicity, we show that the influence of dimebon on the calcium retention capacity (CRC) of mitochondria depends on the mode of calcium addition. No obvious influence of dimebon on CRC was observed under the conditions of calcium infusion in the pump mode but the increase of CRC of rat brain mitochondria was observed when calcium was added in the bolus mode; the addition of calcium in the single pulse mode led to the increase of the lag period of calcium efflux from mitochondria. From these studies it is shown that dimebon is effective against amyloid-β (Aβ) potentiated mitochondrial swelling and decrease of calcium retention capacity (CRC) of the brain mitochondria.

BackgroundKazakhstan belongs to countries with a high level of brucellosis among humans and farm animals. Although antibiotic therapy is the main way to treat acute brucellosis in humans there is still little information on a circulation of the antibiotic-resistant Brucella strains in the Central Eurasia. In this article we describe an occurrence of the drug resistance of Brucella melitensis isolates in Kazakhstan which is among the largest countries of the region.MethodsSusceptibilities to tetracyclin, gentamycin, doxycyclin, streptomycin and rifampicin were investigated in 329 clinical isolates of Brucella melitensis using E-test method.ResultsAll isolates were susceptible to streptomycin, tetracycline and doxycycline. 97.3% of the Brucella isolates were susceptible to gentamycin, although only 37.4% of isolates were susceptible to rifampicin. 21.9% of isolates had intermediate resistance, and 26.4% of isolates were resistant to this antibacterial drug.ConclusionIsolates of Brucella melitensis circulating in Kazakhstan are susceptible to streptomycin, doxicyclin, tetracyclin and gentamycin. At the same time the resistance to rifampicin is widespread, almost half of the isolates were rifampicin-resistant (including the intermediate resistance).