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Increase of extracellular brain calcium involved in interleukin-1 beta-induced pyresis in the rabbit: antagonism by dexamethasone.
No full text1This study investigates the role of extracellular brain calcium in the hyperthermia induced by interleukin-1 beta (IL-1 beta).
2 Intracerebroventricular (i.c.v.) injection of IL-1 beta (12.5 ng kg(-1)) in rabbits caused a prompt and sustained rise in cerebrospinal fluid (CSF) Ca2+ concentration ([Ca2+]) followed by enhanced prostaglandin E(2) (PGE(2)) release and hyperthermia.
3 A linear and significant correlation was observed between the increase in [Ca2+] induced by IL-1 beta and the rise in body temperature.
4 Ventriculo-cisternal perfusion with artificial CSF containing the calcium chelator EGTA (1.3 mM) blocked the IL-1-induced PGE(2) release and countered the febrile response.
5 I.c.v. administration of dexamethasone (Dex) (2.4 and 24 mu g kg(-1)) 100 min prior to IL-1 beta, dose-dependently antagonized the cytokine-induced Ca2+ increase, the PGE(2) release and the febrile response.
6 These results suggest that changes in extracellular brain calcium are involved in the regulation of body temperature. In this light, the antipyretic action of Dex may be related to its effect on Ca2+ uptake
GABA-mediated effects of some taurine derivatives injected i.c.v. on rabbit rectal temperature and gross motor behaviour
No full textSome synthetic taurine analogues, namely ethanolamine-O-sulphate (EOS), N,N-dimethyltaurine (DMT), N,N,N-trimethyltaurine (TMT) and 2-aminoethylphosphonic acid (AEP) were shown to interact with rabbit brain GABA(A)- or GABA(B)-receptors, while (+/-)piperidine-3-sulfonic acid (PSA) inhibited the activity of rabbit brain 4-aminobutyrate transaminase. This suggests that they behave like direct/indirect GABA agonists or GABA antagonists and affect thermoregulation and gross motor behaviour (GMB) which are under GABA control. In the present study micromole (1.2-48) amounts of these compounds were i.c.v. injected in conscious, restrained rabbits while monitoring rectal temperature (RT), ear skin temperature (EST) and GMB. AEP, EOS, DMT and TMT induced a dose-related hyperthermia, ear vasoconstriction and excitation of GMB, while PSA induced a dose-related hypothermia, ear vasodilation and inhibition of GMB. EOS antagonized in a dose-related fashion hypothermia induced by 60 nmol THIP, a GABA(A) agonist, while AEP, DMT and TMT counteracted that induced by 8 nmol R(-)Baclofen, a GABA(B) agonist. In conclusion, EOS and AEP, DMT, TMT seem to act as GABA(A) and GABA(B) antagonists, respectively, while PSA behaves like an indirect GABA agonist, all affecting the central mechanisms which drive rabbit thermoregulation
Role of intracellular Ca2+ and calmodulin/MAP kinase kinase/extracellular signal-regulated protein kinase signalling pathway in the mitogenic and antimitogenic effect of nitric oxide in glia- and neurone-derived cell lines.
No full textTo elucidate the mechanism of cell growth regulation by nitric oxide (NO) and the role played in it by Ca2+, we studied the relationship among intracellular Ca2+ concentration ([Ca2+]i), mitogen-activated protein kinases [extracellular signal-regulated protein kinase (ERK)] and proliferation in cell lines exposed to different levels of NO. Data showed that NO released by low [(z)-1-[2-aminiethyl]-N-[2-ammonioethyl]amino]diazen-1-ium-1,2diolate (DETA/NO) concentrations (10 μM) determined a gradual, moderate elevation in [Ca2+]i (46.8 ± 7.2% over controls) which paralleled activation of ERK and potentiation of cell division. Functionally blocking Ca2+ or inhibiting calmodulin or MAP kinase kinase activities prevented ERK activation and antagonized the mitogenic effect of NO. Experimental conditions favouring Ca2+ entry into cells led to increased [Ca2+]i (189.5 ± 4.8%), ERK activation and cell division. NO potentiated the Ca2+ elevation (358 ± 16.8%) and ERK activation leading to expression of p21Cip1 and inhibition of cell proliferation. Furthermore, functionally blocking Ca2+ down-regulated ERK activation and reversed the antiproliferative effect of NO. Both the mitogenic and antimitogenic responses induced by NO were mimicked by a cGMP analogue whereas they were completely antagonized by selective cGMP inhibitors. These results demonstrate for the first time that regulation of cell proliferation by low NO levels is cGMP dependent and occurs via the Ca2+/calmodulin/MAP kinase kinase/ERK pathway. In this effect the amplitude of Ca2+ signalling determines the specificity of the proliferative response to NO possibly by modulating the strength of ERK activation. In contrast to the low level, the high levels (50–300 μM) of DETA/NO negatively regulated cell proliferation via a Ca2+-independent mechanism
Nitric oxide modulation of interleukin-1[beta]-evoked intracellular Ca2+ release in human astrocytoma U-373 MG cells and brain striatal slices.
No full textIntracellular Ca2+ mobilization and release into mammal CSF plays a fundamental role in the etiogenesis of fever induced by the proinflammatory cytokine interleukin-1β (IL-1β) and other pyrogens. The source and mechanism of IL-1β-induced intracellular Ca2+ mobilization was investigated using two experimental models. IL-1β (10 ng/ml) treatment of rat striatal slices preloaded with 45Ca2+ elicited a delayed (30 min) and sustained increase (125-150%) in spontaneous 45Ca2+ release that was potentiated by L-arginine (300 μM) and counteracted by N-ω-nitro-L-arginine methyl ester (L-NAME) (1 and 3 mM). The nitric oxide (NO) donors diethylamine/NO complex (sodium salt) (0.3 and 1 mM) and spermine/NO (0.1 and 0.3 mM) mimicked the effect of IL-1β on Ca2+ release. IL-1β stimulated tissue cGMP concentration, and dibutyryl cGMP enhanced Ca2+ release. The guanyl cyclase inhibitors 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (100 μM) and 6-[phenylamino]-5,8 quinolinedione (50 μM) counteracted Ca2+ release induced by 2.5 but not 10 ng/ml IL-1β. Ruthenium red (50 μM) and, to a lesser extent, heparin (3 mg/ml) antagonized IL-1β-induced Ca2+ release, and both compounds administered together completely abolished this response. Similar results were obtained in human astrocytoma cells in which IL-1β elicited a delayed (30 min) increase in intracellular Ca2+ concentration ([Ca2+]i) (402 ± 71.2% of baseline), which was abolished by 1 mM L-NAME. These data indicate that the NO/cGMP-signaling pathway is part of the intracellular mechanism transducing IL-1β-evoked Ca2+ mobilization in glial and striatal cells and that the ryanodine and the inositol-(1,4,5)-trisphosphate-sensitive Ca2+ stores are involved
The effect of kainic acid and AMPA on the release of taurine and GABA from the rat substantia nigra in vivo.
No full textInteractions of taurine and structurally related analogues with GABAergic system and taurine binding sites of rabbit brain
No full textThe aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems.
Washed synaptic membranes (SM) from whole rabbit brain were able to bind [3H]muscimol. Saturation experiments of the binding of [3H]GABA to GABAB receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [3H]taurine in a saturable manner (Kd=249.0±6.3 nM and Bmax=3.4±1.0 pmol mg−1 prot).
Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (±)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [3H]taurine binding (Ki=0.13, 0.13, 13.5 and 4.0 μM, respectively). These analogues did not interact with GABAA and GABAB receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity.
3-Aminopropanesulfonic acid (OMO), β-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (±)piperidine-3-sulfonic acid (PSA) inhibited [3H]muscimol binding to GABAA receptors with different affinities (Ki=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 μM, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [3H]GABA to GABAB receptors with Ki's in the μM range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC50=3.72 μM) and PSA GABA transaminase activity (IC50=103.0 μM).
In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents
N-Dealkylation of chlorimipramine and chlorpromazine by rat liver microsomal cytochrome P450 isoenzymes
No full textThe role of different cytochrome P450 isozymes (CYP) in the N-demethylation of chlorimipramine and chlorpromazine has been investigated in liver microsomes from rats by studying the effects of multiple subchronic doses of chlorimipramine, chlorpromazine, phenobarbital and beta-naphthoflavone on the N-demethylation of ethylmorphine, mono-N-demethyl-chlorimipramine and chlorpromazine and on the hydroxylation of aniline. With control microsomes, CYP-dependent metabolism of chlorimipramine and chlorpromazine (100 nmol; 30 min incubation) resulted in the formation of predominantly chlorimipramine (46.5 +/- 4.9 nmol) whereas chlorpromazine (14.1 +/- 0.9 nmol) accounted for only part of the overall metabolism of chlorpromazine. Multiple doses of chlorimipramine increased the capacity of microsomes to N-demethylate ethylmorphine (9.8 +/- 0.73 and 6.08 +/- 0.06 nmol min(-1) (mg protein)(-1) for chlorimipramine-treated and control rats, respectively) as well as itself (4.65 +/- 0.25 and 3.10 +/- 0.33 nmol min(-1) (mg protein)(-1), respectively). Multiple doses of chlorpromazine induced aniline-hydroxylase activity (1.11 +/- 0.16 and 0.94 +/- 0.06 nmol min(-1) (mg protein)(-1) for chlorimipramine and control microsomes, respectively) but the capacity to N-demethylate itself was unchanged. Phenobarbital treatment induced ethylmorphine N-demethylation activity, but did not affect N-demethylation activity, towards chlorimipramine and chlorpromazine. In control microsomes the N-demethylation capacity of chlorimipramine or chlorpromazine (0.160 +/- 0.025 and 0.015 +/- 0.003 nmol min(-1) (mg protein)(-1), respectively) was one order of magnitude lower than that of chlorimipramine or chlorpromazine. The capacity to N-demethylate either chlorimipramine or chlorpromazine was increased by treatment with either phenobarbital or beta-naphthoflavone. In control microsomes, sulphaphenazole markedly inhibited both chlorimipramine-N-mono- and di-N-demethylation, whereas quinidine markedly inhibited the rate of formation of chlorpromazine. The CYP2C and CYP2D subfamilies seem to be involved in the mono N-demethylation of chlorimipramine and chlorpromazine, respectively. Moreover the CYP1A and CYP2B subfamilies might participate in the N-demethylation of either chlorimipramine or chlorpromazine. This could have important implications in the clinical use of chlorimipramine and chlorpromazine in view of the genetic polymorphism of CYP2C and CYP2D isozymes in man
The effect of pulsed electromagnetic fields on the physiologic behaviour of a human astrocytoma cell line.
No full textAbstractWe evaluated the effects of 50 Hz pulsed electromagnetic fields (EMFs) with a peak magnetic field of 3 mT on human astrocytoma cells. Our results clearly demonstrate that, after the cells were exposed to EMFs for 24 h, the basal [Ca2+]i levels increased significantly from 124±51 nM to 200±79 nM. Pretreatment of the cells with 1.2 μM substance P increased the [Ca2+]i to 555±278 nM, while EMF exposure caused a significant drop in [Ca2+]i to 327±146 nM. The overall effect of EMFs probably depends on the prevailing Ca2+ conditions of the cells. After exposure, the proliferative responses of both normal and substance P-pretreated cells increased slightly from 1.03 to 1.07 and 1.04 to 1.06, respectively. U-373 MG cells spontaneously released about 10 pg/ml of interleukin-6 which was significantly increased after the addition of substance P. Moreover, immediately after EMF exposure and 24 h thereafter, the interleukin-6 levels were more elevated (about 40%) than in controls. On the whole, our data suggest that, by changing the properties of cell membranes, EMFs can influence Ca2+ transport processes and hence Ca2+ homeostasis. The increased levels of interleukin-6 after 24 h of EMF exposure may confirm the complex connection between Ca2+ levels, substance P and the cytokine network
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