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PubMedDate not supplied

Prevention of duodenal ulcer formation in the rat by dietary vitamin A supplementation.

We have shown previously that supplemental vitamin A (Vit. A) increases the early inflammatory response to wounding and enhances the collagen content of the intestine of normal and injured rats. We now report the effect of dietary supplementation with Vit. A on the prevention of duodenal ulcer (DU) in rats caused by intragastric administration of cysteamine-HCl. A major way cysteamine-HCl induces DU formation is by enhancing gastric acid secretion. Adult male rats were divided into two groups: (1) rats fed a standard rat Chow (Purina) (15 IU Vit. A/g diet) containing two to three times the National Research Council recommended daily allowance for Vit. A for normal rats; (2) rats fed the same supplemented with 150 IU of Vit. A palmitate per/g Chow. One week later, all rats were given 1 ml of cysteamine-HCl (135 mg) intragastrically. The rats were maintained on their respective diets. Two days later, all rats were killed with ether, the stomach and duodenum excised, and examined for the presence of ulcers. No gastric ulcers were found in either group. There was a statistically significant decrease in the incidence of DUs in the Vit. A-supplemented group when compared to the control group (p less than 0.01) 48 hr following cysteamine-HCl administration; 32% of the Vit. A-supplemented rats developed a DU whereas 74% of rats fed standard Chow had DUs. Most rats had a single DU in the first part of the duodenum, occasionally a second ulcer was noted in the same area. Dietary supplementation with Vit. A had no effect on gastric acid production. In conclusion, our data show that Vit. A dietary supplementation is effective in preventing formation of DUs caused by cysteamine-HCl administration to rats. This effect does not appear to be due to reduction of gastric acid output.

Animals↗
PubMed1998

Treatment with recombinant human growth hormone in short children with nephropathic cystinosis: no evidence for increased deterioration rate of renal function. The European Study Group on Growth Hormone Treatment in Short Children with Nephropathic Cystinosis.

To evaluate the effect of long-term treatment with recombinant human GH (rhGH) on renal function in short children with nephropathic cystinosis with and without concomitant cysteamine treatment, 36 growth-retarded children with nephropathic cystinosis (age 7.3+/-2.7 y; creatinine clearance [C(CR)] 50+/-27 mL (min x 1.73 m2)(-1) were treated with 1 IU rhGH/kg/wk for up to 5 y. The rise in serum creatinine before and during rhGH treatment was compared with that in a historical control group of cystinotic patients. The effect of concomitant cysteamine treatment on the evolution of renal function before and after the start of rhGH was evaluated separately in patients without (group A) and with cysteamine treatment (group B). The decline of C(CR) was also compared with that in noncystinotic patients with chronic renal failure with and without rhGH treatment. At study entry, serum creatinine values in group A were similar to those in the historical controls, whereas group B had significantly lower serum creatinine values. Treatment with rhGH did not accelerate the rise in creatinine independently of cysteamine treatment. There were no significant differences in the mean decline of C(CR) per year in cystinotic compared with noncystinotic patients with chronic renal failure with or without rhGH treatment. rhGH therapy for up to 5 y does not accelerate the deterioration of renal function. This justifies the continuation of controlled studies of rhGH treatment in these patients. The study also provides further evidence that cysteamine therapy reduces the progression of renal failure in children with cystinosis.

Child↗
PubMed1989

[The role of sulfhydryls in indomethacin-induced gastric mucosal injury in rats].

The possible role of sulfhydryls in indomethacin-induced gastric mucosal injury was studied. No significant decrease of the contents of both non-protein and protein-binding sulfhydryls was observed in the gastric mucosa during injury. Indomethacin-induced gastric ulcer was inhibited by cysteamine of 132 and 264 mumol, i.g. or of 132 mumol, s.c. by 82%, 92% and 75% respectively. Such protective effect was not observed with cysteine in equal molar dose. Subcutaneously injected cysteamine (132 mumol) inhibited gastric acid secretion by 46% in indomethacin-treated rats, while no effect was observed on acid secretion when cysteamine was given intragastrically. Cysteamine, given through both routes, did not affect gastric barrier mucus secretion. It is suggested that sulfhydryls in gastric mucosa are not involved in the mechanism of indomethacin-induced injury and that the potent cytoprotective effect of cysteamine against indomethacin-induced ulcer maybe not caused by its sulfhydryl group.

Animals↗
PubMed1985

Temperature-dependent influence of thiols upon glutathione levels in Chinese hamster ovary cells at cytotoxic concentrations.

Chinese hamster ovary cells were exposed to the sulfhydryl compound cysteamine at different temperatures (5 degrees C, 37 degrees C, 44 degrees C) at concentrations known to generate activated oxygen species. At 37 degrees C, the cellular glutathione (GSH) content increased linearly over the time of drug exposure (2 h) as compared to untreated cells or to cells kept at 5 degrees C during drug treatment. The 2-4-fold increase in GSH induced by cysteamine was more rapid at 44 degrees C than at 37 degrees C and showed a saturation effect at the higher temperature. The elevation of GSH could be completely blocked by DL-buthionine-S,R-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, or by incubation in a cystine-free medium during the period of drug treatment. The increased cellular GSH content induced by cysteamine alone at 37 degrees C or combined with heat at 44 degrees C decreased to the range of control values within 22 h after either treatment. Other thiols like cysteamine, namely cysteine, N-acetylcysteine, and dithiothreitol, were found to be similar in their potential to induce GSH elevation in Chinese hamster ovary cells. Cytotoxic effects of these sulfhydryl compounds were observed in the same concentration range as that for cysteamine (0-2 mM), but only if cells were plated at low densities (10(2)-10(4) cells/flask), and were completely blocked by the addition of catalase (50 micrograms/ml). In contrast, the elevation of GSH after thiol treatment (0.8 mM) was not modified by catalase. The data suggest that thiol treatment combined with hyperthermia leads to a rapid increase of GSH biosynthesis in Chinese hamster ovary cells which seems to be independent of the simultaneous generation of activated oxygen species by thiol autoxidation.

Animals↗
PubMed1979

Thermosensitization by sulfhydryl compounds of exponentially growing Chinese hamster cells.

The effect of various sulfhydryl compounds on the survival of exponentially growing monolayer cultures of Chinese hamster cells (HA1) heated to temperatures of 37-43 degrees was examined. Concentrations of cysteamine which were nontoxic or minimally toxic at room temperature or 37 degrees became increasingly toxic at elevated temperatures, greatly potentiating the killing produced by heat alone in the absence of cysteamine. This enhancement of hyperthermia-induced cell killing increased with increasing cysteamine concentration, increasing duration of cysteamine exposure, and increasing temperature. Studies with synchronized Chinese hamster cells heated at 43 degrees for 1 hr in the presence of 16 mM cysteamine demonstrated that the potentiation of heat killing occurred in all phases of the cell cycle. Similarly, enhancement of hyperthermia-induced cell killing was seen for asynchronous cells exposed to 2-amino-ethylisothiourium bromides and cysteine, but the magnitude of the effect differed for the various sulfhydryl compounds.

Animals↗
PubMed1994

Properties of melarsamine hydrochloride (Cymelarsan) in aqueous solution.

The antitrypanosomal drug melarsamine hydrochloride (MelCy) (trade name, Cymelarsan) is a melamino-phenylarsine made by conjugation of one equivalent of melarsen oxide and two equivalents of cysteamine. Immediately after it was dissolved in water, the compound was found to exist as an equilibrium mixture containing MelCy (43%), MelCy which had lost one cysteamine moiety (MelCy -1; 24%), melarsen oxide (33%), and free cysteamine. Small amounts (< 1%) of the oxidation products derived from the last two components were also formed (cystamine and sodium melarsen). On incubation at room temperature, the MelCy content decreased steadily, with an associated increase in the melarsen oxide and sodium melarsen contents. After 5 days in solution at room temperature, 27% of the arsenical agent was MelCy, 14% was MelCy -1, 42% was melarsen oxide, and 17% was sodium melarsen. Since H2O2 production was detectable in MelCy or cysteamine solutions and the addition of small amounts of exogenous H2O2 readily converted the trivalent melarsen oxide to the pentavalent sodium melarsen, it is hypothesized that the nonenzymatic conversion of cysteamine to cystamine produced H2O2, which then oxidized melarsen oxide to sodium melarsen. Similar time course experiments showed that melarsonyl potassium and melarsoprol were more stable in solution.

Arsenicals↗
PubMed2006

Suppression of early growth response factor-1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers.

Previously, we demonstrated that cysteamine releases endothelin-1 in the rat duodenal mucosa, followed by increased expression of early growth response factor-1 (egr-1). We hypothesized that egr-1 is a key mediator gene in the multifactorial mechanisms of duodenal ulcer development and healing because its protein, transcription factor product Egr-1, regulates the expression of angiogenic growth factors. We wanted to determine the effect of egr-1 antisense oligonucleotide on cysteamine-induced duodenal ulcers as well as on the expression of bFGF, PDGF, and VEGF, of which synthesis is modulated by Egr-1. An antisense oligonucleotide to egr-1 was used to inhibit the synthesis of Egr-1 and to determine its effect on ulcer formation in the rat model of cysteamine-induced duodenal ulceration. Real-time RT-PCR and Western blot analysis were used to assess the expression of Egr-1 mRNA and protein as well as ERK, bFGF, PDGF, and VEGF. The antisense Egr-1 oligonucleotide inhibited the expression of egr-1 mRNA and protein and increased the duodenal ulcer size from 8.1 +/- 1.8 mm(2) in controls to 20.7 +/- 4.0 mm(2) (P < 0.01). Cysteamine induced phosphorylation of ERK1/2 and enhanced the synthesis of bFGF, PDGF, and VEGF in the preulcerogenic stages of duodenal ulceration, whereas egr-1 antisense oligonucleotide markedly decreased the expression of these growth factors in the duodenal mucosa. We also demonstrated that Egr-1 expression relates to the ulcerogenic effect of cysteamine because these actions were not exerted by the toxic analog ethanolamine. Thus Egr-1 seems to play a critical role in duodenal ulceration because Egr-1 downregulation aggravates experimental duodenal ulcers, most likely through the transcriptional inhibition of bFGF, PDGF, and VEGF synthesis.

Animals↗
PubMed2003

Effects on in vitro embryo development and intracellular glutathione content of the presence of thiol compounds during maturation of prepubertal goat oocytes.

The low number of embryos produced from in vitro matured, fertilized, and cultured (IVM-IVF-IVC) oocytes of prepubertal goat is mainly due to a low incidence of sperm head decondensation at fertilization (Martino et al., 1995: Theriogenology 43:473-485; Mogas et al., 1997: Theriogenology 48:815-829). Thiol compounds stimulate glutathione (GSH) synthesis and improve the rates of male pronucleus (MPN) formation and embryo development. The present study was carried out to determine whether supplementation of the IVM medium with 100 microM of cysteamine, 100 microM of beta-mercaptoethanol, 0.57 mM of cysteine, and 0.57 mM cystine might improve the embryo development and intracellular GSH level of prepubertal goat oocytes. After 27 hr post IVM, a sample of oocytes was frozen and the intracytoplasmic GSH content was evaluated by spectrophotometry. IVM-oocytes were inseminated with fresh semen and cultured in SOF medium. Only the addition of cysteamine to IVM media significantly improved the percentage of the morula plus blastocyst yield compared to the control group (oocytes matured in absence of thiol compounds) (22.2 vs. 6.4%, respectively; P < 0.05). The percentage of expanded blastocysts in cysteamine and control groups was 13.0 and 2.6%, respectively, and the mean cell number per blastocyst was 86.8 and 60.5, respectively. None of the other thiol compounds studied significantly improved the percentage of embryos obtained. It has been demonstrated that prepubertal goat oocytes synthesize GSH during IVM and that thiol compounds increase this GSH synthesis. In conclusion, only the addition of 100 microM of cysteamine to the maturation medium improves embryo development from prepubertal goat oocytes although all the thiol compounds used in this study increased intracellular GSH content.

Animals↗
PubMed1993

Relationship between tissue calcium content and duodenal ulcer in the rat.

Since the effect of cellular calcium on cell injury has been in question, this study focused on the relationship between tissue calcium content and cysteamine-induced duodenal ulcer. Rats treated with cysteamine showed a high frequency and severity of duodenal ulcer, and the calcium content in the duodenal mucosa was elevated. Furthermore, the level of calcium content in duodenal mucosa was positively associated with the severity of the duodenal lesion. Whereas administration of calcium increased duodenal ulcerative response to cysteamine, verapamil afforded protection against ulceration. We conclude that calcium accumulation in duodenal mucosa is related to duodenal ulceration induced by cysteamine.

Animals↗
PubMed1993

Triphasic vascular effects of thiol compounds and their oxidized forms on dog coronary arteries.

The vascular effects of 2-mercaptoethanol, cysteamine, L-cysteine, glutathione (GSH), cystamine and oxidized GSH (GSSG) on the isometric tension of isolated dog coronary arterial strips were examined, and these effects were compared with the triphasic response induced by dithiothreitol (DTT); a rapid and weak contraction (phase A), an intervening slow relaxation (phase B) and a slowly-developing strong contraction (phase C) which we previously reported. The responses of the arteries induced by 2-mercaptoethanol, cysteamine and L-cysteine consisted of phases A, B and C. The order of contractile potency (ED50 of phase C) was DTT approximately L-cysteine > 2-mercaptoethanol approximately cysteamine, while the order of relaxant potency (ED50 of phase B) was DTT > cysteamine approximately 2-mercaptoethanol. GSSG and cystamine mainly produced relaxation, which corresponded to phase B. The phase C contraction was specific to the reduced forms of thiols, except for GSH, which produced only relaxation. The participation of endothelial cells was not essential for the contracting or relaxing effects of the thiol compounds. The phase C contraction was depressed by W-7, a calmodulin antagonist, while phase A was not. Therefore calmodulin-dependent protein kinases may participate in phase C, not in phase A.

Animals↗
PubMed1993

Sulfhydryl drugs reduce neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse.

Striatal levels of dopamine and its metabolites 3-methoxy-4-hydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased 7 days after subcutaneous injection of MPTP (20 mg/kg) to the mouse. Striatal GSH contents decreased and GSSG/GSH ratios increased one hour after subcutaneous administration of MPTP. Pretreatments of both cysteamine (200 mg/kg, s.c.) and dimercaprol (20 mg/kg, i.m.) reduced the MPTP-induced decreases in striatal dopamine, DOPAC and HVA, and also prevented the MPTP-induced decreases in GSH levels and increases in GSSG/GSH ratios. On the other hand, injection of cysteamine did not modify the MPTP-induced decreases in striatal levels of dopamine and its metabolites when it was done 2 hours after MPTP administration. Moreover, pretreatment of cysteamine did not affect striatal concentrations of MPP+ in MPTP-treated mice. These results suggest that sulfhydryl drugs such as cysteamine and dimercaprol may reduce neurotoxicity of MPTP probably via changes in redox cycle of glutathione in the brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Measurement of cyst(e)amine in physiological samples by high performance liquid chromatography.

Two methods for measurement of cyst(e)amine in physiological samples are described. One method involves reduction of disulfides present in the sample with tributylphosphine, reversed phase chromatography of thiols, and electrochemical detection of cysteamine and other thiols. The other method involves reduction of disulfides with dithiothreitol, derivatization of thiols with 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin, separation of these derivatives by reversed phase chromatography, and fluorometric detection of the thiol adducts. The endogenous concentration of cysteamine in rat liver was estimated to be less than 2.5 nmol/g. Cysteamine is produced in tissues postmortem; rapid sampling/freezing of tissues and rapid inactivation of enzymes during tissue preparation are essential for accurate measurement of endogenous cysteamine concentrations.

Animals↗
PubMed1980

The glutathione peroxidase activity of glutathione S-transferases.

Glutatione transferases (RX:glutathione R-transferases, EC 2.5.1.18) B and AA were purified from rat liver to investigate the mechanism for their apparent GSH peroxidase activity (GSSG formation). Both transferases catalyze an overall reaction in which loss of cumene hydroperoxide is accompanied by a stoichiometric increase in GSSG. Inclusion of cysteamine, a thiol, results in a reduction of GSSG formation but has no effect on hydroperoxide loss. Cysteamine does not inhibit the transferase-catalyzed conjugation of GSH and 1-chloro-2,4-dinitrobenzene. Peroxidase reactions carried out in the presence of cyanide, another nucleophile, also result in a reduction of GSSG formation without altering the rate of cumene hydroperoxide loss; cyanide does not inhibit transferase activity with 1-chloro-2,4-dinitrobenzene. Both cysteamine and cyanide are capable of blocking GSSG formation in the non-enzymic oxidation of GSH by hydrogen peroxide without blocking H2O2 loss. These results are consistent with a mechanism for GSH transferases in which nucleophilic attack by GS- on hydroperoxide results in a reactive intermediate, presumably the sulfenic acid of glutathione, GSOH. GSH + ROOH in equilibrium GSHO + ROH (1) This sulfenic acid then reacts non-enzymically with GSH to produce GSSG. GSOH + GSH in equilibrium GSSG + H2O (2) The summing of Reactions 1 and 2 explains the observed stoichiometry. Cysteamine and cyanide can compete with GSH for the sulfenic acid in Reaction 2, thus reducing GSSG formation. Thios.

Animals↗
PubMed1984

Mechanism of action of paracetamol protective agents in mice in vivo.

The mechanism of action of cysteine, methionine, N-acetylcysteine (NAC) and cysteamine in protecting against paracetamol (APAP) induced hepatotoxicity in male C3H mice in vivo has been investigated by, characterising the effect of the individual protective agents on the metabolism of an hepatotoxic dose of APAP, and determining the efficacy of the protective agents in animals treated with buthionine sulphoximine (BSO), a specific inhibitor of glutathione (GSH) synthesis. Co-administration of cysteine, methionine or NAC increased, while co-administration of cysteamine decreased, the proportion of GSH-derived conjugates of APAP excreted in the urine of mice administered APAP, 300 mg/kg. Pretreatment of animals with BSO abolished the protective effect of cysteine, methionine and NAC, whereas cysteamine still afforded protection against APAP after BSO treatment. In conjunction with other data, these results suggest the most likely mechanism for the protective effect of cysteine, methionine and NAC is by facilitating GSH synthesis, while the most likely mechanism for the protective effect of cysteamine is inhibition of cytochrome P-450 mediated formation of the reactive metabolite of APAP.

Acetaminophen↗
PubMed1988

Role of somatostatin in the regulation of vasopressin secretion.

Intracerebroventricular (i.c.v.) administration of somatostatin-28 (SS-28) (30 ng-1 micrograms) resulted in a dose-dependent elevation of plasma concentrations of vasopressin. Continuous i.c.v. infusion of SS-28 produced a depletion of vasopressin-like immunoactivity within the paraventricular and supraoptic of the hypothalamus as determined by immunocytochemistry. To evaluate the role of endogenous brain somatostatin in the regulation of vasopressin secretion, animals were treated with cysteamine. Cysteamine (90 mg/kg) treatment given s.c. produced a 50% depletion of endogenous brain somatostatin-like peptide concentrations. Pretreatment of animals with cysteamine attenuated hemorrhage-induced elevation of plasma vasopressin levels. The elevation of plasma vasopressin concentrations following the i.v. administration of hypertonic saline or the i.c.v. administration of angiotensin-II were not altered by cysteamine treatment. These results are consistent with the conclusion that an endogenous brain somatostatin may be involved in the physiologic regulation of vasopressin secretion following hemorrhage.

Animals↗
PubMed1993

Working memory deficits following muscarinic blockade combined with depletion of brain somatostatin in rats.

In a working memory task with three-panel runway paradigm, cysteamine, a depletor of somatostatin, at 100 or 200 mg/kg i.p. given 24 h before testing, had no effect on the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points). Cysteamine at 100 mg/kg caused a significant reduction in somatostatin-like immunoreactivity in the rat brain, including the hippocampus and cerebral cortex. Working memory errors were significantly increased by scopolamine, a muscarinic receptor antagonist, at 0.32 mg/kg i.p. given 20 min before testing, whereas errors were not affected by the 0.1 mg/kg dose. Combined administration of 100 mg/kg cysteamine and 0.1 mg/kg scopolamine significantly increased the number of working memory errors. However, cysteamine at 100 mg/kg and scopolamine at 0.1 mg/kg had no effect on reference memory errors, whether they were administered alone or in combination. These results suggest that depletion of brain somatostatin aggravates working memory deficits induced by blockade of muscarinic receptors.

Animals↗
PubMed1994

Possible involvement of brain somatostatin in the memory formation of rats and the cognitive enhancing action of FR121196 in passive avoidance task.

Using the passive avoidance learning task in rats, the role of brain somatostatin in cognitive function was investigated with special reference to that of the brain cholinergic system. In addition, the involvement of both the brain somatostatinergic and cholinergic systems in the anti-amnesic action of a newly introduced cognitive enhancer, FR121196 [N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide], was examined. Treatment with cysteamine (50, 100, 200 mg/kg, s.c.), a depletor of somatostatin, significantly and dose-dependently reduced the retention of single trial passive avoidance task. Similar memory impairments were found in rats which received central cholinergic blockade either by scopolamine (0.1-1 mg/kg) or by lesioning of the nucleus basalis magnocellularis (NBM). Intracerebroventricurally (i.c.v.) administered somatostatin (1-14) (10-1000 ng/rat) significantly ameliorated the memory impairments induced not only by cysteamine (200 mg/kg) but also by scopolamine (1 mg/kg) and NBM-lesioning. Although physostigmine (0.01-1 mg/kg) also ameliorated the memory impairments induced by cysteamine and scopolamine, it failed to affect the memory impairment seen in the NBM-lesioned rats. Administration of FR121196 (0.1-10 mg/kg) significantly ameliorated the memory deficits produced by scopolamine and NBM lesioning but not that induced by cysteamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Effect of thiols on lipid peroxidation in rat liver microsomes.

The stimulatory or inhibitory effects of various thiol compounds on in vitro lipid peroxidation by iron-ascorbate in rat liver microsomes were determined. Glutathione had no measurable pro-oxidant capacity, in contrast, it protected against lipid peroxidation. N-Acetyl l-cysteine and S-methyl-glutathione had no effect on in vitro lipid peroxidation. l-Cysteine stimulated lipid peroxidation and also of d-penicillamine and dl-dithiothreitol the pre-oxidant capacity predominated the anti-oxidant capacity. Cysteamine afforded a pronounced protection against in vitro lipid peroxidation. In contrast to the labile character of the glutathione dependent protection, the protection by cysteamine was not affected by heat-pretreatment of the liver microsomes or alkylating protein sulfhydryl groups by N-ethyl maleimide. Again in contrast to glutathione, the protection against in vitro microsomal lipid peroxidation by cysteamine was not reduced after in vivo lipid peroxidation induced by CC14. This suggests that even after the process of lipid peroxidation has been started, administration of cysteamine might still be beneficial.

Acetylcysteine↗