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Brian R Walker - One of the best experts on this subject based on the ideXlab platform.

  • is 11β hydroxysteroid dehydrogenase type 1 a therapeutic target effects of Carbenoxolone in lean and obese zucker rats
    Journal of Pharmacology and Experimental Therapeutics, 2003
    Co-Authors: Dawn E W Livingstone, Brian R Walker
    Abstract:

    In liver and adipose tissue, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates glucocorticoids from inactive 11-keto metabolites. Pharmacological inhibition or transgenic disruption of 11β-HSD1 attenuates glucocorticoid action and increases insulin sensitivity. Increased adipose 11β-HSD1 may also contribute to the metabolic complications of obesity. Here, we examine the effects of inhibition of 11β-HSDs with Carbenoxolone in obese insulin-resistant Zucker rats, a strain in which tissue-specific dysregulation of 11β-HSD1 (increased in adipose, decreased in liver) mirrors changes in human obesity. Six-week-old male rats were treated orally with Carbenoxolone (50 mg/kg/day) or water (1 ml/kg/day) for 3 weeks. Carbenoxolone inhibited 11β-HSD1 activity in liver (25 ± 3 versus 52 ± 2% conversion in lean; 18 ± 3 versus 35 ± 3% in obese; p < 0.01) but not in adipose tissue or skeletal muscle. Carbenoxolone had no effect on weight gain or food intake, did not affect plasma glucose during an oral glucose tolerance test, and increased the plasma insulin response to glucose. However, high-density lipoprotein cholesterol was increased by Carbenoxolone in obese animals (1.52 ± 0.24 versus 1.21 ± 0.26 mM; p < 0.03). Carbenoxolone did not inhibit hepatic inactivation of glucocorticoid by 5β-reductase and had no significant effect on plasma corticosterone levels. In conclusion, Carbenoxolone provides a model for liver-specific inhibition of 11β-HSD1, which results in improved lipid profile, in Zucker obese rats. Failure to inhibit 11β-HSD1 in adipose tissue and/or skeletal muscle may explain the lack of effect on glucose tolerance and obesity. Inhibition of adipose 11β-HSD1 is probably necessary to gain the maximum benefit of an 11β-HSD1 inhibitor.

  • Carbenoxolone increases hepatic insulin sensitivity in man a novel role for 11 oxosteroid reductase in enhancing glucocorticoid receptor activation
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Brian R Walker, A A Connacher, R M Lindsay, David J Webb, Christopher R W Edwards
    Abstract:

    In the kidney, conversion of cortisol to cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase protects mineralocorticoid receptors from cortisol. In the liver, a different isoform of the enzyme favors 11 beta-reductase conversion of cortisone to cortisol. We have tested the hypothesis that hepatic 11 beta-reductase enhances glucocorticoid receptor activation in the liver by inhibiting the enzyme with Carbenoxolone and observing effects on insulin sensitivity. Seven healthy males took part in a double blind randomized cross-over study in which oral Carbenoxolone (100 mg every 8 h) or placebo was administered for 7 days. Euglycemic hyperinsulinemic clamp studies were then performed, including measurement of forearm glucose uptake. Carbenoxolone increased whole body insulin sensitivity (M values for dextrose infusion rates, 41.1 +/- 2.4 mumol/kg.min for placebo vs. 44.6 +/- 2.3 for Carbenoxolone; P < 0.03), but had no effect on forearm insulin sensitivity. We infer that Carbenoxolone, by inhibiting h...

  • direct and indirect effects of Carbenoxolone on responses to glucocorticoids and noradrenaline in rat aorta
    Journal of Hypertension, 1994
    Co-Authors: Brian R Walker, Kathleen S Sang, Brent C Williams, Christopher R W Edwards
    Abstract:

    Background: In the kidney Carbenoxolone impairs inactivation of glucocorticoids and facilitates their access to mineralocorticoid receptors by inhibiting 11β-hydroxysteroid dehydrogenase (11β-OHSD). 11β-OHSD is also expressed in vascular smooth muscle, and, in humans, Carbenoxolone potentiates vasoconstrictor sensitivity to cortisol and noradrenal ine. Objective: To establish in vitro whether the vascular effects of Carbenoxolone are mediated by inhibition of 11β-OHSD. Methods: Noradrenaline-induced vasoconstriction was measured in helical de-endothelialized rat aortic strips following 2-5 h exposure to one or more of: Carbenoxolone, corticosterone, a mineralocorticoid-receptor antagonist (spironolactone) and a glucocorticoid- and progesterone-receptor antagonist (RU 38486)

Andres Navarrete - One of the best experts on this subject based on the ideXlab platform.

  • Carbenoxolone gastroprotective mechanism participation of nitric oxide c gmp k atp pathway in ethanol induced gastric injury in the rat
    Fundamental & Clinical Pharmacology, 2011
    Co-Authors: Aracely Evangelina Chavezpina, Gabriela Rubi Tapiaalvarez, Adelfo Reyesraminrez, Andres Navarrete
    Abstract:

    Carbenoxolone, a semi-synthetic triterpenoid, exhibits gastroprotective activity related to the participation of nitric oxide (NO); however, the complete NO/(c) GMP/K(ATP) channels pathway for Carbenoxolone is unknown. Therefore the aim of this study was to examine the NO/(c) GMP/K(ATP) channels pathway as the gastroprotective mechanism of Carbenoxolone in the ethanol-induced gastric injury model in the rat. Oral administration of Carbenoxolone (30 mg/kg, p.o.) exhibited gastroprotective effect against ethanol-induced gastric injury in rats. Pretreatment with N(G) -nitro-l-arginine methyl ester (L-NAME, 70 mg/kg, i.p.); 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, guanylate cyclase inhibitor, 10 mg/kg, i.p.); or glibenclamide (K(ATP) channels inhibitor, 1 mg/kg, i.p.) reversed the gastroprotective effect of Carbenoxolone for ethanol-induced gastric injury. Furthermore, gastric prostaglandins and NO levels increased after Carbenoxolone administration in ethanol-induced gastric injury in rats. In conclusion, our results suggest that the increase of NO levels in gastric tissue after pretreatment with Carbenoxolone activates the NO/(c)GMP/K(ATP) channels pathway, the principal gastroprotective mechanism of Carbenoxolone.

Faruk Bagirici - One of the best experts on this subject based on the ideXlab platform.

  • interaction between Carbenoxolone and valproic acid on pentylenetetrazole kindling model of epilepsy
    International Journal of Clinical and Experimental Medicine, 2015
    Co-Authors: Fatih Sefil, A E Arik, M O Bostanci, Faruk Bagirici, Ramazan Kozan
    Abstract:

    Gap junctions play an important role in the synchronized neuronal discharges. The main reason of the epileptic seizures is disruption of this synchronization. Therefore, the aim of the present study is to explore the combination valproic acid with Carbenoxolone in pentylenetetrazole-kindled rats. In the first set of experiments, pentylenetetrazole (35 mg/kg intraperitoneally was administered to the rats to produce the kindling and then permanent screw electrodes to record electroencephalographic signals. The kindled rats were divided into six groups. While electroencephalographic recordings received from animals, behavioral evaluation was done by an observer. The data analysis was performed using T test and Mann-Whitney U tests. The dose of 40 mg/kg Carbenoxolone was the most effective in Carbenoxolone treatment groups. It prevented generalized seizures by 50%, reduced seizure stage, seizure duration and spike frequency. There was no significant difference between Carbenoxolone-valproic acid combination and valproic acid on any seizure parameters. The current study is the first study which shows the interaction of Carbenoxolone with valproic acid in pentylenetetrazole kindling model. As a result, Carbenoxolone-valproic acid combination was not more effective than the standalone use of these drugs.

  • Original Article Interaction between Carbenoxolone and valproic acid on pentylenetetrazole kindling model of epilepsy
    2015
    Co-Authors: Fatih Sefil, Faruk Bagirici, Meryem D Acar, Ramazan Kozan
    Abstract:

    Gap junctions play an important role in the synchronized neuronal discharges. The main reason of the epileptic seizures is disruption of this synchronization. Therefore, the aim of the present study is to explore the combination valproic acid with Carbenoxolone in pentylenetetrazole-kindled rats. In the first set of experiments, pentylenetetrazole (35 mg/kg intraperitoneally was administered to the rats to produce the kindling and then per- manent screw electrodes to record electroencephalographic signals. The kindled rats were divided into six groups. While electroencephalographic recordings received from animals, behavioral evaluation was done by an observer. The data analysis was performed using T test and Mann-Whitney U tests. The dose of 40 mg/kg Carbenoxolone was the most effective in Carbenoxolone treatment groups. It prevented generalized seizures by 50%, reduced seizure stage, seizure duration and spike frequency. There was no significant difference between Carbenoxolone-valproic acid combination and valproic acid on any seizure parameters. The current study is the first study which shows the interaction of Carbenoxolone with valproic acid in pentylenetetrazole kindling model. As a result, Carbenoxolone- valproic acid combination was not more effective than the standalone use of these drugs.

  • influence of Carbenoxolone on the anticonvulsant efficacy of phenytoin in pentylenetetrazole kindled rats
    Acta Neurobiologiae Experimentalis, 2012
    Co-Authors: Fatih Sefil, Faruk Bagirici, Cafer Marangoz
    Abstract:

    Abnormal synchronized neuronal discharges mediated by gap junctions have an important role in epileptic seizures. The analysis of anticonvulsant drugs acting on gap junctions is still a priority in epilepsy research. Therefore, the present study was designed to investigate the effect of Carbenoxolone, a gap junction blocker, on the anticonvulsant efficacy of phenytoin in pentylenetetrazole kindled rats. Male Wistar albino rats, 14 weeks of age, were used. In the first step of the study, animals were given PTZ 35 mg/kg intraperitoneally (i.p.) three times a week until kindling was produced. Then, indwelling screw electrodes – allowing EEG monitoring of conscious rats – were implanted into the crania of the kindled rats. In this way, we were able to record EEG activity and evaluate seizure stage at the same time. In the second step of the study, the interaction between Carbenoxolone (40 mg/kg i.p.) and phenytoin (60 mg/kg, i.p.) was investigated. The data analysis was performed using a one-way ANOVA with LSD post-hoc test. Total spike number and the generalized seizure duration were reduced in the Carbenoxolone treated group compared to the PTZ group. Phenytoin decreased generalized seizure duration, total spike number and seizure severity score. Carbenoxolone and phenytoin have anti-seizure effects in PTZ kindled rats. There was no significant difference between the Carbenoxolone + phenytoin combination and phenytoin in terms of generalized seizure duration, total spike number and seizure stage. The results indicate that Carbenoxolone combined with phenytoin is not more effective than the use of these drugs alone.

  • anticonvulsive effects of Carbenoxolone on penicillin induced epileptiform activity an in vivo study
    Neuropharmacology, 2007
    Co-Authors: Omer M Bostanci, Faruk Bagirici
    Abstract:

    Abstract Epilepsy is an important problem in neurological disorders. Recent studies claimed that gap junctions have a critical role in epileptic neuronal events. The aim of present study is to investigate the effects of gap junction blocker Carbenoxolone on penicillin-induced experimental epilepsy. For this purpose, 4-month-old male Wistar rats were used in the present study. Permanent screw electrodes allowing EEG monitoring from conscious animals and permanent cannula providing the administration of the substances to the brain ventricle were placed into the cranium of rats under general anesthesia. At the end of the postoperative recovery period, epileptiform activity was generated by injecting 300 IU crystallized penicillin through the ventricular cannula. Epileptiform activity monitored from a digital recording system, when it reached its maximum intensity, Carbenoxolone (100, 200, 500 nmol) was applied in the same way with penicillin. Effects of Carbenoxolone on epileptiform activity were assessed by both electrophysiological and behavioral analysis. Carbenoxolone suppressed epileptiform activity by decreasing the amplitude and frequency of epileptiform spikes and by attenuating the epileptiform behavior. The results of this study suggest that the blockade of electrical synapses may contribute to the prevention and amelioration of epileptic activity.

B M Peskar - One of the best experts on this subject based on the ideXlab platform.

  • effect of Carbenoxolone on the biological activity of nitric oxide relation to gastroprotection
    British Journal of Pharmacology, 1991
    Co-Authors: A Dembinskakiec, Dirk Pallapies, Th Simmet, B M Peskar
    Abstract:

    Abstract 1. The interactions between Carbenoxolone and nitric oxide (NO) were examined by investigating their effects on human platelet aggregation, on rat aortic strips precontracted by phenylephrine and on protection of rat gastric mucosa against ethanol-induced injury. 2. Carbenoxolone (100-300 microM) caused a significant and concentration-dependent potentiation of rat peritoneal neutrophil (RPN)- 3-morpholino-syndnonimine (SIN-1)- or iloprost-induced inhibition of platelet aggregation. Higher concentrations (500 microM) of Carbenoxolone alone markedly inhibited platelet aggregation. Pretreatment with Carbenoxolone (100-300 microM) antagonized the reversal of the RPN- or SIN-1-induced antiaggregatory effect by oxyhaemoglobin (10 microM). 3. Rat aortic strips with intact endothelium precontracted by phenylephrine (0.1-0.3 microM) were relaxed by Carbenoxolone (100-300 microM) in a concentration-dependent manner. Relaxations were abolished by mechanical removal of the endothelium or by incubation with methylene blue (10 microM) or NG-nitro-L-arginine (L-NNA, 100 microM). Sodium nitroprusside (10 nM)-induced relaxations of endothelium-denuded rat aortic strips were potentiated by Carbenoxolone (100 microM). . The Carbenoxolone (200 mg kg-1, p.o.)-induced gastroprotection against ethanol was antagonized by L-NNA (5-40 mg kg-1) in a dose-dependent manner. Pretreatment of rats with indomethacin (10 mg kg-1, s.c.) increased the effect of L-NNA. 5. The results suggest that the activity of Carbenoxolone in the experimental systems tested is due to phosphodiesterase inhibition, although radical scavenging properties of the drug could contribute to some of the effects observed. In the rat gastric mucosa both increased prostaglandin levels and effects on the NO system could contribute to the protective action of Carbenoxolone.

Hossein Hosseinzadeh - One of the best experts on this subject based on the ideXlab platform.

  • the effects of Carbenoxolone a semisynthetic derivative of glycyrrhizinic acid on peripheral and central ischemia reperfusion injuries in the skeletal muscle and hippocampus of rats
    Phytomedicine, 2005
    Co-Authors: Hossein Hosseinzadeh, Siavash Parvardeh
    Abstract:

    Abstract As Carbenoxolone, a semisynthetic derivative of glycyrrhizinic acid, has a free radical scavenging property, thus the effects of Carbenoxolone during ischemia-reperfusion was evaluated on an animal model of ischemia-reperfusion injury in the rat hind limb and hippocampus. Peripheral and central ischemia were induced by free-flap surgery in skeletal muscle and four-vessel-occulation (4VO) of rat, respectively. Carbenoxolone (50–200 mg/kg) and normal saline (10 ml/kg) were administered intraperitoneally. In peripherlal ischemia, during preischemia, ischemia and reperfusion conditions the electromyographic (EMG) potentials in the muscles were recorded. The malondialdehyde (MDA) was measured by the thiobarbituric acid (TBA) test after reperfusion in peripheral and central ischemia. In peripheral ischemia, the average peak-to-peak amplitude during ischemic-reperfusion was found to be significantly larger in Carbenoxolone group (100–200 mg/kg) in comparison to control group. The MDA levels were recovered significantly upon Carbenoxolone (100–200 mg/kg) therapy in the skeletal muscle and hippocampus of ischemic rats. These results suggest that Carbenoxolone can salvage the skeletal muscle and hippocampus from acute ischemia-reperfusion injury.

  • the effects of Carbenoxolone on spatial learning in the morris water maze task in rats
    Medical Science Monitor, 2005
    Co-Authors: Hossein Hosseinzadeh, Siavash Parvardeh, Seyed Mohammad Tagi Mansouri
    Abstract:

    High-frequency oscillations (ripples) are proposed to be involved in memory consolidation. Ripple oscillations persist in the absence of chemical synaptic transmission and inhibitors of gap junctions were shown to block high-frequency oscillations in hippocampal slices. In this study we investigated the effects of Carbenoxolone, as a gapjunction blocker, on spatial learning in the rat. Cognitive performance was assessed using the Morris water maze (MWM). Adult male rats were bilaterally cannulated into the CA1 region of their hippocampus. Carbenoxolone (1.23, 2.46, 4.92 μg/side), scopolamine (3 pg/side), and saline were injected through the cannulas before 4 consecutive training trials and one test trial that conducted 24 h after the training trials with the platform removed. The results showed that Carbenoxolone could significantly reduce the percentages of time spent, distance traveled, and entry into Q2 (the target quadrant) compared with the control group. The Carbenoxolone group failed to use a selective search strategy during the final test trial, in which the platform was removed. The results of this study suggest that Carbenoxolone as a gapjunction channel blocker can decelerate the learning performances of rats in a spatial memory task, such as the MWM, that requires the integrity of the hippocampus.

  • Anticonvulsant, sedative and muscle relaxant effects of Carbenoxolone in mice.
    BMC Pharmacology, 2003
    Co-Authors: Hossein Hosseinzadeh
    Abstract:

    Background Carbenoxolone, as an antiulcer medicine, has some pharmacological properties such as: the inhibition of gap junctional (GJ) intercellular communication. In vitro studies have shown, Carbenoxolone to abolish the generation of full or partial ectopic spike generation, by 4-aminopyridine, as well as spontaneous epileptiform activity in CA3 or CA1 regions of the rat hippocampal slices via closing GJ channels. Thus, we considered the possible anticonvulsant effects of Carbenoxolone in animal seizure models.

  • Anticonvulsant, sedative and muscle relaxant effects of Carbenoxolone in mice.
    BMC pharmacology, 2003
    Co-Authors: Hossein Hosseinzadeh, Marjan Nassiri Asl
    Abstract:

    BACKGROUND: Carbenoxolone, as an antiulcer medicine, has some pharmacological properties such as: the inhibition of gap junctional (GJ) intercellular communication. In vitro studies have shown, Carbenoxolone to abolish the generation of full or partial ectopic spike generation, by 4-aminopyridine, as well as spontaneous epileptiform activity in CA3 or CA1 regions of the rat hippocampal slices via closing GJ channels. Thus, we considered the possible anticonvulsant effects of Carbenoxolone in animal seizure models.\n\nRESULTS: ED50 values of diazepam and Carbenoxolone in the pentylenetetrazole model were 1.13 mg/kg and 283.3 mg/kg, respectively. In this model, Carbenoxolone in doses of 200 and 300 mg/kg prolonged the onset time of seizure and decreased the duration of seizures. In the maximal electroshock model, Carbenoxolone in a dose of 400 mg/kg decreased the duration of seizure producing protection against seizure but failing to protect against mortality in comparison with diazepam. In the potentiation of pentobarbitone sleep test, Carbenoxolone significantly increased sleeping time and decreased latency in doses of 100, 200 and 300 mg/kg in mice dose dependently. In the traction test, Carbenoxolone (400 mg/kg) showed muscle relaxant activity and in the accelerated rotarod test, Carbenoxolone in doses of 200 and 300 mg/kg showed a decline in motor coordination.\n\nCONCLUSION: It can be concluded that Carbenoxolone possesses anticonvulsant, muscle relaxant and hypnotic effects, which could contribute to the control of petit mal and grand mal seizures.