CENTRAL AND PERIPHERAL EFFECT OF MPTP VIA DOSE-DEPENDENT MAGNESIUM MODULATION.

Background: Recent studies suggested that MPTP could cause gastrointestinal motility deficits additionally to its nonconclusive and controverted effects on the CNS (behavior and brain oxidative stress) in rats. A possible interaction between MPTP typical impairments and magnesium modulatory potential was previously suggested, as magnesium role was described in neuroprotection, gastrointestinal function, and oxidative stress. Aim: To investigate the possible modulatory effect of several magnesium intake formulations (via drinking water) in MPTP neurotoxicity and functional gastrointestinal impairment induction. Materials and Methods: Adult male Wistar rats were subjected to 3-week magnesium intake-controlled diets (magnesium depleted food and magnesium enriched drinking water) previously to acute subcutaneous MPTP treatment (30 mg/ kg body weight). Gastrointestinal motility (one hour stool collection test), and behavioral patterns (Y maze task, elevated plus maze test, open field test, forced swim test) were evaluated. Followingly, brain and bowel samples were collected, and oxidative stress was evaluated (glutathione peroxidase activity, malondial-dehyde concentrations). Results: MPTP could lead to magnesium intake-dependent constipation-like gastrointestinal motility impairments, anxiety- and depressive-like affective behavior changes, and mild pain tolerance defects. Also, we found similar brain and intestinal patterns in magnesium-dependent oxidative stress. Conclusion: While the MPTP effects in normal magnesium intake could be regarded as not fully relevant in rat models and limited to the current experimental conditions, the abnormalities observed in the affective behavior, gastrointestinal status, pain tolerance, peripheric and central oxidative status could be indicative of the extent of the systemic effects of MPTP that are not restricted to the CNS level, but also to gastro-intestinal system.

Actual data concerning the brain--immune system interface.

After a brief presentation of the immune system as sensorial and effector organ, which recognizes and defends against cellular aggressions, the main psycho-neuro-endocrine components of immune reaction regulation and modulation will be shown. Both central nervous structures that control the hormonal emissions, the vegetative innervation of the lymphoid organs as well as the afferent neurohumoral pathways involved in the making of the self-regulating and neuromodulating circuits of the humoral and cellular immune responses will be mentioned. An important position will be held by the interrelations between the hypothalamus-pituitary-corticoadrenal gland, the sympathetic-parasympathetic efferent pathways and the chemical messengers (hormones, neurotransmitters, interleukins, neurotrophins) which make possible the bi-directional neuroimmune communication for maintaining the homeostatic balances on this third effector pathway, too. Also will be presented experimental proof concerning the ability of central neurons to secrete neuromodulator cytokines and the presence of specific receptors for the various neuroactive molecules within lymphoid organs and circulating lymphocytes. To close, the psychoemotional components of the neuro-immunomodulator circuits will be mentioned, using as examples the changes induced by stress generally and oxidative stress in particular.

Interactions between the oxidative and nitrosative stress in nociceptive processing in rat.

During the last years, special emphasis was directed towards the relation between the molecular and cellular alterations produced by free oxygen radicals and the normal and pathologic implications of nitric oxide. Moreover, lately it is believed that a true radical cascade might exist between the reactive species of oxygen and nitrogen during stress of various causes. In this way, their succession would produce a temporal prolongation of the complex cellular alterations produced by stressing aggressions. In the present paper, we were interested in presented some selective aspects regarding the interactions between oxidative and nitrosative stress in the modulation of the nociceptive behavior in rats. We report here a significant correlation between the results of the hot-plate latency time and the values of some oxidative and nitrosative stress markers.

Antioxidant activity in rat models of nociceptive stress.

UNLABELLED: Pain is an important problem and has been the subject of many studies in recent years. MATERIAL AND METHOD: The present study has investigated the response of the antioxidant defense systems in contention stress, which mimics nociceptive stress. Contention stress was made by immobilizing the rat, Wistar rats, on an operating table in a specific position with paws tied, for thirty minutes. The determinations evaluate the levels of oxidative stress markers like reduced glutathione (GSH) and malondialdehyde (MDA) and the levels of the protecting enzymes against of free radicals in brain. RESULTS: After the application of contention stress, GSH level increased insignificantly, while MDA level increased significantly compared with the normal animals. These have demonstrated that in our model of nociceptive stress actioned the mechanisms of membrane lipid peroxidation. The activity of the antioxidant enzymes GSH, GPX and SOD decreased in the stressed animals compared with the normal group. This experiment has revealed that in our model of nociception stress, many reactive oxygen species (ROS) were generated, which reduced the enzymatic defense mechanisms and activated lipid peroxidation mechanisms.

Biosynthesis and physio-pharmacological actions of angiotensin peptides: 2. Physio-pharmacological properties.

The classic concept of the renin-angiotensin system being substantially accomplished by the new cognitive and applicative acquisitions, a natural reconsideration and completion is imposed. In consequence, ample referrals are made to the main central and peripheral actions of Angiotensins through specific receptors. Emphasis is given to the effects of Angiotensin IV and Angiotensin 1-7 which are different of those of Angiotensin II, underlining their possible role as counteracting factors to its actions, in order to remove the imbalances created by the predominating stimulation of vasoconstricting AT, receptors. There are also taken into account the mainly central neural actions of Angiotensin IV, while Angiotensin 1-7 seems to be active only in the periphery. At the end are mentioned the results of our own research on the vasodilating effects of Angiotensin 1-7 and its interrelations with Angiotensin II. New experimental proofs are brought both in favor of the endocrine, paracrine and autocrine role of the circulating and tissue renin-Angiotensin system and of the counteracting of the effects of Angiotensin II by a part of its metabolism products.

Biosynthesis and physio-pharmacological actions of angiotensin peptides: 1. Synthetic enzymes.

The present work introduces a brief review of the actual knowledge concerning the enzymes involved in the biosynthesis of the active angiotensins, followed by a presentation of their main physio-pharmacological actions. The enzymatic pathways that generate active ang. II (1-8) are complemented with data concerning its transformation into angiotensin III (2-8), ang. IV (3-8), ang. V (1-5) and ang. 1-7. Besides the classic renin of renal origin, the tissue isorenins, represented by tonin and cathepsins D and G, inactive angiotensin-I-forming are also reviewed. Furthermore, chymase and the new angiotensin-converting enzyme 2 (ACE2), which generates angiotensin 1-7, having opposite properties from the mother-substance (Ang. II) are discussed at length. The presentation of properties of angiotensin-generating enzymes is followed by the presentation of the action of angiotensinases (aminopetidases, carboxypeptidase and endopeptidases), which are involved both in the generation of biologically active angiotensin peptides and in their inactivation.

In vivo and in vitro research on the biological effects of deuterium-depleted water: 1. Influence of deuterium-depleted water on cultured cell growth.

Deuterium depleted-water (DDW) is a new available tool for decreasing deuterium concentration in the environment of cells in culture. Several types of established cell lines, both normal and neoplastic were grown in culture media dissolved with DDW and compared with the same strains, in the same amounts, grown in media dissolved with normal distilled water. Naive mice splenocytes were grown, under stimulation with proliferation triggers, like bacterial lipopolysaccharide (LPS) and Concanavalin A (ConA) in the same conditions. The growth and proliferation were estimated using the MTT assay. Both established cell types and explanted splenocytes in the DDW-media had a significantly higher growth rate than cell cultured in normal media. In an attempt to identify the membrane mechanisms involved in the growth stimulation by DDW, the membrane proton transporters Na+/H+ antiporter and H+/K+ATP-ase were inhibited with their selective blockers amiloride and respectively lansoprazole. The results, however incomplete, point towards a lack of involvement of the Na+/H+ antiporter and a possible implication of the H+/K+ATP-ase.

Present data concerning the renin-angiotensin system of extrarenal origin.

After a brief historical incursion regarding RAS of renal origin, we present the main extrarenal angiotensin-forming enzymes, starting with isorenin, tonin, D and G cathepsin and ending with the conversion enzyme and chymase. This is followed by a short presentation of data concerning tissue RAS in the heart and vessels, brain and neurocranial accessory glands, cortico-suprarenal and gonadal glandular territory. In the end we refer to the relations between circulating RAS of renal origin and the extrarenal RAS specific to tissue underlying the fact that the two RAS components cooperate and constitute a unitary hormonal system, regulating the major functions of the organism and maintaining the main homeostatic equilibria. While the circulating RAS of renal origin is acutely activated to contribute to the accomplishment of short term homeostatic reactions, tissue RAS, in paracrine or autocrine ways, exerts local-regional adaptive actions of long duration.

[Current data on the extrarenal renin-angiotensin system]. / Date actuale privind sistemul renina-angiotensina de origine extrarenala.

After a brief historical incursion regarding SRA of renal origin we present the main extrarenal angiotensin-forming enzymes, starting with isorenin, tonin, cathepsin D si G and ending with the conversion enzyme and chymase. This is followed by a short presentation of data concerning tissue SRA in the heart and vessels, brain and neurocranial accessory glands, cortico-suprarenalian and gonadal glandular territory. In the end we refer to the relations between circulating SRA of renal origin and the tissue extrarenal one, underlying the fact that the two SRA components cooperate and constitute a unitary hormonal system, towards the regulation of the major functions of the organism and the maintenance of the main homeostatic equilibria. While the circulating SRA of renal origin is acutely activated to contribute to the accomplishment of short term homeostatic reactions, tissue SRA, in paracrine or autocrine ways, exerts loco-regional adaptive actions of long duration.

New bioactive angiotensins formation pathways and functional involvements.

After a brief review of the actual knowledge concerning the circulating and tissue Renin-Angiotensin System (RAS) as a unitary hormonal system, the cognitive acquisitions regarding the formation and action mechanisms of the new biologically active angiotensins will be presented. The review of the enzymatic pathways for their synthesis and inactivation, as metabolism products of angiotensin II (1-8), will be followed by the presentation of the main physio-pharmacological actions of angiotensin III (2-8), angiotensin IV (3-8) and angiotensin (1-7). The functional involvements of the cerebral angiotensin IV in what concerns its possible participation in the normal neurochemical processes of memory and in the neurodegenerative processes of Alzheimer disease will be exposed, together with the vasodilating effects of angiotensin (1-7) as counteracting factor for the constricting effects of angiotensin II. The data concerning the bioactive fragments of angiotensin II will be accompanied by those regarding its implication in the cardiovascular modeling and the induction of oxidative stress, inflammation, atherogenesis, etc. In their turn, personal researches bring new experimental evidences in favor of interactions between angiotensin (1-7) and angiotensin II within the rat thoracic aorta. Biphasic, dose-dependent effects were observed for angiotensin (1-7), induced both through nitric oxide, kinins and prostaglandin release for counteracting the vasoconstricting effects of angiotensin II and the modulation of its own vasodilator action.

Research concerning the radioprotective and immunostimulating effects of deuterium-depleted water.

Mice fed for 15 days with Deuterium-Depleted Water (30 ppm deuterium) had a statistically significant increased survival rate compared with control groups fed with normal distilled water (150 ppm deuterium), after 8.5 Gy irradiation (61% survival in the test group versus 25% in the control group). The hematological picture showed that normal WBC, RBC and platelet counts were maintained in the test groups. Immunological parameters (serum opsonic and bactericidal capacity, bactericidal capacity of the peritoneal macrophages) showed a marked increase in the test groups compared to a severe decrease in the control groups. Auxiliary tests using chemical radiomimetics (hydrochloric embihine) and immunosuppressors (cyclophosphamide) showed a strong protective effect of deuterium-depleted water against the decrease of the leukocyte counts and other immunologic parameters. In conditions of experimental inflammation induced with subcutaneous-implanted pellets, deuterium-depleted water feeding resulted in a statistically significant increase of the inflammatory response, demonstrated by increased percentages of PMN and lymphocytes in the peripheral blood and the increased phagocytic capacity of the peripheral blood PMN. Experimental infections induced with K. pneumoniae 506 and S. pneumoniae 558 in mice irradiated or treated with cyclophosphamide showed increased, non-specific immunity parameters. All results show a marked intensification of the immune defenses and increased proliferation of the peripheral blood cells, probably accounting for the radioprotective effects.

Preliminary research on possible relationship of NO with agmatine at the vascular level.

The comparative study of the vascular effects of agmatine and L-arginine as physiological precursors of NO indicated the following: When administered intravenously, both vasoactive substances produced a decrease of the systemic blood pressure in rats and rabbits, diminished in the case of agmatine and suppressed in that of arginine by the previous administration of L-NAME. Myorelaxing vascular effects were obtained in isolated thoracic aorta rings, precontracted with phenylephrine and noradrenaline. Endothelium removal suppressed the myorelaxing properties of L-arginine, without affecting the effects of agmatine, both before and after administration of L-NAME or yohimbine. The persistence of the relaxing effects of agmatine after NOS and guanylate-cyclase inhibition with methylene blue excludes the participation of NO and cGMP in their occurrence. The enhancement of agmatine myorelaxation by moxonidine pleads for the stimulation of imidazoline receptors.

Effects of heavy and deuterium-depleted water on vascular reactivity.

The comparative study of heavy and deuterium-depleted water on the vascular reactivity has shown significant changes of the basal tone in the smooth muscle of the rat thoracic aorta rings. While the heavy water induced relaxing effects, the deuterium-depleted water increased basal tone and vasoconstrictor responses at phenylephrin, noradrenalin and angiotensin. Endothelial nitric oxide seems to be involved in generating the muscular relaxing effects of heavy water.