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PubMed2005

Partial mitochondrial inhibition causes striatal dopamine release suppression and medium spiny neuron depolarization via H2O2 elevation, not ATP depletion.

Mitochondrial dysfunction is a potential causal factor in Parkinson's disease. We show here that acute exposure to the mitochondrial complex I inhibitor rotenone (30-100 nM; 30 min) causes concentration-dependent suppression of single-pulse evoked dopamine (DA) release monitored in real time with carbon-fiber microelectrodes in guinea pig striatal slices, with no effect on DA content. Suppression of DA release was prevented by the sulfonylurea glibenclamide, implicating ATP-sensitive K+ (KATP) channels; however, tissue ATP was unaltered. Because KATP channels can be activated by hydrogen peroxide (H2O2), as well as by low ATP, we examined the involvement of rotenone-enhanced H2O2 generation. Confirming an essential role for H2O2, the inhibition of DA release by rotenone was prevented by catalase, a peroxide-scavenging enzyme. Striatal H2O2 generation during rotenone exposure was examined in individual medium spiny neurons using fluorescence imaging with dichlorofluorescein (DCF). An increase in intracellular H2O2 levels followed a similar time course to that of DA release suppression and was accompanied by cell membrane depolarization, decreased input resistance, and increased excitability. Extracellular catalase markedly attenuated the increase in DCF fluorescence and prevented rotenone-induced effects on membrane properties; membrane changes were also largely prevented by flufenamic acid, a blocker of transient receptor potential (TRP) channels. Thus, partial mitochondrial inhibition can cause functional DA denervation via H2O2 and KATP channels, without DA or ATP depletion. Furthermore, amplified H2O2 levels and TRP channel activation in striatal spiny neurons indicate potential sources of damage in these cells. Overall, these novel factors could contribute to parkinsonian motor deficits and neuronal degeneration caused by mitochondrial dysfunction.

Adenosine Triphosphate↗
PubMed2006

P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling.

Modulation of synaptic transmission and brain microcirculation are new roles ascribed to astrocytes in CNS function. A mechanism by which astrocytes modify neuronal activity in the healthy brain depends on fluctuations of cytosolic Ca2+ levels, which regulate the release of "gliotransmitters" via an exocytic pathway. Under pathological conditions, however, the participation of other pathways, including connexin hemichannels and the pore-forming P2X7R, have been proposed but remain controversial. Through the use of genetically modified 1321N1 human astrocytoma cells and of spinal cord astrocytes derived from neonatal Cx43- and P2X7R-null mice, we provide strong evidence that P2X7Rs, but not Cx43 hemichannels, are sites of ATP release that promote the amplification of Ca2+ signal transmission within the astrocytic network after exposure to low divalent cation solution. Moreover, our results showing that gap junction channel blockers (heptanol, octanol, carbenoxolone, flufenamic acid, and mefloquine) are antagonists of the P2X7R indicate the inadequacy of using these compounds as evidence for the participation of connexin hemichannels as sites of gliotransmitter release.

Adenosine Triphosphate↗
PubMed2002

Androgen receptors in prostate cancer.

The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.

Androgen Antagonists↗
PubMed1983

Prostanoid synthesis by cultured gastric and duodenal mucosa: Possible role in the pathogenesis of duodenal ulcer.

Cultured duodenal mucosa obtained from normal subjects synthesized and secreted significantly less prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) than cultured gastric mucosa obtained from the same subjects. Accumulation of PGE2, 6-keto-PGF1 alpha, and TXB2--the stable metabolites of prostacyclin I2 and thromboxane A2, respectively--by cultured gastric mucosa obtained from 21 untreated patients with active duodenal ulcer was significantly lower than their respective accumulation by cultured gastric mucosa obtained from 14 normal subjects. Accumulation of all three prostanoids by cultured duodenal mucosa obtained from patients with active duodenal ulcer and from normal subjects was not significantly different. PGE2, 6-keto-PGF1 alpha, and TXB2 accumulation was five to six times higher than their respective content in fresh tissue before culture and was inhibited by flufenamic acid. These results suggest that a decrease in endogenous gastric prostanoid synthesis may have a role in the pathogenesis of peptic ulcer disease.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Do band 3 protein conformational changes mediate shape changes of human erythrocytes?

The bilayer-couple model predicts a reversible membrane crenation for an increasing ratio of external to internal monolayer area. This was comprehensively proven. However, individual erythrocytes may undergo dramatic shape changes within seconds when the suspension medium is changed. In contrast, under physiological conditions with no addition of membrane active compounds, active phospholipid translocation and passive flip-flops are comparatively slow. We propose that conformational changes of the anion-exchange protein, band 3, may rapidly alter the monolayer area ratio. Band 3 occupies about 10% of the total membrane area of human erythrocytes. Under physiological conditions, its conformers are asymmetrically distributed with about 90% of the transport sites facing the cytoplasm. This distribution is altered when external conformations are recruited by changing the transmembranous Cl- gradient, the external pH, or by the application of inhibitors. In experiments, recruitment by low ionic strength caused a rapid, temporary formation of echinocytes. This suspension effect could also be found at high ionic concentrations, when Cl- was replaced by SO4(2-). Inhibitors known to recruit the external band 3 conformation, like DIDS, SITS and flufenamic acid, are echinocytogenic. For inhibitors not recruiting a certain conformation, e.g. phenylglyoxal and niflumic acid, no shape effect was found. Since band 3 ensures a fast equilibrium of internal and external anions these ions are usually distributed according to the transmembrane potential (TMP). In the literature, a correlation of TMP and band 3 conformation, as well as a correlation of TMP and red cell shape, is described. In the proposed model, low external Cl- concentrations, inhibitors, or a negative TMP may recruit the transport sit outwards.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1995

Linear and non linear competition plots in the deoxyribose assay for determination of rate constants for reaction of nonsteroidal antiinflammatory drugs with hydroxyl radicals.

Performing the deoxyribose (DR) assay for determination of the rate constants for reaction of non steroidal antiinflammatory drugs with hydroxyl radicals led to some unusual competition plots. The molecules from the arylpropionic family of drugs: ibuprofen, flurbiprofen, ketoprofen and naproxen produced the linear relationship. However, acemetacin, diclofenac Na, flufenamic acid, indometacin, indometacin, niflumic acid, tolmetin Na and sulindac presented non linear competition plots manifesting at relatively low drug concentrations. This effect was corrected by increasing DR concentrations from 2.8 mM to 15 mM. The modification did not affect rate constants values for those derivatives which already presented a linear plot at 2.8 mM, but allowed to calculate rate constants for other compounds. It is suggested that the experimental conditions have to be adapted particularly for those derivatives with a relatively high rate constant for reaction with the radical species. The oxicam derivatives (tenoxicam and piroxicam) presented another kind of deviation that revealed a prooxidant effect in this system: non linear plots were also observed at relatively low drug concentrations, but in the opposite direction than for the other molecules. This last effect was independent of DR concentration but could be corrected by increasing ascorbate concentration in the system.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Direct activation of rat spinal dorsal horn neurons by prostaglandin E2.

Whole-cell patch-clamp and intracellular recording techniques have been used to study the action of prostaglandin E2 (PGE2) on neurons in adult rat transverse spinal cord slices. Bath-applied PGE2 (1-20 microm) induced an inward current or membrane depolarization in the majority of deep dorsal horn neurons (laminas III-VI; 83 of 139 cells), but only in a minority of lamina II neurons (6 of 53 cells). PGE2 alone never elicited spontaneous action potentials; however, it did convert subthreshold EPSPs to suprathreshold, leading to action potential generation. PGE2-induced inward currents were unaffected by perfusion with either a Ca(2+)-free/high Mg(2+) (5 mm) solution or tetrodotoxin (1 microm), indicating a direct postsynaptic action. Both 17-phenyl trinor prostaglandin E2 (an EP1 agonist) and sulprostone (an EP3 agonist) had little effect on membrane current, whereas butaprost methyl ester (an EP2 agonist) mimicked the effect of PGE2. Depolarizing responses to PGE2 were associated with a decrease in input resistance, and the amplitude of inward current was decreased as the holding potential was depolarized. PGE2-induced inward currents were reduced by substitution of extracellular Na(+) with N-methyl-d-glucamine and inhibited by flufenamic acid (50-200 microm), which is compatible with activation of a nonselective cation channel. These results suggest that PGE2, acting via an EP2-like receptor, directly depolarizes spinal neurons. Moreover, these findings imply an involvement of spinal cord-generated prostanoids in modulating sensory processing through an alteration in dorsal horn neuronal excitability.

Action Potentials↗
PubMed2003

The history of tocolysis.

In 1950, the World Health Organisation (WHO) defined prematurity as a birthweight of 2500 g or less and in 1961 as a gestational age of less than 37 weeks. The time in between marks an era in which there was growing recognition of the importance of gestational age at birth and how to influence it. The latter was facilitated too by the development of tocography, which permitted some semi-objective measurement of uterine contractility. Along with it, came a growing interest in agents that could control uterine contractility beyond the earlier classical approaches of hormones and gastrointestinal spasmolytics. Hence, the early 1960s saw much research interest in agents, such as nylidrine, isoxsuprine, and orciprenaline that could suppress uterine contractility as one of their many beta-agonist properties. Subsequently, two approaches would be used to shift the balance towards uterine function over and above the influence on other bodily functions. One consisted of supplementing these drugs with agents, such as calcium antagonists and beta-receptor blockers that were hoped to suppress non-uterine actions. The other was a search for drugs in the same class with greater uterospecificity and more selective binding to uterine as opposed to other receptors. Neither of these approaches has ever fully fulfilled the hopes that were pinned on them, but they resulted in the availability of a large number of agents to suppress uterine contractility. The advent of prostaglandins as regulators of uterine contractility and the ability to suppress their biosynthesis saw another range of attempts to suppress uterine activity. They included aspirin, sodium salicylate, flufenamic acid, sulindac and indomethacin, but some were clearly based on a defective understanding of how uterine prostaglandin synthesis can be influenced. In the meantime, a flurry of other agents came and went, often more than once, testifying to the ingenuity of clinicians in trying to solve a problem that is poorly understood. Some, such as relaxin and ethanol, came and disappeared. Others, such as calcium antagonists, entered the scene as protectors against the non-uterine effects of other agents, went, and re-entered the scene in their own right. Still others, such as magnesium sulphate, came, lingered around, and became credited with effects in preterm labour that do not depend on affecting uterine contractility. Amidst this all arose the term tocolysis, coined in 1964 by Mosler from the Greek stems 'tauomicronkappaomicronzeta' and 'lambdaupsilonepsiloniotanu', to epitomise all of this ingenuity.

Female↗
PubMed1976

Effect of some antirheumatics on connective tissue components.

The effects of a number of classical and modern antirheumatics on the biosynthesis of glycosaminoglycans and collagen were studied comparatively. The experimental results indicate that the antirheumatics deeply affect the metabolism of the main components of connective tissue. With regard to the methods used for testing, it may be stated that phenylbutazone, flufenamic acid, ibuprofen, mefenamic acid and trimetazone belong to the most effective of the entire series of antirheumatics tested.

Animals↗
PubMed1992

Chloride transport blockers prevent N-methyl-D-aspartate receptor-channel complex activation.

In cultured spinal cord neurons, we found that blockers of chloride transport (furosemide, a widely used loop diuretic, and the related compounds piretanide and bumetanide, as well as niflumic and flufenamic acids, used as antiinflamatory agents) prevented N-methyl-D-aspartate (NMDA) receptor activation in a dose-dependent manner and are specific for this class of glutamate receptor. Antagonism of NMDA-mediated currents by chloride transport blockers was voltage independent and showed fast on-ff kinetics. The action was noncompetitive with NMDA and did not arise from interaction with the Zn2+ inhibitory site, because blockade of NMDA-induced responses by furosemide and Zn2+ was additive. The inhibition was greater in a low concentration of glycine, but it could not be overcome by increasing the glycine concentration (up to 100 microM). In contrast, the inhibition was attenuated by the polyamine spermine. Because the presence of spermine was not required for inhibition to develop, we conclude that chloride transport blockers are noncompetitive antagonists of the NMDA receptor, likely acting as inverse agonists of the polyamine site. This action may explain the protective effect that has been shown for some of these drugs in neuronal degeneration; because they also prevent neuronal swelling, they may be good starting compounds for synthesis of appropriate therapeutic agents to ameliorate excitotoxicity.

Animals↗
PubMed2003

[Characterization of pacemaking currents in cultured interstitial cells of Cajal from mice small intestine].

BACKGROUND/AIMS: Gastrointestinal motility is initiated by the periodic generation of slow waves. Interstitial cells of Cajal (ICC) are pacemaker cells that generate slow waves and drive spontaneous mechanical contractions of the gastrointestinal smooth muscle. Slow waves generate the periodic activation of spontaneous inward currents (pacemaker currents). The aim of this study was to investigate the characterization of pacemaker currents of ICC. METHODS: The ICC in mice small intestine were cultured with stem cell factor for 2 days, and then we recorded pacemaker currents and slow waves using a whole-cell patch clamp technique. RESULTS: Under voltage clamp at -80 mV of holding potential, ICC generated pacemaker currents. Tetrodotoxin and nifedipine did not affect on the pacemaker currents. In addition, tetraethylammonium, 4-aminopyridine and glibenclamide did not affect on the pacemaker currents. The reduction of external Na+ concentrations inhibited pacemaker currents. Moreover, these currents were completely abolished in the external Ca2+-free condition. Gadolinium and flufenamic acid, inhibitors of non-selective cationic currents, inhibited pacemaker currents. Thapsigargin and cyclopiazoic acid, inhibitors of Ca2+-ATPase in endoplasmic reticulum, abolished pacemaker currents. Carbachol depolarized membrane potential and increased inward currents. CONCLUSIONS: These results suggest that pacemaker currents are mediated by the activation of non-selective cation channel and become a target of neurotransmitters in regulation of intestinal motility.

Animals↗
PubMed1992

Extrinsic plasminogen activator response to exercise after a single dose of propranolol.

The level of plasminogen activators was measured in 12 volunteers at rest and after maximum exercise. Two formulations of a beta-blocker "propranolol," or placebo, were given (oral dose, 10 mg) 2 h before exercise commenced. At weekly intervals over 21 d, randomized double-blind, cross-over trials were conducted. Two hours after drug/placebo administration, subjects exercised to maximal capacity using an incremental exercise protocol on a bicycle ergometer. Before and 2 h after drug/placebo administration and immediately after maximum exercise, heart rate, blood pressure, and oxygen consumption were measured, venous blood was removed, and plasma separated for the measurement of plasminogen activators using the fibrin plate method. Duplicate portions of plasma were taken: portion 1 for determination of total plasminogen activators activity, by the addition of dextran sulphate and flufenamic acid; portion 2 to assay extrinsic plasminogen activator, intrinsic plasminogen activator being blocked by the addition of C1-inactivator. Resting and postmaximum exercise heart rates showed significant decreases (P less than 0.05), with a nonsignificant difference in the resting level of extrinsic and intrinsic activators when the subjects were premedicated with either of the two formulations. Total and extrinsic activities, but not intrinsic activity, were significantly increased (P less than 0.05) to maximum exercise when subjects were given placebo. However, premedication with the drug formulations 1 and 2 significantly decreased (P less than 0.05) the normal total and extrinsic activities response to maximum exercise, with no effect on the intrinsic activity. It is suggested that the resting level of activators activity may not be affected by premedication with propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2006

Calcium antagonist isradipine-induced calcium influx through nonselective cation channels in human gingival fibroblasts.

Isradipine raises the cytosolic Ca2+ concentration ([Ca2+]i) in human gingival fibroblasts by enhancing Ca2+ influx through the plasma membrane. To research the pathways through which Ca2+ enters the cells, we examined the interactive effects of isradipine and blockers or enhancers of nonselective cation channels (NSCCs) and Na+/Ca2+ exchangers (NCXs). Normal human gingival fibroblast Gin-1 cells were used. The [Ca2+]i was measured with the Ca2+-sensitive fluorescent dye fura-2/AM. Changes in the fluorescence intensity of fura-2 in the cells were recorded with a video-imaging analysis system. Ca2+ antagonists (nifedipine, verapamil, and diltiazem in the concentration range of 1 to 20 microM) other than isradipine also raised the [Ca2+]i. All of the NSCC inhibitors (SK&F 96365, GdCl3, HgCl2 and flufenamic acid), but none of the NCX inhibitors (KB-R 7943 and benzamil), significantly decreased the [Ca2+]i raised by isradipine (3 microM). Neither the Na+ ionophore monensin nor Na+/K+ ATPase inhibitor ouabain had any significant effect on the isradipine-induced [Ca2+]i rise. Taken together, our data indicate that Ca2+ entry through the NSCCs is involved in the isradipine-induced [Ca2+]i rise. The results obtained here play an important role in the development of drugs for etiologic therapy of gingival overgrowth.

Calcium Channel Blockers↗
PubMed1989

Overexpression of a 123-kDa anion transport inhibitor binding protein and two cytoskeleton proteins in Drosophila Kc cell variants resistant to disulfonic stilbenes.

Drugs of the disulfonic stilbene class, which inhibit anion transport in the cell membrane in many cell types, have been found to inhibit anion transport and cell growth in Drosophila Kc cells. Cell variants selected by a stepwise selection protocol for the ability to grow in the presence of the disulfonic stilbenes are severalfold resistant to growth inhibition by the drugs. Both the resistant populations and a cloned cell line show dramatic overexpression of three polypeptides. The most highly overproduced protein is a 123-kDa plasma membrane protein which binds the reversible anion transport inhibitor, flufenamic acid, in a protection biotinylation experiment. The 123-kDa putative anion transport protein copurifies with, and immunologically cross-reacts with, two detergent-insoluble cytoskeleton proteins of 46- and 62-kDa molecular weight, which are each overexpressed more than 8-fold in the variants. Resistance to growth inhibition by the disulfonic stilbenes and amplified expression of the 123-, 62-, and 46-kDa proteins are simultaneously lost over a period of 30 weeks in the absence of selective conditions, suggesting that the function of the overproduced polypeptides is related to growth control in Drosophila cells.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1979

Effects of anti-inflammatory drugs on platelet aggregation in rabbits.

Effects of non-steroidal anti-inflammatory drugs (aspirin, indimethacin, flufenamic acid, tiaramide and HG-70) on rabbit platelet aggregation were studied using Evans aggoregometer and a modified form of Chandler's loop method. Tiaramide in 10(-4) and 10(-5)M inhibited effectively the aggregation caused by ADP in the optical density method and accelerated the restoration of the time course of disaggregation in the loop method. The other 4 drugs were ineffective. In collagen-induced aggregation all 5 drugs inhibited the aggregation. Among them tiaramide was most potent. Only tiaramide prolonged the time taken to induce snow storm and aggregates in the loop method.

Adenosine Diphosphate↗
PubMed1983

The modulation of decidual cells proliferation and differentiation by progesterone and prostaglandins.

The ability of prostaglandins and progesterone to modulate the rate of DNA synthesis and the differentiation of endometrial cells into polyploid decidual cells was studied in vivo and in vitro. Intraperitoneal administration of indomethacin (5 mg/kg), an inhibitor of PG synthesis, on the 3rd or 4th day of leukocytic vaginal smear (day L3 or L4, respectively), but not on the 5th day (L5), suppressed the induction of deciduomata in vivo. The injection of indomethacin to pseudopregnant rats on day L3 had no effect on the rate of DNA synthesis by endometrial cells which were explanted from the uterus on day L4. Indomethacin and other inhibitors of PG synthesis, such as flufenamic acid, cortisol, and progesterone had a stimulatory effect on the rate of DNA synthesis when added to cultures of cells explanted from deciduoma on day L5. PGE2 (5-10 micrograms/ml) inhibited DNA synthesis in control, indomethacin-treated and progesterone-treated L5 cell cultures. Inclusion of indomethacin in the culture medium during enzymatic dissociation of endometrial cells and during the subsequent culture of the cells for four days, did not prevent the appearance of polyploid and multinucleated decidual cells. In vivo administration of indomethacin (5 mg/kg, i.p.) on day L3 or on day L4 (3 h before collecting the endometrial cells), reduced the incidence of polyploidy in the 4-day cultures. This effect of indomethacin could be prevented in endometrial cells (harvested 3 h but not 24 h after treatment with the drug) by the addition of progesterone. These results suggest that: (1) the cooperation between prostaglandins and progesterone at the late sensitization period of the uterus may lead to a programmed expression of polyploidization during the 4-day culture; and (2) the rate of DNA synthesis in the deciduoma at the proliferation phase may be influenced by steroid-induced changes in PGE content of the tissue.

Animals↗
PubMed1982

Prostanoid synthesis by cultured peripheral blood mononuclear cells in inflammatory diseases of the bowel.

Prostanoid synthesis by cultured peripheral blood mononuclear cells and monocytes in inflammatory bowel disease patients was determined because monocytosis was reported in inflammatory bowel diseases and prostanoids are synthesized by peripheral blood mononuclear cells in response to inflammatory stimuli. Prostaglandin E2 and thromboxane B2 accumulation in the medium of cultured peripheral blood mononuclear cells isolated from patients with active Crohn's disease was two and three times higher than their respective accumulation by peripheral blood mononuclear cells isolated from normal subjects or patients in remission. In ulcerative colitis, prostaglandin E2 and thromboxane B2 accumulation was not enhanced. 6-Keto-prostaglandin F1 alpha was not detected in any of the cultured medium. The absolute number of monocytes was determined according to their adherence to plastic surfaces, and the percent of phagocytic cells was significantly higher among peripheral blood mononuclear cells in patients with Crohn's disease and ulcerative colitis as compared with peripheral blood mononuclear cells isolated from normal subjects. However, prostaglandin E2 secretion, by the same number of cultured monocytes isolated from all groups of patients, was similar. Flufenamic acid, methylprednisolone, and 5-aminosalicylic acid significantly inhibited prostaglandin E2 and thromboxane B2 accumulation. These results suggest that in Crohn's disease enhanced prostanoid synthesis is probably due to the monocytosis, whereas in ulcerative colitis the monocytosis is not accompanied by a significant increase in prostanoid synthesis in vitro.

6-Ketoprostaglandin F1 alpha↗