A study of the mechanism of the antiarrhythmic action of Allapinin

Allapinin (lappaconitine hydrobromide) is a drug used for the treatment of cardiac rhythm disturbances; its properties are characteristic of class IC antiarrhythmics. The mechanism of its electrophysiological action involves the blockade of Na⁺ channels with a subsequent decrease of depolarization rate leading to a slowing of impulse propagation and a decrease of excitability in the conductive system of the heart. Factors underlying the side effects of Allapinin (tachycardia, arterial hypertension, impaired coordination, etc.) are currently unknown, and therefore a study of the molecular mechanisms of its action seems relevant. The target genes of the drug were identified in rats with induced aconitine arrhythmia using the commercially available Rat Neuroscience Ion Channels & Transporters RT² Profiler? PCR Array kit (SA Biosciences). A comparison of expression levels of 84 genes in rats treated with Allapinin, after the induction of arrhythmia by aconitine (experiment) and in physiological saline-treated arrhythmic rats (control), revealed 18 mRNAs which were up- or downregulated twofold or more in the experiment relative to the control. Allapinin was shown to stimulate the expression of genes coding for various types of K⁺ channels (kcna6, kcnj1, kcnj4, kcnq2, and kcnq4), Ca²⁺ channel (cacna1g), and vesicular acetylcholine transporter (slc18a3). A decrease in mRNA levels was detected for genes coding for K⁺ channels (kcne1, kcns1), a Na⁺ channel (scn8a), and membrane transporter genes (atp4a, slc6a9). Our data shows that Allapinin administered to animals with aconitine arrhythmia modulates the expression of genes accounting for ion current conductances involved in the formation of various phases of action potential (I _Na , I _to , I _Ks , I _K1 , I _CaT ). The effect of the drug on the levels of mRNAs coding for acetylcholine and glycine transporters suggests the involvement of these neuromediators in the mechanisms underlying the antiarrhythmic effect of Allapinin.     

Analysis of polymorphism of the glutathione S-transferase gene in populations of the Volga-Ural region

The frequency of the GSTM1 gene deletion homozygotes in eight populations of the Volga-Ural region belonging according to linguistic classification to Turkic (Bashkirs, Tatars, and Chuvashs), Finno-Ugric (Maris, Komis, Mordovians, and Udmurts), and Eastern-Slavic (Russians) ethnic groups, was examined by means of PCR technique. The frequency of the deletion homozygotes varied from 41.4% in Bashkirs to 61.3% in Mordovians. The mean deletion frequency comprised 50.1%, which was consistent with the data for European populations (chi 2 = 0.009).     

cDNA macroarray analysis of gene expression changes in rat brain after a single administration of a 2-aminoadamantane derivative

The Atlas Rat cDNA Expression Array (BD Biosciences, United States) has been used to analyze changes in the expression of 588 genes in rat brain cells in response to a single administration of Ladasten, a 2-aminoadamantane derivative that has psychostimulating and anxiolytic effects. The analysis of hybridization on macroarrays, confirmed by the results of real-time quantitative RT-PCR, has demonstrated that Ladasten alters the expression of 12 genes in the rat brain. The GAT3 and CARBH genes are presumed to be pharmacologically important targets of Ladasten. The changes in their activity explain the mechanisms of the anxiolytic and mood-stabilizing effects of the drug. Ladasten has been shown to induce the genes whose products are involved in various signal pathways (APC, Rb, PKCIP, and PMCA), as well as the genes of cytoskeletal proteins (Tub1 and actin), synaptic proteins (SynIA&IB and PLP), and enzymes (Gapdh and NSE). The proteins encoded by these genes are presumably involved in compensatory and/or neuroplastic adaptation to the effects of Ladasten.__________Translated from Molekulyarnaya Biologiya, Vol. 39, No. 2, 2005, pp. 276–285.Original Russian Text Copyright © 2005 by Vakhitova, Yamidanov, Vakhitov, Seredenin.     

Animal in vivo model of arrhythmia for genes target identification for 5-amino-exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one

The goal of the current work is to study the molecular mechanisms underlay the action of 5- amino-exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one (P-11) with combined antiarrhythmic, nootropic, anti-inflammatory and anaesthetic activities. The aconitine-induced experimental rat model of cardiac arrhythmia has been used in our study. Aconitine was administered once intravenously in a dose 50 microg/kg whereas experimental animal group received P-11 in a dose 0.3 mg/kg (the compound was injected intravenously 2 min before acute aconitine treatment). Expression macroarray (Atlas Rat cDNA Expression Array, #7738-1; BD Biosciences) was used to identify the target genes for P-11 compound. Comparative analysis of changes in the status of expression of genes in the heart of rats induced by P-11 against the simulated in vivo arrhythmia identified 16 genes that reproducibly alter the level of expression.These genes encode the extracellular matrix proteins (glypican 1, Gpc1; tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp 3); intracellular signaling molecules (rho GTPase activating protein 7, Dlc1; protein tyrosine phosphatase 4a1, Ptp4a1; phosphodiesterase 4D, PDE4D; PI3-kinase regulatory subunit alpha, PIK3R1; guanine nucleotide binding protein alpha 12, Gna12) and protein of intermediate junctions (junction plakoglobin, Jup), proteins involved in glycolysis (phosphofructokinase I, Pfk1) and hemostasis (tissue plasminogen activator, Plat), plasma membrane transporters (Solute carrier family 16, member 1, Slc16a1; ATPase, Na+/K+ transporting, Atp1a), and ets. (c-fos protooncogene, c-fos; telomerase protein component 1, tlp; Annexin 1, anxa 1). Thus, the data about the selective effect of P-11 on genes whose products are involved in the aritmogenesys mechanisms, allow us to consider this compound as a promising means of pathogenetically oriented pharmacotherapy of cardiac arrhythmias.     

Genes targets identification of 5-amino-<Emphasis Type="Italic">exo</Emphasis>-3-azatricyclo[5.2.1.0<Superscript>2,6</Superscript>]decane-4-one in an in vivo model of arrhythmia

The molecular mechanisms of action of 5-amino-exo-3-azatricyclo[5.2.1.0^2,6]decane-4-one (P11), a compound possessing strong antiarrhythmic, nootropic, anti-inflammatory and analgesic activity, have been studied. Cardiac rhythm disturbances were modeled by administering the arrhythmogenic compound aconitin in a dose of 50 μg/kg to the animals from the control group. P-11 in a dose of 0.3 mg/kg was injected intravenously in the experimental group of animals 2 min before aconitin administration. P-11 target genes were identified using the Atlas™ Rat cDNA Expression macroarray (#7738-1, BD Biosciences, United States). Reproducible changes in the expression levels of 16 genes in the heart of rats treated with P-11 concommitantly to arrhythmia modeling in vivo were detected. The genes regulated by the substance coded for proteins of the extracellular matrix are (glypican 1, Gpc1; tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp3), intracellular signaling proteins (rho GTPase activating protein 7, Dlc1; protein tyrosine phosphatase 4a1, Ptp4a1; phosphodiesterase 4D, PDE4D; PI3-kinase regulatory subunit alpha, PIK3R1; guanine nucleotide binding protein alpha 12, Gna12), proteins involved in glycolysis (phosphofructokinase 1, Pfk1), intercellular interactions (junction plakoglobin, Jup), and hemostasis (tissue plasminogen activator, Plat), membranebound pumps and transporters (solute carrier family 16, member 1, Slc16a1; ATPase, Na⁺/K⁺ transporting, Atp1a), and others (c-fos proto-oncogene, c-fos; telomerase protein component 1, tlp; Annexin 1, anxa1). Therefore, the data concerning the selective effect of P-11 on genes coding for proteins involved in arrhythmogenesis allow for considering this compound as a promising medication for pathogenetically oriented therapy of arrhythmias.     

Synthesis and evaluation of camphor and cytisine-based cyanopyrrolidines as DPP-IV inhibitors for the treatment of type 2 diabetes mellitus

In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27–15.78?µM). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.