[Dose-dependent effects of neuroimmunomodulator interferon alpha on behavior of humans and animals].

The review analyses the literature on polyfunctional activity of the cytokine interferon-alpha (IA) which has neuroimmunomodulatory properties and is used for treatment of viral and oncologic diseases. The major intention is devoted to action of small and high doses of IA on different forms of animals and human behavior. We suggest that chronic treatment with small IA doses is more effective than high dose therapy.

[The role of interferon-alpha in regulation of nervous system functions].

The review analyses contemporary data on the role of the interferon-alpha in the central nervous systems. Interferon-alpha is one of the key polyfunctional cytokines providing integrative activity of the neuro-immuno-endocrine complex. The emphasis is made on the molecular mechanisms of anti-viral, anti-proliferative and neuromodulating actions of the interferon-alpha in the brain. Mechanisms of its involvement in regulation of pain, sleep, body temperature, circadian rhythms, food consumption etc. are considered. Based on the literature and our data we hypothesized a dose-dependent action of exogenous interferon-alpha on the nervous system. We suggest that optimal schemes of chronic application of small interferon-alpha doses can be more expedient for treatment of viral or oncologic diseases than large doses causing neuropsychiatric disorders.

The central nucleus of the amygdaloid body of the brain: cytoarchitectonics, neuronal organization, connections.

This review considers the questions of the structural-functional organization of the central nucleus (CN) of the amygdaloid body (AB) of the brain in relation to new data on its involvement in the formation of stress reactions and adaptive behavior in animals. Data are presented on the distribution of neuropeptides, neurotransmitters, and modulators in the CN. It is noted that the CN, appearing at the earliest stages of establishment of the AB, is reorganized with it and reflects the evolution of the whole AB. Detailed data are presented on the cytoarchitectonics of the CN of the AB, its heteromorphousness, and subdivision into zones (subnuclei) based on the use of different study methods and assessment criteria. The neuronal organization of the CN and its subnuclei is considered; detailed descriptions of different types of neurons are provided, with consideration of their topographies, sizes, and shapes and of their perikarya, the orientation and type of branching of their dendrites, the organization of the spine apparatus, and axon structure. The characteristics of the development of the CN of the AB in the ontogenesis of mammals and man are discussed. Analysis of published data and our own results supports the role of the CN not only as an intra-amygdalar integrative center, but also as one of the major channels for the afferent and efferent connections of the AB with the rest of the brain.

Role of antioxidant enzymes and antioxidant compound probucol in antiradical protection of pancreatic beta-cells during alloxan-induced diabetes.

The severity of disturbances in carbohydrate metabolism in rats with alloxan-induced diabetes depended on activity of antioxidant enzymes in the target organ (pancreas). Damage to the pancreas is related to intensive generation of reactive oxygen species, free radicals, and lipid peroxides. Alloxan-induced diabetes in rats is a free radical disease, which in vivo serves as a useful model for the search for pharmacological preparations with antiradical and antioxidant properties. The antioxidant compound probucol indirectly increased activity of antioxidant enzymes in the pancreas and prevented the development of alloxan-induced diabetes in rats. Our results indicate that different sensitivity of laboratory animals of various species (rats and guinea pigs) to the influence of alloxan is associated with abnormal variations in activity of enzymes utilizing reactive oxygen species and lipid peroxides in mammalian pancreatic cells.

Antidiuretic hormone-V2-receptor-aquaporin-2 system in rat kidneys during acute inflammation.

Expression of antidiuretic hormone V(2)-receptor, water channel protein aquaporin-2, and cytokines interleukin-1b and interleukin-6 was studied in the kidneys of rats with acute inflammation produced by intraperitoneal injection of lipopolysaccharide in a dose of 250 microg/100 g. Reduced expression of aquaporin-2 and V(2)-receptor led to impairment of concentration capacity in the kidneys and decrease in urine osmolarity.

[Neuroimmunoendocrinology: beginning and prospective development]. / Neiroimmunoéndokrinologia: istoki i perspektivy razvitiia.

The paper gives analytical consideration of what, as to how evolved current notions of the new branch of neurobiology, the neuroimmunoendocrinology, dealing with integration of the main physiological regulatory systems--netvous, endocrine and immune, with special reference paid to the developmental likeness of their controlling mechanisms, letting to assume their cooperative action. Taking the latter into consideration the opportunity is discussed, suggesting that breakage of those would result in various kinds of disregulatory pathology including autoimmune one.

Effect of bacterial endotoxin on secretion and synthesis of vasopressin during saline load in rats.

Secretion and synthesis of vasopressin was studied in adult male Wistar rats receiving lipopolysaccharide in a dose of 250 microg/100 g body weight and subjected to moderate osmotic stimulation (2% NaCl perorally for 6 days). Lipopolysaccharide stimulated secretion of vasopressin into the blood. It should be emphasized that the content of vasopressin mRNA in gigantocellular nuclei of the hypothalamus decreased, which probably reflected intensification of its translation. The observed changes and slight increase in transcription of the vasopressin gene (determined by the content of heterogeneous nuclear RNA) provide intensive secretion of this neurohormone into the blood.

[Neuroimmunoendocrine interaction in the pathogenesis of chronic heart failure]. / Neiroimmunoéndokrinnye vzaimodeistviia v patogeneze khronicheskoi serdechnoi nedostatochnosti.

Chronic heart failure (CHF) is a common complication of patients with heart dysfunction and of those suffering from various chronic illnesses. Although recently developed therapies revolutionized treatment of CHF, life expectancy of the survivors is still significantly reduced. Proposed neurohoromonal approach in CHF treatment is on the whole rather unsatisfactory. Recently the interest of clinical investigators has been focused on immune mechanisms in the pathogenesis of CHF. In this review we tried to summarize data concerning contribution of inflammatory cytokines to pathogenesis of CHF. The source and site of action of pro- and antiinflammatory cytokines and number of interactions among cytokines and neuroendocrine systems under CHF are considered. Finally we discuss novel therapies managing correction of both immune and neurohormonal status of the patient.

[Brain central amygdaloid nucleus: cytoarchitechtonics, neuronal organization, connections]. / Tsentral'noe iadro mindalevidnogo tela mozga: tsitoarkhitektonika, neironnaia organizatsiia, sviazi.

This review describes different aspects of structural and functional organization of amygdaloid central nucleus (CN) in association with the findings indicating its involvement in the development of stress reactions and adaptive behavior in animals. The data on the distribution of neuropeptides, neurotransmitters and neuromodulators in CN are discussed. It is emphasized that CN appears at the earliest stages of amygdaloid formation, undergoes remodeling together with it and reflects the evolution of the whole amygdaloid. The detailed data are presented on the cytoarchitectonic of amygdaloid CN, its heteromorphism and subdivision into zones (subnuclei), based on the different methods of investigation and evaluation criteria. The neuronal organization of CN and its subnuclei is discussed, and the detailed description of neurons of different types is given according to their topography, cell body dimensions and shape, dendrite orientation and branching pattern, organization of spine apparatus and axon structure. The developmental features of amygdaloid CN in mammalian animal and human ontogenesis are considered. The analysis covering the literature data and the results of authors' own investigations indicates that CN functions not only as intraamigdaloid integrative center, but also as one of the major channels providing both afferent and efferent connections of amygdaloid with other brain structures.

[Evolutionary aspects of a stress reaction]. / Evoliutsionnye aspekty stressornoi reaktsii.

Interconnections between the integrative systems, such as nervous, endocrine, and immune ones, are clearly seen during a stress response. The sources of such a cooperation should be sought at the earliest stages of evolution of multicellular organisms. The paper deals with the main points of the formation of a stress response and the development of the systems involved in this process. Based on the data available in the literature and their own findings, the authors conclude that just primitive multicellular organisms, such as coelenterates, have hemolymph cells (chemocytes) that combines the properties of all regulatory systems of more highly organized species. However, the need for such cells no longer arises afterwards. Glucocorticoids, one of the major stress hormones, show up during the development of a stress response relatively late--in fish. While in fish, the production of ACTH and glucocorticoids in the pituitary cells is under urotensin control, this function belongs to corticotropin-releasing hormone of pituitary origin in more advanced animals. The predominant value of corticotropin-releasing hormone simultaneously occurs with the development of the pituitary portal vascular system. Such transformations lead to the formation of the hierarchically arranged neuroendocrine axes that are responsible for showing a stress response, on the one hand, and to the development of qualitatively new interactions between the nervous, endocrine, and immune systems, on the other.

[Neuroimmunoendocrinology of the fat tissue]. / Neiroimmunoéndokrinologiia zhirovoi tkani.

Recent information concerning the white fat tissue allows considering it as endocrine system involved in the neuro-immune-endocrine interactions in regulating various aspects of homeostasis. The contribution presented sums up the latest evidence of adipocyte secreting hormones (leptine and resistine), cytokine (TNF alpha), as well as shedlight on mechanisms, involved in control of energy metabolism, immune reactions and food intake monitoring.

Expression of neuronal and inducible nitric oxide synthases in the thymus under normal conditions and after administration of bacterial endotoxin.

The topography of thymocytes expressing neuronal and inducible nitric oxide synthases and changes in the content of luminescent immunoreactive products in these cells after intraperitoneal injection of bacterial lipopolysaccharide were studied by double immunohistochemical labeling. Under normal conditions neuronal nitric oxide synthase-immunopositive cells formed a wide network in thymus medulla (except for perivascular regions). Inducible nitric oxide synthase was expressed in single cells at the corticomedullary boundary. Lipopolysaccharide markedly increased the intensity of luminescence and number of inducible nitric oxide synthase-immunoreactive cells. However, this agent sharply decreased the intensity of luminescence in neuronal nitric oxide synthase-immunopositive cells of the stroma. Our results indicate that neuronal and inducible nitric oxide synthases are synthesized in various stromal cells of the thymus. Expression of these enzyme isoforms undergoes opposite changes during inflammation.

[Neuroimmunoendocrine interactions: their role in dysregulatory pathologies]. / Neiroimmunoéndokrinnye vzaimodeistviia: ikh rol' v disreguliatornoi patologii.

The author reviews the trends in development of views of interaction of the basic regulating systems (nervous, endocrine and immune) supporting control and adaptive functions of the brain. Two historical periods are singled out: the period of neuroendocrinology and neuroimmunoendocrinology. Mechanisms of interaction of brain regulating systems and various autoimmune diseases resulting from defects in the above mechanisms are considered. Development of cooperative interactions of the above regulating systems at early evolutionary stages is suggested.

[Vasopressin and inflammation]. / Vasopressin i vospalenie.

At least three vasopressinergic brain systems are involved in inflammatory reaction. The first one is VP neurons of the bed nucleus of stria terminalis, projecting to antipyretic center in the preoptic forebrain region. The second system is neurons of the parvocellular subnucleus of the hypothalmic paraventricular nucleus. VP from these neurons reaches portal blood through the external zone of the median eminence. VP potentiates the effect of corticotropin releasing hormone on ACTH cells in the anterior pituitary. Synergetic modulation of pituitary-adrenal axis by these neurohormones maintains synthesis and release of glucocorticosteroids. The latter plays crucial role as endogenous immunosuppresants. The third VP system is magnocellular hypothalamic neurons that release vasopressin into general circulation. Systemic VP is capable of compensating the water lost caused by symptoms of inflammation. The review is devoted to analysis of current information concerning physiology and interactions between these systems during acute and chronic inflammation. The special reference has been made on the magnocellular neurons and the role of circulating vasopressin in the renal function regulation.

Effects of vagotomy and bacterial lipopolysaccharide on food intake and expression of cyclooxygenase-2 mRNA in rat brain vessels.

Effects of bilateral subdiaphragmatic vagotomy on food intake and expression of cyclooxygenase-2 mRNA in cerebral vessels in rats intraperitoneally injected with bacterial lipopolysaccharide were studied using in situ hybridization technique. Low doses of lipopolysaccharide decreased food intake in sham-operated animals, but did not affect this parameter in vagotomized rats. Comparison of hybridization signals in brain slices showed that low doses of endotoxin did not affect expression of cyclooxygenase-2 mRNA in vessels of control and experimental animals. High doses of lipopolysaccharide reduced food intake in vagotomized and sham-operated rats and elevated cyclooxygenase-2 mRNA expression in vascular endothelial cells of the brain parenchyma and meninges. The data suggest that the vagus nerve activates central structures responsible for manifestation of anorexia after intraperitoneal injection of low doses of lipopolysaccharide. High doses of endotoxin activate the vagus-independent mechanism of cyclooxygenase-2 synthesis in the endothelium of cerebral vessels. It is assumed that prostaglandins synthesized by cyclooxygenase-2 diffuse into the brain parenchyma and cause anorexia by activating target nerve structures.

Effects of blockers of carbohydrate and lipid metabolism on expression of mRNA of some hypothalamic neuropeptides.

The effects of single injections of 2-deoxyglucose or 2-mercaptoacetate on the expression of mRNA of neuropeptide Y, pro-opiomelanocortin, and melanin-concentrating hormone in rat hypothalamus were studied by in situ hybridization in order to elucidate the role of these neuropeptides in the mechanisms of alimentary behavior caused by decreased levels of available fatty acids and glucose. The levels of neuropeptide Y mRNA in arcuate nuclei neurons are significantly increased under conditions of glucose deficiency, while the synthesis of melanin-concentrating hormone in the lateral hypothalamic neurons is increased in fatty acid deficiency. These data indicate that glyco- and lipodeprivation are different metabolic signals activating various neuropeptide systems responsible for alimentary behavior.

Effect of transection of various branches of the vagus nerve on lipopolysaccharide-induced synthesis of corticotropin-releasing hormone mRNA in the paraventricular nuclei of rat hypothalamus.

Effects of selective transection of the gastric, celiac, and hepatic branches of the vagus nerve on expression of corticotropin-releasing hormone mRNA in small cell neurons of the hypothalamic paraventricular nuclei in rats administered with bacterial lipopolysaccharide were studied using in situ hybridization technique. Low doses of lipopolysaccharide stimulated expression of corticotropin-releasing hormone mRNA in rats subjected to axotomy of the gastric or celiac branches of the vagus nerve, but did not change the intensity of autoradiographic labeling in animals with transected hepatic branches. High doses of lipopolysaccharide enhanced expression of corticotropin-releasing hormone mRNA in vagotomized rats of all groups, which indicated the existence of a vagus-independent mechanism responsible for activation of paraventricular neurons mediating the effect of this hormone. The data suggest that the inflammation-dependent activation of stress-regulating neurons in the hypothalamus is controlled by several mechanisms, whose activation depends on the severity of inflammatory processes.

[The hierarchical relationships between the organs of the hypothalamo-hypophyseal-adrenal system (HHAS) in inflammation]. / Ierarkhicheskie vzaimootnosheniia mezhdu organami gipotalamo-gipofizarno-adrenalovoi sistemy (GGAS) pri vospalenii.

The HPA axis is the major system of adaptation to the action of different stressors, including inflammatory agents. The glucocorticoids, the end product of HPA axis prevent the extension of inflammation. In this article we discuss the classic direct and feedback loops in the HPA axis during acute bacterial inflammation. On the basis of literary and own findings we put forward a speculation that different systemic cytokines released one by one during inflammation induce the appearance of new functional relations between the organs of HPA axis. Because of cytokines are involved in the modulation of hormonal sensitivity in the HPA axis the serious modification of direct as well as feedback relations is postulated. On the other hand cytokines and immune cells induce autocrine and paracrine production of cytokines in the HPA axis, that result in autonomization of pituitary and adrenals functions. So, the acute inflammation factors could be seen as "short-time" functional dominants of HPA axis functioning.

[The participation of the nontraditional neuromediator nitric oxide in the mechanisms of adaptation to extreme conditions]. / Uchastie netraditsionnogo neiromediatora okisi azota v mekhanizmakh adaptatsii k ékstremal'nym usloviiam.

The investigation was performed on the medial (MMS) and lateral (LMS) magnocellular subdivisions of the hypothalamic paraventricular nuclei (HPN). The histochemical activity NO synthesizing enzyme nitric oxide synthase or NOS whose histochemical marker is NADPH-diaphorase (NADPH-D), immunocytochemical content of oxytocin (OXY), vasopressin (VP) and nucleoli sizes (squares) were studied in the mature male rats under experimental reconstruction of the both micro- and macrogravity, which are factors of the gravity field changes acting to the body during the space flight. Two experimental effects were used: B--tail suspending (imitation of the microgravity effects), C--centrifugation at 2 G (imitation of the macrogravity effects). The effect durations were designed as a time period when body is mostly affected by (1 day) and adapted (15 days) to the stress. There were 6 animal groups. 1--B(15 days), 2--B(15 days) succeeded by C(1 day), 3--B(15 days) succeeded by C(15 days), 4--C(1 day), 5--C(15 days), 6--intact animals. The histochemically and immuno-cytochemically stained neurons developing the high, moderate and small reaction intensity were counted in serial HPN sections under the light microscope and the results obtained were transformed to percent neuron contents. The nucleoli squares were examined by using the TV analyser. The histochemical staining intensity of NADPH-D in MMS is enhanced in the animals of the groups 1-4; the number of NADPH-D staining neurons with high enzyme activity was increased in 8-14 times. In the animals of group 5 the NADPH-D activity did not differ from the intact animals. The number of MMS neurons with high OXY immunoreactivities was increased up to 1.5-1.7 times in groups 1-5 if compared to those of intact controls. VP-positive neurons of LMS developed the similar increase in number of the high staining neurons in experimental animals as well as OXY-positive neurons of MMS. The nucleoli enlargement was observed in MMS (in 1.3-1.5 times) of groups 1-5 (insignificantly in group 5) and in the most magnocellular neurons LMS (in 1.5-1.7 times) of group 2-5 except group 1 where nucleoli were insignificantly decreased. The nucleoli sizes of group 4 were more than group 5. So the hypothalamo-neurohypophyseal system was activated in the animals subjected of the earthly correlates of micro- and macrogravity. The data obtained suggest involvement both the nonconventional neurotransmitter NO and stress-related peptides OXY and VP in the mechanisms subserving adaptation to the extreme factors by what a human has to be faced with during the space flight.