Characteristics of the antihypoxic action of piracetam

Pyracetam was found to inhibit free-radical lipid peroxidation, slow oxygen consumption in the liver mitochondria and increase hemoglobin oxygen-binding properties. It is assumed that the ability of pyracetam to inhibit lipid peroxidation is a mechanism which determines its antihypoxic effect.     

Mechanism of the ganglion-blocking action of bis-ammonium compounds

The action of polymethylene bis-ammonium compounds on acetylcholine-activated channels was investigated on voltage-clamped neurons of the isolated rabbit superior cervical ganglion. The kinetics of complex formation by the compound and the open channel was determined from shortening of decay of the fast excitatory postsynaptic current, the rate of which corresponds to the rate of channel closure, whereas the kinetics of dissociation of this complex was determined by recovery of the second response to application of two pulses of acetylcholine. With membrane hyperpolarization complex formation was found to be accelerated, and its dissociation retarded. The potential-dependence of interaction between compound and channel increases with lengthening of the polymethylene chain. Variation of one of the two cationic groups in a compound with a tetramethylene chain does not affect potential-dependence. In a series of bis-ammonium compounds, ganglion-blocking activity, determined on the cat superior cervical ganglionin situ was found to correlate with the velocity constant of binding with the open channel. It is concluded that the ganglion-blocking action of bis-ammonium compounds is determined by their channel-blocking activity.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 16, No. 1, pp. 54–61, January–February, 1984.     

Some mechanisms of antihypoxic action of taurine]

It is shown that preliminary taurine treatment prevents the disturbances of energy metabolism in the brain, heart and liver tissues of Wistar rats with acute hypoxic hypoxia. Administration of taurine restored to normal the parameters of adenine pool: the concentration of ATP increased within the cytoplasm, while that of ADP and AMP diminished; mitochondrial respiration proceeded more rapidly; the concentrations of pyruvate and malate decreased; isocitrate dehydrogenase activity, P/O and NAD/NADH ratios increased. Taurine treatment resulted in a decreased level of lipid peroxides in the rat tissues with hypoxia. The role of intracellular calcium content and biomembranes structure changes as the mechanisms of taurine action on energy metabolism and lipid peroxidation is discussed.     

Differences in the mechanism of the antihypoxic action of benzodiazepine receptor agonists and muscimol

Neuropharmacological analysis of previously revealed antihypoxic activity of benzodiazepines (BDZ) has been performed in experiments on mice exposed to hypoxia. Antihypoxic effect of diazepam is shown to be antagonized by the central BDZ receptor blocker, Ro 15-1788. A certain degree of antihypoxic activity also abolished by Ro 15-1788 is exhibited by hypothetical ligands of BDZ receptors: inosin, nicotinamide, ethyl-beta-carboline-3-carboxylate. The effect of dipyridamole, a drug with high affinity for BDZ receptors of the peripheral type is not antagonized by Ro 15-1788, another evidence of Ro 15-1788 affinity precisely to the central BDZ receptors. GABA-mimetics (muscimol and GABA cetyl ester) were also found to have marked antihypoxic activity. Unlike BDZ receptor agonists, this effect is reduced by bicuculline and not by Ro 15-1788. The data obtained suggest that antihypoxic activity of BDZ is caused by their direct interaction with the central BDZ receptors, probably with the type which is not modulated by GABAA receptors.     

Mechanism of the antistressor and antiradiation action of plant phenol compounds]

The article analyses critically the date from literature as well as own date concerning appropriateness and mechanisms of antiradiation, capillary strengthening and antistress effect of plant phenolic compounds. Knowledge on antioxidant effect as the most fundamental mechanism being in the basic of the above mentioned biologic effects of plant phenolic compounds is grounded.     

Mechanism of the radioprotecting action of chemical compounds on Escherichia coli cells.

Summary The effect of radioprotection of indolylakylamines (5-methoxytryptamine) and aminothiols (cysteamine) on E. coli cells is practically absent if the cells have genetic defects in the repair systems. This means that the explanation of radioprotection by scavenging of free radicals is invalid and that specific repair mechanisms may be involved. In order to explain the radioprotective mechanism it was suggested that the radioprotectors interact with the damaged sites in DNA so that they become partly screened from repairing endonucleases. Under these conditions the reduction of incision rate results in diminished enzymatic induction of lethal double-strand breaks in DNA, this being important only in wild type cells.To prove this hypothesis an experimental procedure was developed using bacterial cells carryng plasmids (ColE1). This procedure enabled to determine the in vivo rate of enzymatic incision of -sites. It was found that the protectors did not change the total amount of -damages in DNA but reduced the rate of enzymatic incision.     

Mechanism of action of lignins and lignin model compounds with horseradish peroxidase

Horseradish peroxidase displayed a ping-pong kinetic reaction mechanism with lignin model compounds and lignins. Oxidation of the α carbon on acetosyringone or acetovanillone failed above pH 6.5, while conversion of α-methylsyringyl (or guaiacyl) alcohol to acetosyringone (or vanillone) occurred optimally at pH 7.8. Small MW fragments were not formed from lignins at pH 6.4 and 7.8. These observations provide evidence for the growing concept that freely soluble peroxidase is not a lignolytic enzyme.     

Coordinative compounds of zinc with N-substituted thiocarbamoyl-N'-pentamethylensulfenamides--activity modifiers of enzymes of proteolytic and glycolytic action

The influence of a number of coordinative compounds of zinc with N-substituted thiocarbamoil-N'-pentamethylensulfenamides on activity of elastase, alpha-L-rhamnosidase and alpha-galactosidases evidence for a possibility of their usage as stimulators or inhibitors of enzymes tested have been studied. It was shown that all the compounds in concentration of 0.1 and 0.01% inhibited by 90-100% Bacillus thuringiensis 27-88Els+ elastase activity. [Zn(L2)Br2], [Zn(L1)(NCS)2] and [Zn(L3)(NCS)2] at 20 h exposition activated Cryptococcus albidus 1001 alpha-L-rhamnosidase activity. The rest of compounds influenced it on the control level or inhibited it by 7-23%. The obtained results testify that essential role is not played by separate fragments (L-ligand and anions), but by molecules of zinc complexes as a whole. All the studied complexes, exept for [Zn(L3)(NCS)2], induced alpha-L-rhamnosidase activity of Eupenicillium erubescens 248 (7 to 60%). All zinc compounds (concentration 0.01%, exposition time - 60 min) influenced at the control level Aspergillus niger and Cladosporium cladosporioides alpha-galactosidases activity, however inhibited (up to 20%) activity of Penicillium canescens alpha-galactosidase. The increasing of exposition time of the compounds tested with enzymes up to 20 h testify to selective action of separate compounds on enzymes tested. The data obtained prove, that the character of interaction of zinc complexes is changed depending on the enzyme tested and its strain-producer.     

Solubilization of insoluble zinc compounds by Gluconacetobacter diazotrophicus and the detrimental action of zinc ion (Zn2+) and zinc chelates on root knot nematode Meloidogyne incognita

AIM: To examine the zinc (Zn) solubilization potential and nematicidal properties of Gluconacetobacter diazotrophicus. METHODS AND RESults: Atomic Absorption Spectrophotometer, Differential Pulse Polarography and Gas Chromatography Coupled Mass Spectrometry were used to estimate the total Zn and Zn(2+) ions and identify the organic acids present in the culture supernatants. The effect of culture filtrate of Zn-amended G. diazotrophicus PAl5 on Meloidogyne incognita in tomato was examined under gnotobiotic conditions. Gluconacetobacter diazotrophicus PAl5 effectively solubilized the Zn compounds tested and 5-ketogluconic acid was identified as the major organic acid aiding the solubilization of zinc oxide. The presence of Zn compounds in the culture filtrates of G. diazotrophicus enhanced the mortality and reduced the root penetration of M. incognita under in vitro conditions. CONCLUSIONS: 5-ketogluconic acid produced by G. diazotrophicus mediated the solubilization process and the available Zn(2+) ions enhanced the nematicidal activity of G. diazotrophicus against M. incognita. SIGNIFICANCE AND IMPACT OF THE STUDY: Zn solubilization and enhanced nematicidal activity of Zn-amended G. diazotrophicus provides the possibility of exploiting it as a plant growth promoting bacteria.     

Detubulation effects on the action of zinc on frog skeletal muscle action potential

Summary Detubulation of the untreated fiber decreases the time constant of the action potential's foot ( _f ) and increases the maximal rate of rise of the spike ( ). Zinc at all concentrations, and regardless of whether the fiber is intact or detubulated, increases _f and decreases , and thus seems to decrease Na activation of the fiber. Detubulation was used principally to elucidate the localization and mechanism of the Zn²⁺-induced retardation of the falling phase of the frog sartorius fiber action potential, which evidently results from a general depression of delayed rectification. At 50 to 1000 m, Zn²⁺ not only prolongs repolarization of intact fibers (measured by increase int _0.5, the half-time of the spike's fall), but also produces a marked hump early in this phase. Detubulation of zinc-free fibers reducest _0.5 to about 80% of its intact value, and under Zn²⁺ treatmentt _0.5 is increased but only to about 80% of that produced in the intact fiber, and the falling-phase hump is completely obliterated. Thus, detubulation decreasest _0.5 in Zn²⁺-treated fibers not only by generally eliminating T-tubular participation in action potential generation, but also by subtracting a Zn²⁺-induced retardation of tubular delayed rectification. Tubular delayed rectification must therefore be an intrinsic feature of normal excitation. These results are further analyzed by means of (i) Stanfield's findings about retardation of delayed rectification by Zn²⁺ and (ii) Adrian-Peachey's theory of T-tubule participation in action potential generation, which suggests that the Zn²⁺-evoked repolarization hump signals onset of Zn²⁺-altered active participation of T-tubules in determining the spike's shape.Died April 17, 1978. Previously known as: P.M.K. Dass, and so listed in the reference Dass and Sandow (1972).     

Possible modes of action of the artemisinin-type compounds

Artemisinin-type compounds are used for the treatment of uncomplicated and severe forms of malaria. They reduce parasitaemia more rapidly than any other antimalarial compound known, and are effective against multidrug-resistant parasites. However, uncertainties remain as to how they act on the parasite and cause toxicity. In this review, we summarize current ideas.     

Determining the mode of action of bioactive compounds

Matching bioactive molecules with molecular targets is key to understanding their modes of action (MOA). Moving beyond the mere discovery of drugs, investigators are now just beginning to integrate both biochemical and chemical-genetic approaches for MOA studies. Beginning with simple screens for changes in cell phenotype upon drug treatment, drug bioactivity has been traditionally explored with affinity chromatography, radiolabeling, and cell-based affinity tagging procedures. However, such approaches can present an oversimplified view of MOA, especially in light of the recent realization of the extent of polypharmacology and the unexpected complexity of drug-target interactions. With the advent of more sophisticated tools for genetic manipulation, a flood of powerful techniques has been used to create characteristic drug MOA 'fingerprints'. In particular, whole genome expression profiling and deletion and overexpression libraries have greatly enhanced our understanding of bioactive compounds in vivo. Here we highlight challenges and advances in studying bioactive compound-target interactions.