Knockdown of interleukin-10 induces the redistribution of sigma1-receptor and increases the glutamate-dependent NADPH-oxidase activity in mouse brain neurons.

BACKGROUND: In the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. This cytokine is primarily produced by glial cells and has beneficial effects on the neuronal viability. However, the mechanisms of IL-10-elicited neuroprotection are not clear. RESULTS: Membrane preparations, isolated from wild-type (Wt) and IL-10 knockout (KO) mice brain were used in this study. It has been shown that compared to wild-type mice, in IL-10 KO mice brain, the amount of immunoglobulin binding protein (BiP) is greatly increased, whereas the content of sigma receptor-1 (SigR1) is not changed significantly. Co-immunoprecipitation experiments have shown that the association of SigR1 with small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1), NR2B subunit of NMDA-receptor (NMDAR) and inositol-3-phosphate receptor (IP3R) is higher in the IL-10 KO mice brain than in the Wt mice brain. Besides, we have found that either glutamate or sigma ligands, separately or together, do not change glutamate-induced NADPH-oxidase (NOX) activity in Wt-type mice brain membrane preparations, whereas in IL-10 KO mice high concentration of glutamate markedly increases the NOX-dependent production of reactive oxygen species (ROS). Glutamate-dependent ROS production was decreased to the normal levels by the action of sigma-agonists. CONCLUSIONS: It has been concluded that IL-10 deprivation, at least in part, can lead to the induction of ER-stress, which causes BiP expression and SigR1 redistribution between components of endoplasmic reticulum (ER) and plasma membrane. Moreover, IL-10 deficiency can change the specific organization of NMDAR, increasing the surface expression of SigR1-sensitive NR2B-containing NMDAR. In these conditions, glutamate-dependent ROS production is greatly increased leading to the initiation of apoptosis. In this circumstances, sigma-ligands could play a preventive role against NMDA receptor-mediated excitotoxicity.

Knockdown of interleukin-10 induces the redistribution of sigma1-receptor and increases the glutamate-dependent NADPH-oxidase activity in mouse brain neurons

BACKGROUND: In the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. This cytokine is primarily produced by glial cells and has beneficial effects on the neuronal viability. However, the mechanisms of IL-10-elicited neuroprotection are not clear. RESULTS: Membrane preparations, isolated from wild-type (Wt) and IL-10 knockout (KO) mice brain were used in this study. It has been shown that compared to wild-type mice, in IL-10 KO mice brain, the amount of immunoglobulin binding protein (BiP) is greatly increased, whereas the content of sigma receptor-1 (SigR1) is not changed significantly. Co-immunoprecipitation experiments have shown that the association of SigR1 with small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1), NR2B subunit of NMDA-receptor (NMDAR) and inositol-3-phosphate receptor (IP3R) is higher in the IL-10 KO mice brain than in the Wt mice brain. Besides, we have found that either glutamate or sigma ligands, separately or together, do not change glutamate-induced NADPH-oxidase (NOX) activity in Wt-type mice brain membrane preparations, whereas in IL-10 KO mice high concentration of glutamate markedly increases the NOX-dependent production of reactive oxygen species (ROS). Glutamate-dependent ROS production was decreased to the normal levels by the action of sigma-agonists. CONCLUSIONS: It has been concluded that IL-10 deprivation, at least in part, can lead to the induction of ER-stress, which causes BiP expression and SigR1 redistribution between components of endoplasmic reticulum (ER) and plasma membrane. Moreover, IL-10 deficiency can change the specific organization of NMDAR, increasing the surface expression of SigR1-sensitive NR2B-containing NMDAR. In these conditions, glutamate-dependent ROS production is greatly increased leading to the initiation of apoptosis. In this circumstances, sigma-ligands could play a preventive role against NMDA receptor-mediated excitotoxicity.

Synaptic and non-synaptic mitochondria in hippocampus of adult rats differ in their sensitivity to hypothyroidism.

Hypothyroidism in humans provokes various neuropsychiatric disorders, movement, and cognitive abnormalities that may greatly depend on the mitochondrial energy metabolism. Brain cells contain at least two major populations of mitochondria that include the non-synaptic mitochondria, which originate from neuronal and glial cell bodies (CM), and the synaptic (SM) mitochondria, which primarily originate from the nerve terminals. Several parameters of oxidative stress and other parameters in SM and CM fractions of hippocampus of adult rats were compared among euthyroid (control), hypothyroid (methimazol-treated), and thyroxine (T4)-treated hypothyroid states. nNOS translocation to CM was observed with concomitant increase of mtNOS's activity in hypothyroid rats. In parallel, oxidation of cytochrome c oxidase and production of peroxides with substrates of complex I (glutamate + malate) were enhanced in CM, whereas the activity of aconitase and mitochondrial membrane potential (ΔΨm) were decreased. Furthermore, the elevation of mitochondrial hexokinase activity in CM was also found. No differences in these parameters between control and hypothyroid animals were observed in SM. However, in contrast to CM, hypothyroidism increases the level of pro-apoptotic K-Ras and Bad in SM. Our results suggest that hypothyroidism induces moderate and reversible oxidative/nitrosative stress in hippocampal CM, leading to the compensatory elevation of hexokinase activity and aerobic glycolysis. Such adaptive activation in glycolytic metabolism does not occur in SM, suggesting that synaptic mitochondria differ in their sensitivity to the energetic disturbance in hypothyroid conditions.

mGluR1 interacts with cystic fibrosis transmembrane conductance regulator and modulates the secretion of IL-10 in cystic fibrosis peripheral lymphocytes.

Cystic fibrosis (CF) is caused by the mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. CFTR dysfunction in T cells could lead directly to aberrant immune responses. The action of glutamate on the secretion of IL-8 and IL-10 by lymphocytes derived from healthy subjects and cystic CF patients, as well as the expression of metabotropic glutamate receptor subtype 1 (mGluR1) in the membrane fractions of lymphocytes was investigated. Our results have shown that CF-derived T-cells in the presence of IL-2 produce more IL-8 and IL-10, than T-cell from healthy control. However, only in normal lymphocytes a significant increase (144%) in the IL-10 secretion during exposure to high concentration of glutamate (10(-4)M) was detected. Glutamate-dependent secretion of IL-10 was not inhibited either by NMDA-receptor (NMDAR), or by AMPA-receptor (AMPAR) antagonist. Only mGluR1 antagonist, LY367385, strongly decreases the production of IL-10. Furthermore, the content of mGluR1, as well as cystic fibrosis transmembrane conductance regulator-associated ligand (CAL), Na(+)/H(+) exchanger regulatory factor 1 (NHERF-1), was analyzed in plasma membrane of lymphocytes after immunoprecipitation of CFTR. We have found that normal, non-mutated CFTR, as well as mutated forms of CFTR were associated with metabotropic mGluR1, but the level of surface exposed mGluR1 in CF-lymphocytes was much lower than in normal cells. Besides, our results have shown that normal, non-mutated CFTR, as well as mutated forms of CFTR were associated with NHERF-1 and CAL; however in lymphocytes with CFTR mutation the amount of cell-surface expressed CFTR-CAL complex was greatly decreased. We have concluded that CFTR and mGluR1 could compete for binding to CAL, which in turn downregulates the post-synthetic trafficking of mGluR1 and decreases the synthesis of IL-10.

S-nitrosylation decreases the adsorption of H-Ras in lipid bilayer and changes intrinsic catalytic activity.

Structural, chemical, and mutational studies have shown that C-terminal cysteine residues on H-Ras could potentially be oxidized by nitrosylation. For investigating the effect of nitrosylation of Ras molecule on the adsorption of farnesylated H-Ras into lipid layer, experiments with optical waveguide lightmode spectroscopy were used. The analysis of association/dissociation kinetics to planar phospholipids under controlled hydrodynamic conditions has shown that preliminary treatment of protein by S-nitroso-cysteine decreased the adsorption of farnesylated H-Ras. The authors have found that compared with nitrosylated forms, farnesylated H-Ras has more compact configuration, because of the smaller area occupied by protein upon absorption at the membrane. The association rate coefficient for unmodified H-Ras was lower than similar parameter for farnesylated and nitrosylated forms. However, the desorbability, i.e., parameter, which reflects the rate of dissociation of protein from lipids is higher for farnesylated H-Ras. In addition, it was have found that farnesylation of cytoplasmic H-Ras, in contrast to membrane-derived forms, inhibits intrinsic GTPase activity of protein, and preliminary treatment of H-Ras by S-nitroso-cysteine restores the activity to the control level. These data suggest that nitrosylation of H-Ras rearranges the adsorptive potential and intrinsic GTPase activity of H-Ras through modification of C-terminal cysteines of molecule.

[Effectiveness of unimag in the treatment of catarrhal gingivitis].

Results of microbiological investigation of catarrhal gingivitis on the background of treatment with Unimag are presented in the work. Preparation Unimag is a stable suspension of magnetic nano-particles. Unimag is magnetic-sensitive, X-ray contrast, bactericidal substance; it increases functional activity of phagocytes and characterizes with high penetration ability in tissues. Studies have revealed that treatment with Unimag of the patients with catarrhal and gingivitis rapidly normalizes quantity of microbes in the oral cavity, substituting the gram-negative pathogenic flora for the gram-positive microorganisms in the oral cavity. Unimag increases sensitivity of pathogenic flora towards the anti-bacterial preparations. All the above-mentioned are significant for efficient impact on damaging factors during inflammation.

Haloperidol induces neurotoxicity by the NMDA receptor downstream signaling pathway, alternative from glutamate excitotoxicity.

The NMDA receptor is believed to be important in a wide range of nervous system functions including neuronal migration, synapse formation, learning and memory. In addition, it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. Besides of agonist/coagonist sites, other modulator sites, including butyrophenone site may regulate the N-methyl-D-aspartate receptor. It has been shown that haloperidol, an antipsychotic neuroleptic drug, interacts with the NR2B subunit of NMDA receptor and inhibits NMDA response in neuronal cells. We found that NMDA receptor was co-immunoprecipitated by anti-Ras antibody and this complex, beside NR2 subunit of NMDA receptor contained haloperidol-binding proteins, nNOS and Ras-GRF. Furthermore, we have shown that haloperidol induces neurotoxicity of neuronal cells via NMDA receptor complex, accompanied by dissociation of Ras-GRF from membranes and activation of c-Jun-kinase. Inclusion of insulin prevented relocalization of Ras-GRF and subsequent neuronal death. Haloperidol-induced dissociation of Ras-GRF leads to inhibition of membrane-bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way. Our results suggest that haloperidol induces neuronal cell death by the interaction with NMDA receptor, but through the alternative from glutamate excitotoxicity signaling pathway.

[Anti-ulcerogenic properties of psychostimulants of the phenylalkylsydnone imine series]. / Antiul'tserogennye svoistva psikhostimuliatorov fenilalkilsidnoniminovogo riada.

In rats, administration of 96% ethanol to the stomach causes ulcerative damages to its mucosa just 8 minutes later, which are of significant dimensions, reaching their maximum size following 3 hours. The sydnonimine psychostimulant OF-743 in combination with ethanol substantially reduces mucosal damage. The use of ethanol after OF-743 injections results in less ulcerative damage. The findings suggest that the drug has not only protective (preventive) effects, but beneficial properties.

[Anti-ulcerogenic action of a combination of a psychostimulator of the phenylalkylsydnone imine series and arginine]. / Antiul'tserogennoe deistvie kombinatsii psikhostimuliatora fenilalkilsidnoniminovogo riada i arginina.

It has been revealed that OF 743, one of the psychostimulators belonging to phenylalkylsydnonimine derivatives, exerts anti-ulcerogenic action in case of stress- and ethanol-induced damage of gastric mucosa in rats. However OF 743 was not effective in case of indomethacin-induced gastric mucosal damage. Complex administration of OF 743 and arginine was accompanied by a considerable decrease of indomethacin-induced gastric mucosal damage. That combination was more effective than OF 743 alone in case of ethanol-induced gastric mucosal damage.

[Antiulcerogenic (therapeutic and preventive) properties of a phenylalkyl syndonimine psychostimulant]. / Antiul'tserogennoe (lechebnoe i profilakticheskoe) svoistvo odnogo iz psikhostimuliatorov fenilalkil sidnoniminovogo riada.

Intragastric administration of 96% ethanol, 1 ml/100 g of body mass, induced ulcerous impairments of rat gastric mucosal membrane, which were marked within 8 min after ethanol administration and reached the maximal size within 3 hrs. Psychostimulants of the phenylalkyl sydnonimime series OF 743, administered after the ethanol treatment, decreased distinctly the ethanol-induced impairments of gastric mucosal membrane and this effect was higher in simultaneous inoculation of the drug and ethanol. The data obtained suggest that preparation OF 743 exhibited both protective and curative antiulcerogenic efficiency.

[Comparison of the inhibitory effects of a psychostimulant of the sydnonimine series on the development of stress and ethanol induced lesions in the rat gastric mucosa]. / Sopostavlenie tormoziashchego deistviia psikhostimuliatora sidnoniminovogo riada na razvitie stressornykh i étanolovykh povrezhdenii slizistoi obolochki zheludka u krys.

The possibility of the inhibitory influence of one of the psychostimulators of sydnonimine derivatives OF 743 on stress--and ethanol-induced mucosal lesions was studied in rats. Large doses (15 mg/kg) OF 743, which induced both central, psychostimulator, peripheral, and vagolytic effects equally decrease stress- and ethanol-induced mucosal lesions. The smaller doses, which show only peripheral effects, largely inhibit ethanol-induced lesions. The degree of the inhibitory influence of OF 743 is comparable with the same atropine influence and considerably exceeds the degree of the inhibitory influence of pirenzepine.

[The antiulcer action of antidepressants. II. The effect of the antidepressants inkazan, azafen, and OF-743 in combination with arginine on ethanol-evoked damage to the gastric mucosa in rats]. / Protivoiazvennoe deistvie nekotorykh antidepressantov. II, Vliianie antidepressantov inkazana, azafena i OF-743 v kombinatsii s argininom na vyzvannye étanolom povrezhdeniia slizistoi obolozhki zheludka krys.

Mucosal gastric damages in rats induced by intragastric ethanol introduction decreased considerably on the background of action of one of the antidepressants (asaphen, inkasan and OF-743) in combination with arginine. The combination OF-743 with arginine has the largest protective action, the least one--asaphen with arginine. A comparison of protective action of some antidepressants with action of antidepressants in combination with arginine revealed a tendency to more expressed antiulcerogenic effect in studied combinations.