Effect of amiridine and tacrine,drugs effective in Alzheimer's disease,on synaptosomal neurotransmitter uptake

All-Union Research Centers for Safety of Biologically Active Substances. (Presented by Academician I. P. Ashmarin, Academy of Medical Sciences.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 4, pp. 379–381, April, 1992,     

Effect of thymoptin on the behavior of experimental animals

A study is made of the effect of thymoptin, a preparation containing a complex of acid peptides from the thymus, on the behavior of experimental animals. It is found that in a dose of 400 μg/kg the preparation enhances motor activity, raises the body temperature, augments pain sensitivity, stimulates behavior in the open field test, and facilitates learning and memory processes. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121 N ^o 3, pp. 285–287, March, 1996 Presented by Yu. A. Romanov, Member of the Russian Academy of Medical Sciences     

Early Resistance to experimental plague in animals immunized with recombinant plague vaccine

The protective properties of recombinantSalmonella minnesota R595/pFS1 strain soon after immunization (1–3 days) are studied in a model of experimental mouse plague. Unlike the commercial EV strainYersinia pestis vaccine produced at the Saratov Anti-Plague Institute (Mikrob Research-Manufacturing Conglomerate), the experimental recombinant p preparation affords a high level of protection from the 1st day postvaccination, and surpasses the commercial preparation in such parameters as LD₅₀, mean survival time, and percentage of survivors. By the 21st day the protective indexes of both preparations are comparable. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny,Vol. 119, N ^o 1, pp. 54–57, January, 1995 Presented by A. A. Vorob'ev, Member of the Russian Academy of Medical Sciences     

The role of adenosine A1 receptors in mediating the inhibitory effects of low frequency stimulation of perforant path on kindling acquisition in rats

Low frequency stimulation (LFS) has an inhibitory effect on rapid perforant path kindling acquisition. In the present study the role of adenosine A₁ and A_2A receptors in mediating this inhibitory effect was investigated. Rats were kindled by perforant path stimulation using rapid kindling procedures (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, and 50–150 μA) was applied to the perforant path immediately after termination of each rapid kindling stimulation. 1,3-Dimethyl-8-cyclopenthylxanthine (CPT; 50 μM), a selective A₁ antagonist and ZM241385 (ZM, 200 μM), a selective A_2A antagonist were daily microinjected into the lateral ventricle 5 min before kindling stimulations. LFS had an inhibitory effect on kindling development. Pretreatment of animals with CPT reduced the inhibitory effect of LFS on kindling rate and suppressed the effects of LFS on potentiation of population EPSP during kindling acquisition. In addition, CPT was able to antagonize the effects of LFS on kindling-induced increase in early (10–50 ms intervals) and late (300–1000 ms intervals) paired pulse depression. ZM pretreatment had no effect on antiepileptogenic effects of LFS in kindling acquisition. In addition, LFS prevented the kindling-induced elevation of cyclic AMP (cAMP) levels in kindled animals. Based on these results, we suggest that the antiepileptogenic effects of LFS on perforant path kindling might be mediated through activation of adenosine A₁, but not A_2A receptors. Moreover, modulation of cAMP levels by LFS may potentially be an important mechanism which explains the anticonvulsant effects of LFS in kindled seizures.     

Effect of malaben on catecholamine content in organs of animals with experimental myocardial infarction

The content of adrenalin and noradrenalin was determined in tissues of the heart, adrenals, spleen, and brain of rats with experimental myocardial infarction. A considerable fall in the tissue catecholamine level was found. Malaben restores the normal catecholamine content in the tissues in myocardial infarction, posibly as a result of the antihitamine properties of the compound.Department of Pharmacology, Leningrad Institute of Pharmaceutical Chemistry. (Presented by Academician of the Academy of Medical Sciences of the USSR S. V. Anichkov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 7, pp. 49–51, July, 1977.     

Effects of 17β-estradiol and its isomer 17α-estradiol on learning in rats with chronic cholinergic deficiency in the brain

It was shown for the first time that estrogens 17β- and 17α-estradiols compensate impaired cognitive functions in rats with partial chronic deprivation of cholinergic functions in the central nervous system induced by intracerebral administration of selective cholinergic neurotoxin AF64A. 17β-Estradiol produced strong dose-dependent changes in the weights of hormone-sensitive endocrine glands, while 17α-estradiol did not affect the weight of the gonads and slightly influenced (in high concentration) the weights of the adrenal glands and thymus. The positive effects of exogenous 17β- and 17α-estradiols on cognitive functions are due to their antioxidant properties, rather than due to specific action on hormone-sensitive endocrine glands. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 129, No. 5, pp. 525–527, May, 2000     

Genetic deletion or antagonism of kinin B(1) and B(2) receptors improves cognitive deficits in a mouse model of Alzheimer's disease

Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signs of Alzheimer's disease (AD) that have been widely associated to inflammatory response. We have recently shown that a single i.c.v. injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400 pmol/mouse) results in marked deficits of learning and memory in mice which are related to oxidative stress and synaptic dysfunction. In the present study, we investigated by means of genetic or pharmacological approaches the role of kinin system in the Abeta(1-40) cognitive effects on the water maze paradigm. Spatial learning and memory deficits observed at 7 days following Abeta(1-40) treatment were significantly reduced by the i.c.v. administration of the selective kinin B(2) receptor antagonist d-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-BK (Hoe 140). A similar effect was found in mice lacking kinin B(2) receptor. On the other hand, genetic deletion of the inducible kinin B(1) receptor or its blockage by i.c.v. injection of des-Arg(9)-[Leu(8)]-BK antagonist attenuated only the long-term (30 days after treatment) cognitive deficits induced by Abeta(1-40). Moreover, treatment with Abeta(1-40) resulted in a sustained increase in the expression of the kinin B(1) receptor in the hippocampus and prefrontal cortex of mice, while it did not alter the expression of the kinin B(2) receptor in these brain areas. These findings provide convincing evidence that kinins acting via activation of B(1) and B(2) receptors in the CNS exert a critical role in the spatial learning and memory deficits induced by Abeta peptide in mice. Therefore, selective kinin receptor antagonists, especially the new orally active non-peptide antagonists, might represent drugs of potential interest for the treatment of AD.     

Damage to the internal organs of experimental animals infected with Marburg's virus

It is shown that in grivets and guinea pigs Marburg's virus reproduces in cells of the mononuclear phagocyte system, in hepatocytes, and in a few endotheliocytes. Marked pathological changes develop in the liver, spleen, and kidneys. A peculiarity of infection in monkeys is the entire absence of morphological manifestations of an inflammatory reaction and of immune system activation. Cells of the mononuclear phagocyte system are thought to play a crucial role in the development of pathological changes in the organism of infected monkeys and guinea pigs. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 117, N ^o 4, pp. 430–434, April, 1994     

Pathological anatomy of an experimental disease of small laboratory animals caused by encephalomyocarditis virus strain ÉMK-70

The results of a pathomorphological investigation of an experimental disease of small laboratory animals caused by strain ÉMK-70 of encephalomyocarditis virus isolated from monkeys are described. Regardless of the method of infection of the newborn and juvenile mice with the virus, they developed lesions of the brown fat, striated muscle, brain, and heart. The changes in guinea pigs were characterized by the development of severe myocarditis and encephalitis, accompanied by accumulation of virus antigen. The disease, caused by strain ÉMK-70 could not be differentiated from Coxsackie infection on the basis of the pathomorphological data. This fact must be taken into account when problems concerning the diagnosis of virus diseases at autopsy are examined.Institute of Experimental Pathology and Therapy, Academy of Medical Sciences of the USSR, Sukhumi. (Presented by Academician of the Academy of Medical Sciences of the USSR B. A. Lapin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84 No. 9, pp. 368–372, September, 1977.     

Increased density and synapto-protective effect of adenosine A2A receptors upon sub-chronic restraint stress

Stress initially causes adaptive changes in the brain and can lead to neurodegeneration if continuously present. Noxious brain conditions trigger the release of adenosine that can control brain function and neurodegeneration through inhibitory A(1) and facilitatory A(2A) receptors. We tested the effect of restraint stress on the density of adenosine receptors and their effect on the outcome of stress, focusing in a known affected region, the hippocampus. Sub-chronic restraint stress (6 h/day for 7 days) caused a parallel decrease of the density of A(1) receptors (15-20%) and an increase (near 250%) of A(2A) receptor density in rat hippocampal nerve terminals. This indicates that sub-chronic stress unbalances adenosine receptors, up-regulating A(2A) and down-regulating A(1) receptors. Sub-chronic stress did not cause hippocampal neurodegeneration but decreased the immunoreactivity (immunohistochemistry and Western blot) of a synaptic marker, synaptophysin. The blockade of A(2A) receptors with 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (0.05 mg/kg, daily i.p. injection) attenuated the loss of synaptophysin immunoreactivity observed in the hippocampus of rats subjected to sub-chronic restraint stress. This ability of A(2A) receptor antagonists to prevent the earliest stress-induced synaptic modifications provides a neurochemical and morphological correlate for the interest of A(2A) receptor antagonists to attenuate the burden of chronic stress.     

The relationship between the neuromodulator adenosine and behavioral symptoms of autism

The neuromodulator adenosine is an endogenous sleep promoter, neuroprotector and anticonvulsant, and people with autism often suffer from sleep disruption and/or seizures. We hypothesized that increasing adenosine can decrease behavioral symptoms of autism spectrum disorders, and, based on published research, specific physiological stimuli are expected to increase brain adenosine. To test the relationship between adenosine and autism, we developed a customized parent-based questionnaire to assess child participation in activities expected to influence adenosine and quantify behavioral changes following these experiences. Parents were naive to study hypotheses and all conditions were pre-assigned. Results demonstrate significantly better behavior associated with events pre-established as predicted to increase rather than decrease or have no influence on adenosine. Understanding the physiological relationship between adenosine and autism could open new therapeutic strategies – potentially preventing seizures, improving sleep, and reducing social and behavioral dysfunction.     

Effect of amiridine and tacrine on reuptake of neurotransmitters in experimental amnesia

It is demonstrated that a single administration of amiridine, tacrine, piracetam, and physostigmine has no effect on the reuptake of adrenalin, noradrenalin, dopamine, and glycine, or of γ-aminobutyric, glutamic, and aspartic acids. Scopolamine (single administration or a 20-day treatment) also has no effect on the reuptake of these neurotransmitters. Administration of amiridine to intact rats during a 20-day period leads to a decrease in the reuptake of dopamine and γ-aminobutyric acid. A course of amiridine therapy of rats after repeated administration of scopolamine results in a reduced reuptake of dopamine. Tacrine, piracetam, and physosostigmine exhibit no activity under the chosen experimental conditions. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 5, pp. 512–514, May, 1995 Presented by Yu. A. Romanov, Member of the Russian Academy of Medical Sciences     

Blood hyperviscosity syndrome: Adequacy of experimental model in SHR rats

In comparison with Wistar rats, SHR rats demonstrated significantly higher viscosity of the whole blood and plasma, fibrinogen content, and erythrocyte aggregation, but a lower erythrocyte deformability. The differences in hemorheological indices in SHR and Wistar rats correspond to the deviation of these indices in the blood hyperviscosity syndrome observed in hypertensive patients. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 8, pp. 150–151, August, 1998     

Emotional state and one-trial learning in OXYS rats with hereditarily elevated production of oxygen radicals

Comparative analysis of unconditioned and conditioned behavior of Wistar and prematurely aging OXYS rats revealed that the latter have significantly reduced locomotor and exploratory activities, increased anxiety in the elevated plus-maze test, spatial disorientation, and abnormal associative learning. OXYS rats can be used as a biological model for studying molecular, neurobiological, and neurochemical mechanisms of brain aging. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 8, pp. 155–158, August, 2000     

Neuroanatomical mapping of juvenile rat brain regions with prominent basal signal in [(35)S]GTPgammaS autoradiography

[(35)S]GTPgammaS autoradiography represents a powerful functional approach to detect receptor-dependent G(i/o) protein activity in anatomically defined brain structures. Inherent to this technique, however, is the notable basal signal evident in several brain regions in the absence of receptor stimulation by exogenously added agonist. In the rat brain, much of this basal labelling derives from tonic activation of adenosine A(1) and lysophosphatidic acid LPA(1) receptors in the gray and white matter regions, respectively. Despite the elimination of the two receptor activities, prominent basal [(35)S]GTPgammaS labelling is still evident in discrete brain structures, possibly reflecting regional enrichment of G(i/o) and/or constitutive receptor activity or the presence of still unknown endogenous ligands activating their orphan receptors. Here, the anatomical distribution of the enhanced basal signal was systematically mapped in brain sections of 4-week-old male Wistar rats. Regions with prominent basal [(35)S]GTPgammaS labelling represented neuroanatomically distinct structures, in particular various thalamic and hypothalamic nuclei. For instance, the paraventricular thalamic nucleus, the bed nucleus of the stria terminalis and the subfornical organ were highly labelled, as were the periaqueductal gray and the nucleus of the solitary tract. Pre-treatment with N-ethylmaleimide (NEM), an alkylating agent preventing all known receptor-driven G protein activity in cryostat sections markedly decreased the basal binding in all examined regions. In preliminary screening, selective antagonists for various brain-enriched G(i/o)-coupled receptors failed to suppress the basal signal in any of the studied regions.     

Effect of glutamate and antagonists of N-methyl-D-aspartate receptors on experimental parkinsonian syndrome in rats

Ontranigral administration of glutamate to rats with parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine augmented the development of parkinsonian symptoms (oligokinesia and muscular rigidity), but did not affect motor activity of intact animals. Memantine administered intraperitoneally in parallel with induction of parkinsonian syndrome weakened the development of oligokinesia and muscular rigidity in a dose-dependent manner starting from 5 mg/kg and abolished toxic effect of glutamate. Ketamine (15 mg/kg) under the same conditions less potently prevented the development of oligokinesia, did not prevent the development of muscular rigidity, and did not antagonize glutamate toxicity. The data attest to an important role of glutamate and activation of N-methyl-D-aspartate receptors in the induction and development of parkinsonian syndrome. Translated fromByulleten' Eksperinmental'noi Biologii i Meditsiny, Vol. 130, No. 7, pp. 20–23, July, 2000     

Peritoneal endotoxicosis,morphology, and morphogenesis of biosystem involvement in experimental animals

Experimental acute peritonitis was induced by single and repeated injections of 1.5–3% fecal autosuspension in the abdominal cavity of white rats. The blood content of medium-weight molecular proteins, which increases 1.5-2-fold during the course of entry of toxic products into the blood over 1–3 days, was measured. Examination of the vascular system and parenchymatous elements of many organs helped reveal three morphogenetic mechanisms of their injury: hyperfunction of cells, followed by their depletion and death; the direct action of toxic products on membranous structures of cells due to severe impairment of the histohematic barrier at the level of the microcirculation; the destructive effect of hypoxia due to the development of the disseminated intravascular coagulation syndrome. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 118, N ^o 12, pp. 636–639, December, 1994 Presented by D. S. Sarkisov, Member of the Russian Academy of Medical Sciences     

Dysrhythmias caused by histamine release in guinea pig and human hearts

Summary Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heartin vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heartin vitro.Arrhythmogenic effects of histamine include enhancement of normal automaticity, induction of abnormal automaticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction, and increase in the vulnerability of the ventricles to fibrillation. A combination of H₁ and H₂ antihistamines is needed to block the arrhythmogenic effects of histamine. Certain arrhythmogenic effects of histamine (e.g. induction of slow responses and delayed afterdepolarizations) can also be blocked by drugs which inhibit the influx of cations through slow channels. In contrast, the commonly-used drug digitalis potentiates the arrhythmogenic effects of histamine.We propose that histamine release produced by drugs and surgical procedures may be an overlooked factor in fatal cardiac arrhythmias. Experimental studies suggest that selective pharmacological methods can be developed to block the arrhythmogenic effects of histamine.Post-Doctoral Research Fellow supported by 1F32 HL 05536     

Effect of glutamate and antagonists of N-methyl-D-aspartate receptors on experimental parkinsonian syndrome in rats

Ontranigral administration of glutamate to rats with parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine augmented the development of parkinsonian symptoms (oligokinesia and muscular rigidity), but did not affect motor activity of intact animals. Memantine administered intraperitoneally in parallel with induction of parkinsonian syndrome weakened the development of oligokinesia and muscular rigidity in a dose-dependent manner starting from 5 mg/kg and abolished toxic effect of glutamate. Ketamine (15 mg/kg) under the same conditions less potently prevented the development of oligokinesia, did not prevent the development of muscular rigidity, and did not antagonize glutamate toxicity. The data attest to an important role of glutamate and activation of N-methyl-D-aspartate receptors in the induction and development of parkinsonian syndrome. Translated fromByulleten' Eksperinmental'noi Biologii i Meditsiny, Vol. 130, No. 7, pp. 20–23, July, 2000