Geropsychotropic properties of an antioxidant of the 3-hydroxypyridine class in an experiment

Comparative experimental investigation of albino male rats 3 and 16 months old has been performed. 16-month-old rats demonstrated age-dependent functional insufficiency in some behavioural tests. 2 month injection of 3-hydroxypyridine antioxidant (50 mg/kg/day) normalized memory function, motor skill learning and motor coordination function in 16-month-old rats.     

Role of the GABA- and cholinergic systems in the formation of a dissociated state to an antioxidant of the 3-hydroxypyridine class

The experiments on rats have shown that the elaboration of conditioned drinking reflex in T-maze during administration of 2-ethyl-6-methyl-3-hydroxypyridine antioxidant with an anti-stress effect was accompanied by the development of state dependent learning. However, its formation was slower, as compared to state dependent learning in response to the known psychotropic drugs. The replacing test with the injection of bicuculline, picrotoxin, Ca valproate, Ro-15-1788, benactyzine, Cleregil, etc. during state dependent learning made it possible to establish the role of GABA and cholinergic systems in the formation of state dependent learning and in the development of disorders in emotional behavioural reactions after long-term administration and withdrawal of 3-hydroxypyridine.     

Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans

This brief resume enumerates the multiple actions of melatonin as an antioxidant. This indoleamine is produced in the vertebrate pineal gland, the retina and possibly some other organs. Additionally, however, it is found in invertebrates, bacteria, unicellular organisms as well as in plants, all of which do not have a pineal gland. Melatonin's functions as an antioxidant include: a), direct free radical scavenging, b), stimulation of antioxidative enzymes, c), increasing the efficiency of mitochondrial oxidative phosphorylation and reducing electron leakage (thereby lowering free radical generation), and 3), augmenting the efficiency of other antioxidants. There may be other functions of melatonin, yet undiscovered, which enhance its ability to protect against molecular damage by oxygen and nitrogen-based toxic reactants. Numerous in vitro and in vivo studies have documented the ability of both physiological and pharmacological concentrations to melatonin to protect against free radical destruction. Furthermore, clinical tests utilizing melatonin have proven highly successful; because of the positive outcomes of these studies, melatonin's use in disease states and processes where free radical damage is involved should be increased.     

The biochemical mechanisms of action of the interferons

The interferon family of proteins consists of a variety of antigenically distinct types that are encoded by different genes. Several of these genes have been cloned and the availability of large amounts of the recombinant interferons has greatly facilitated characterization of their biochemical and biological activities. The specificity of interaction of interferons with cell surface receptors has been investigated in binding and covalent cross-linking experiments employing 125I-labeled interferons. In addition to their antiviral activity, the interferons have effects on cell growth and differentiation. The interferons also are potent modulators of the immune response. The interferons exert their biological activities by altering the expression of several cellular proteins. Current knowledge about the mechanisms of signal transduction and the regulation of expression of interferon-induced mRNAs and proteins are discussed.     

Mechanism of action of an anticonvulsant, sodium dipropylacetate

The hypothesis that the brain GABA level increase which is induced by a sodium dipropyl acetate treatment arises either through inhibition of succinic semialdehyde dehydrogenase (SSADH), or through inhibition of GABA transaminase by succinic semialdehyde (SSA), has been considered. It appeared that in vivo brain GABA level increase cannot be attributed to SSADH inhibition, and that SSA is not a GABA precursor. It has been shown that SSA is neither in vivo nor in vitro a GABA-transaminase inhibitor. 4-hydroxybenzaldehyde, a potent SSADH inhibitor did not increase GABA level at a dosage which induces a 99% inhibition of SSADH.     

Surveying the manifold divergence of an entire protein class for statistical clues to underlying biochemical mechanisms

Certain residues have no known function yet are co-conserved across distantly related protein families and diverse organisms, suggesting that they perform critical roles associated with as-yet-unidentified molecular properties and mechanisms. This raises the question of how to obtain additional clues regarding these mysterious biochemical phenomena with a view to formulating experimentally testable hypotheses. One approach is to access the implicit biochemical information encoded within the vast amount of genomic sequence data now becoming available. Here, a new Gibbs sampling strategy is formulated and implemented that can partition hundreds of thousands of sequences within a major protein class into multiple, functionally-divergent categories based on those pattern residues that best discriminate between categories. The sampler precisely defines the partition and pattern for each category by explicitly modeling unrelated, non-functional and related-yet-divergent proteins that would otherwise obscure the analysis. To aid biological interpretation, auxiliary routines can characterize pattern residues within available crystal structures and identify those structures most likely to shed light on the roles of pattern residues. This approach can be used to define and annotate automatically subgroup-specific conserved domain profiles based on statistically-rigorous empirical criteria rather than on the subjective and labor-intensive process of manual curation. Incorporating such profiles into domain database search sites (such as the NCBI BLAST site) will provide biologists with previously inaccessible molecular information useful for hypothesis generation and experimental design. Analyses of P-loop GTPases and of AAA+ ATPases illustrate the sampler's ability to obtain such information.     

A biochemical analysis of the possible mechanisms of the ulcerostatic action of atranes

Stimulatory effect of metalloatrans on the development of stomach wall connective tissue components was examined in rats with experimental acetate ulcer. Metalloatrans were shown to inhibit peroxide oxidation processes of lipids in blood and stomach tissue.     

Effects of a membrane modulator derived from 3-hydroxypyridine class on the development of pulmonary edema

The experiment on white rats has revealed that water-soluble antioxidant-emoxipin, having obvious membrane modulating effect, does not influence the rate of watering and congestion of the lungs, the speed of reabsorption of fluid from lung tissue, the permeability of the capillary-alveolar barrier both in the blood-tissue direction and vice versa. Preliminary introduction of emoxipin increased the amount of edema fluid in the lungs when noradrenaline, centrogenic and especially vasopressin pulmonary edema developed, but in did not influence the development of vagotomic pulmonary edema. Stimulation of adenylcyclase or introduction of prostacyclin slowed down the development of centrogenic and vasopressin edema of the lungs. On the basis of these data it can be concluded that the intensification of pulmonary edema after emoxipin introduction is connected with its antioxidant activity.     

Pharmacokinetic, behavioral and neurophysiological aspects of the action of 2-ethyl-6-methyl-3-hydroxypyridine in rats

Specific features of 2-ethyl-6-methyl-3-hydroxypyridine (3-OP) action were investigated in white rats. A correlation has been established between pharmacokinetic parameters and basic manifestations of psychotropic 3-OP effect. Correlations have been also observed between the level of manifestation of anxiolytic effect and changes in 3-OP concentrations in the rat brain. Electroencephalographic findings of the nootropic effect in sensorimotor cortex correlate with 3-OP brain concentrations. The authors describe specific drug pharmacokinetics and possible mechanisms of realization of psychotropic effects.     

Electrophysiological and biochemical responses of mouse vomeronasal receptor cells to urine-derived compounds: possible mechanism of action

Receptor cells of the vomeronasal organ (VNO) are thought to detect pheromone-like molecules important for reproductive physiology. Several compounds derived from male mouse urine have been demonstrated to affect endocrine events in female mice. In the present study, the ability of these compounds to affect VNO activity was tested. In dissociated VNO cells held under voltage clamp conditions, application of dehydro-exo-brevicomin (DHB) evoked an outward current at negative holding potentials and an inward current at positive holding potentials. Under current clamp, DHB reduced action potential firing. Since DHB application caused a decrease in membrane conductance, this compound appeared to act by reducing inward current through closing an ion channel. Biochemical experiments tested the effects of DHB and 2- (sec-butyl)-4,5-dihydrothiazole (SBT) on cAMP levels in the VNO. A mixture of DHB and SBT decreased cAMP levels in VNO sensory tissue and had no effect on VNO non-sensory tissue. The results suggest that pheromones have an inhibitory influence on action potential generation and on cAMP levels in receptor cells of the VNO.      

Electrophysiological mechanisms of atrial flutter

Atrial flutter (AFL) is a common arrhythmia in clinical practice. Several experimental models such as tricuspid regurgitation model, tricuspid ring model, sterile pericarditis model and atrial crush injury model have provided important information about reentrant circuit and can test the effect of antiarrhythmic drugs. Human atrial flutter has typical and atypical forms. Typical atrial flutter rotates around tricuspid annulus and uses the crista terminalis and sometimes sinus venosa as the boundary. The IVC-tricuspid isthmus is a slow conduction zone and the target of radiofrequency ablation. Atypical atrial flutter may arise from the right or left atrium. Right atrial flutter includes upper loop reentry, free wall reentry and figure of eight reentry. Left atrial flutter includes mitral annular atrial flutter, pulmonary vein-related atrial flutter and left septal atrial flutter. Radiofrequency ablation of the isthmus between the boundaries can eliminate these arrhythmias.     

Electrophysiological investigation of the texture discrimination mechanisms

In electrophysiological and psychophysical experiments, we investigated mechanisms of the visual system underlying local and global texture processing. Textures included rectangular matrixes composed of Gabor patches (sine wave grating windowed by a Gaussian envelope). Orientation of each grating varied from 0 to 165 degrees with the step of 15 degrees. Matrixes differed by the amount of Gabor patches with vertical or horizontal orientation. The observers' task was to discriminate the dominant orientation. The advantage of such stimuli involved a possibility to calculate global statistics of the textures, which we considered as the difference between whole amount of vertical and horizontal orientations in the stimulus irrespective of their location. The local statistics was calculated as relative amount of spatially organized nearby gratings (i. e. collinear contours). The subjects' accuracy was low in discriminating less organized textures and gradually improved with the amount of vertically of horizontally oriented Gabor patches, while the reaction time decreased. Visual evoked potentials (VEPs) recorded from occipital lobes revealed different dependencies of their components' magnitude on the amount of equally oriented gratings. Amplitude of the late positive component P3 with latency 400 ms directly depended on the texture discriminability, and N2 wave with latency 180 ms had an S-like dependence. Opposite to that, the magnitude of P2 wave with latency 260 ms was maximal in response to less organized textures and gradually decreased with the amount of equally oriented gratings. The dependencies received were compared with the textures' statistics. Data analysis allowed us to suppose that, in the conditions of our experimental paradigm, two mechanisms were involved in discrimination of the textures--the local and the global processing. We believe that by recording VEPs one can separately investigate activity of these two processes.     

A study of the action of anticonvulsant drugs on an experimental model of epilepsy

Repeated electrical low intensity stimulation of various regions of the brain has been shown to induce epileptic seizure activity. This experimental model of epilepsy has been used in our laboratory in rats. Male rats, anaesthetized with nembutal (20 mg/kg, i.p.) and ketalar (60 mg/kg, i.p.) were implanted stereotaxically with electrodes in the dorsal hippocampus and neocortex and received 2 hours stimulation sessions via the hippocampal electrodes (1 sec, 60 Hz, 200-800 microA) one stimulus per minute, during which electrographical and behavioral seizures were induced. The effect of anticonvulsant drugs was tested on this model: phenobarbital (40 mg/kg) reduced the quantity of epileptic electrographic activity and abolished the behavioral aspects of the seizures; diphenylhydantoin (20 mg/kg) reduced the quantity of epileptic electrographic activity, but had no effect on the behavioral component of the seizures; diazepam (6 mg/kg) only blocked the behavioral component of the seizures leaving the animal stuporous and immobile, but the electrographical component was unaffected; carbamazepine (10 mg/kg) had no effect on the electrographical epileptic seizures and reduced the behavioral aspects, but to a lesser extent than diazepam.     

Molecular mechanisms of antioxidant action of dalargin on the liver in experimental cholestasis]

Changes of antioxidant activity of dalargin in the liver after naloxone (100 micrograms/kg) administration were examined in experiment on 144 rats with cholestasis. It was found that dalargin inhibited the activity of xanthine oxidase by 32-37% in different time periods after the injection. Dalargin and naloxone, when used in combination, had no effect on the enzyme activity. Glutathione-S-transferase activity rose by 38.0% and 21.8% on hour 1 and 3 after the injection, respectively, while simultaneous injection of dalargin and naloxone induced no changes in the enzyme activity after 1 hour, though decreased it by 36.8% and 26.4% on hour 3 and 5, respectively. Dalargin inhibited lipid peroxidation by 29-35%, simultaneous injection of dalargin and naloxone raised lipid peroxidation by 109.2%, 80.7% and 25.7% after 1, 3 and 5 hours, respectively. Dalargin injection elucidated a marked tendency to lowering of blood release of the liver-specific enzymes histidase and urokaninase in line with enhancement of their activity in the liver. A combined injection of dalargin and naloxone promoted high release of histidase and urokaninase in blood and did not change histidase activity in the liver in all cases. Urokanidase activity elevated in 5 hours. It was noticed that dalargin raised leu-enkephalin levels in the liver 3.5-fold 1 h after the injection. The reduced dalargin antioxidant effect coupled with naloxone pretreatment demonstrated indirect action of the neuropeptide on the liver via neuron receptors of the liver.     

Pharmacokinetics of a water-soluble antioxidant from the class of 3-hydroxypyridines

The study of pharmacokinetics of water-soluble 2-ethyl-6-methyl-3-hydroxypyridine salt (EM-3-HP) in rats has shown this substance to be quickly absorbed from the abdominal cavity of animals. Its maximal concentrations in the plasma, brain and liver were determined 2-3 hours later, with the following monoexponential decrease in EM-3-HP level with the elimination half-life of 2-6 hours observed. Considerable EM-3-HP tropism to membranes of endoplasmic reticulum in the liver and brain cells is suggested to cause its membranomodulatory effect and to facilitate its pharmacological activity.     

Oxidative inactivation of paraoxonase1, an antioxidant protein and its effect on antioxidant action

Paraoxonase1 (PON1), one of antioxidant proteins to protect low density lipoprotein (LDL) from the oxidation, is known to lose its activity in the oxidative environment. Here, we attempted to elucidate the possible mechanisms for the oxidative inactivation of PON1, and to examine the capability of hydroxyl radicals-inactivated PON1 to prevent against LDL oxidation. Of various oxidative systems, the ascorbate/Cu₂₊ system was the most potent in inactivating the purified PON1 (PON1) as well as HDL-bound PON1 (HDL-PON1). In contrast to a limited inactivation by Fe₂₊ (2.0 μM), the inclusion of Cu₂₊ (0.1-1.0 μM) remarkably enhanced the inactivation of PON1 in the presence of ascorbate (0.5 mM). A similar result was also obtained with the inactivation of HDL-PON1. The inactivation of PON1 by ascorbate/Cu₂₊ was pevented by catalase, but not general hydroxyl radical scavengers, supporting Cu₂₊-catalyzed oxidative inactivation. In addition, Cu₂₊ alone inactivated PON1, either soluble or HDL-bound, by different mechanisms, concentration-dependent. Separately, there was a reverse relationship between the inactivation of PON1 and its preventive action against LDL oxidation during Cu₂₊-induced oxidation of LDL. Noteworthy, ascorbate/Cu₂₊-inactivated PON1, which was charaterized by the partial loss of histidine residues, expressed a lower protection against Cu₂₊-induced LDL oxidation, compared to native PON1. Based on these results, it is proposed that metal-catalyzed oxidation may be a primary factor to cause the decrease of HDL-associated PON1 activity under oxidative stress, and radicals-induced inactivation of PON1 may lead to the decrease in its antioxidant action against LDL oxidation.     

Electrophysiological mechanisms of ventricular fibrillation induction

Ventricular fibrillation (VF) is known as a main responsible cause of sudden cardiac death which claims thousands of lives each year. Although the mechanism of VF induction has been investigated for over a century, its definite mechanism is still unclear. In the past few decades, the development of new advance technologies has helped investigators to understand how the strong stimulus or the shock induces VF. New hypotheses have been proposed to explain the mechanism of VF induction. This article reviews most commonly proposed hypotheses that are believed to be the mechanism of VF induction.