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PubMed1988

Thiols as myeloperoxidase-oxidase substrates.

Nine low-Mr thiols were compared with regard to their ability to function as myeloperoxidase-oxidase substrates under conditions where no auto-oxidation of the thiols could be observed. The methyl and ethyl esters of cysteine were found to be about twice as active as cysteamine at pH 7.0, in terms of increased O2 consumption. Cysteine itself was poorly active, whereas glutathione, N-acetylcysteine and penicillamine were completely inactive as myeloperoxidase-oxidase substrates under these conditions. The structure-activity relationships indicated that both a free thiol and free amino group were required for peroxidase-oxidase activity, and also that a free carboxy group abolished activity. In analogy with cysteamine, the activities of both cysteine esters were inhibited by superoxide dismutase (less than 5 micrograms/ml) and by catalase and not by the hydroxyl-radical scavenger mannitol. In contrast with cysteamine, the activities of both cysteine esters were stimulated more than 2-fold by high concentrations (greater than 5 micrograms/ml) of superoxide dismutase. The activities of both cysteine esters exhibited broad pH optima at pH 7. A mechanism for the myeloperoxidase-oxidase oxidation of the cysteine esters is proposed, which is partly different from that previously proposed for cysteamine.

Catalase↗

PubMed1988

Role of epidermal growth factor in gastroduodenal mucosal protection.

Epidermal growth factor (EGF) is a polypeptide produced in the submandibular glands, Brunner's glands, and the kidneys. The peptide is secreted in an exocrine fashion into saliva, duodenal juice, and urine. EGF stimulates cellular growth and differentiation and inhibits gastric acid secretion. Removal of the submandibular glands decreases the amount of EGF in saliva and gastric juice and subsequently the synthesis of DNA in the gastric mucosa is reduced as well as its resistance to bile-salt-induced gastric lesions. Intragastric instillation of EGF can prevent gastric ulcerations induced by aspirin as well as cysteamine in rats. EGF also accelerates the healing of chronic gastric ulcers induced by acetic acid. Cysteamine is a duodenal ulcerogen in rats. After cysteamine administration, the secretion of EGF from Brunner's glands decreases and the glands become depleted of mucus. Intraduodenal instillation of EGF can partly prevent formation of cysteamine-induced duodenal ulcers. Oral administration of EGF can accelerate healing of chronic duodenal ulcers in rats. The beneficial effect of EGF on healing of chronic gastroduodenal ulcers is probably due to the delayed effects of EGF such as stimulation of RNA and DNA synthesis. The protective effects of EGF are probably related to the early actions of the peptide such as activation of cell surface proteins and increased glycosaminoglycan synthesis.

Animals↗

PubMed1987

Somatostatin augments the spread of limbic seizures from the hippocampus.

The role of the neuropeptide somatostatin in limbic seizures was studied using electrical stimulation of the hippocampus in kindled rats. Cysteamine, an agent which selectively and reversibly depletes brain somatostatin stores, had a biphasic action. An early proconvulsant effect was seen within a few hours, consisting of prolonged electrographic seizures in the hippocampus and more severe behavioral convulsions. A later anticonvulsant effect, maximal at 1 to 2 days and dissipating within a week, was manifested by less intense behavioral convulsions without change in the duration of electrical seizure activity. Both effects were dose-dependent. No change in afterdischarge thresholds was detected at any time after the administration of cysteamine. Intraventricular administration of somatostatin to animals with behavioral seizures attenuated by cysteamine treatment restored the responses to precysteamine levels. We conclude that somatostatin facilitates the spread of seizures over limbic circuits from a region of focal seizure initiation.

Animals↗

PubMed1993

Role of somatostatin in regulation of insular-acinar axis.

Cysteamine is known to deplete somatostatin from pancreatic D cells. In the isolated perfused rat pancreas we investigated its effects on somatostatin and glucagon release as well as exocrine pancreatic secretion in the presence of 1.8 mM glucose. Cysteamine, 10 mM, released somatostatin, but had no effect on CCK-stimulated amylase secretion. Arginine-stimulated glucagon release, however, was significantly inhibited by cysteamine. Concomitantly we still observed stimulation of somatostatin secretion, but also a potentiation of CCK-stimulated amylase secretion. Our results are consistent with a role of somatostatin in the regulation of exocrine pancreatic secretion via its effect on pancreatic A and B cells.

Amylases↗

PubMed1988

Biphasic effect of duodenal ulcerogens on gastric emptying in the rat.

The effect of the duodenal ulcerogen cysteamine on gastric emptying of a liquid meal was compared to that of two newly identified duodenal ulcerogens, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and mepirizole. Emptying rates after acute and chronic treatment with duodenal ulcerogens were obtained. Acute administration of cysteamine, MPTP, or mepirizole significantly delayed gastric emptying of the meal. Chronically treated rats, however, showed either no change or accelerated gastric emptying after cysteamine, MPTP, or mepirizole. Gastric emptying in chronically treated animals was faster in rats that developed the most severe duodenal ulcers. These results indicate that delayed gastric emptying instead of accelerated emptying is a more common abnormality during duodenal ulceration. After the ulcer develops, however, unaltered or accelerated gastric emptying is observed experimentally, thus suggesting that accelerated gastric emptying in duodenal ulcers is an acquired alteration. The implications that these experimental findings may have in the pathogenesis of duodenal ulcer, in light of the clinical data available, are discussed.

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

PubMed1988

Role of prostanoids in experimental duodenal ulcer in rat.

The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E2 (PGE2) and prostacyclin (PGI2) generation was 235 +/- 25 and 832 +/- 40 ng/g/min, respectively, whereas full-thickness duodenal PGE2 and PGI2 generation was 665 +/- 46 and 662 +/- 49 ng/g/min, respectively. Over an intraperitoneal dose range of 0-25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm2) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE2 generation, while having no effect on PGI2 generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE2 generation 39% compared to control values. In fed male rats, gastric mucosal PGE2 and PGI2 generation was 179 +/- 18 and 813 +/- 61 ng/g/min, respectively, whereas duodenal PGE2 and PGI2 generation was 321 +/- 27 and 454 +/- 38 ng/g/min, respectively. Duodenal ulceration (7.7 +/- 2.3 mm2) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE2 generation compared to control values, while having no effect on PGI2 generation. Subcutaneous aspirin, 100 mg/kg, which reduced duodenal PGE2 generation to a greater degree than either ulcerogen, given in conjunction with pentagastrin, did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Determination of cystamine by high-performance liquid chromatography.

A highly sensitive and specific assay method for cystamine using high-performance liquid chromatography has been developed. The method is based on postcolumn derivatization of cystamine with o-phthaladehyde in the presence of 2-mercaptoethanol and sodium hypochlorite. The separation of cystamine was achieved using a cation exchange column (ISC-05/S0504). The assay was linear over the concentration range of 2 to 200 pmol. For the application of this assay method to biological materials, the pretreatment with a cation exchange column (Dowex 50W X 8) was necessary to remove interfering o-phthaladehyde-reactive substances. Since cysteamine in biological materials was quantitatively converted to cystamine during these sampling procedures, this method was found to be suitable for assaying the cysteamine plus cystamine content in various organs and tissues. The cysteamine-cystamine content in various tissues of rat determined by the present assay method has been presented.

Animals↗

PubMed1989

Synergism between substrate and non-substrate thiols in peroxidase-oxidase reactions.

Cysteamine and reduced glutathione were shown to act synergistically as peroxidase-oxidase substrates as measured by oxygen consumption and Nitro Blue Tetrazolium reduction. Cysteine methyl ester could be substituted for cysteamine and N-acetylcysteine and penicillamine could be substituted for glutathione. The involvement of reduced oxygen species and the effects of pH and chloride were studied. A possible mechanism of peroxidase-oxidase oxidation of cysteamine and glutathione is proposed. These studies show that peroxidase oxidase reactions can occur with close to physiological concentrations of peroxidase and thiols.

Chromatography, High Pressure Liquid↗

PubMed1990

Duodenal SP-like immunoreactivity is decreased in experimentally-induced duodenal ulcers.

Substance P-like immunoreactivity (SP-li) is decreased in duodenal samples of animals treated with a single dose of an ulcerogen such as dulcerozine, mepirizole or cysteamine. Unlike dulcerozine- or mepirizole-induced ulcers the degree of cysteamine-induced duodenal lesions is inversely correlated with the levels of duodenal SP-li. A significant decrease in duodenal SP-li was observed at 24 h, but not at 6 h after a single oral dose of cysteamine. These findings show that endogenous SP may play an important local role in duodenal ulcerogenesis.

Animals↗

PubMed1992

Enzymatic synthesis of S-aminoethyl-L-cysteine from pantetheine.

The recently characterized compound S-aminoethylcysteine ketimine can be synthesized from purified S-aminoethylcysteine by enzymatic systems (transaminases or L-amino acid oxidase) present in mammalian tissues. S-Aminoethylcysteine, which could be considered as the natural precursor of the ketimine, is produced from L-serine and cysteamine by the action of the enzyme cystathionine-beta-synthase. We demonstrate in this paper that pantetheine, a normal cellular component, is an efficient cysteamine donor for the synthesis of S-aminoethylcysteine and of S-aminoethylcysteine ketimine in the place of free cysteamine, and we describe the enzymatic system, composed of partially purified enzymes, for the in vitro synthesis of S-aminoethylcysteine ketimine from pantetheine. This seems to indicate a new biological role for pantetheine.

Amidohydrolases↗

PubMed1995

Changes in brain somatostatin in memory-deficient rats: comparison with cholinergic markers.

To clarify the functional role of the brain somatostatinergic system in cognitive processes, changes in the performance in passive avoidance and water maze tasks and in brain somatostatin contents were comparatively investigated in young Fischer rats subjected to brain cholinergic and somatostatinergic depletion, and in aged Fischer rats. Lesioning of the nucleus basalis magnocellularis and administration of cysteamine (200 mg/kg, s.c.), a depletor of somatostatin, resulted in significant deficits in passive avoidance, but complete transection of the fimbria-fornix hardly affected the performance in the task. When cognitive performance was assessed in the Morris water maze, lesions of the nucleus basalis magnocellularis and the fimbria-fornix, and administration of cysteamine, significantly impaired the acquisition of navigatory spatial memories of rats. On the other hand, aged rats (24-27 months) showed severe impairments of memory acquisition in both tasks. Neurochemistry measurements showed that lesions of the nucleus basalis magnocellularis produced a selective reduction both in the cortical cholinergic marker choline acetyltransferase and in striatal somatostatin level, whereas lesioning of the fimbria-fornix caused a marked loss of choline acetyltransferase in the hippocampus and posterior cortex, and a significant reduction in hippocampal somatostatin. On the other hand, treatment with cysteamine significantly reduced the contents of somatostatin in all the brain regions examined, but minimally affected choline acetyltransferase activity. However, significant reduction in the striatal choline acetyltransferase activity and elevation in somatostatin content in the frontal cortex were found in aged rats compared with young rats. Taken together, these results strongly suggest that changes in the brain somatostatinergic transmission are involved in the cognitive deficits in the experimental animal models of dementia presently employed. Furthermore, the present comparative study further implies that there are differences in the relative involvement of the cholinergic and somatostatinergic systems in the performance of rats on two different tests of mnemonic function.

Aging↗

PubMed1991

Effects of sulfhydryl modulation on ethyl acrylate-induced forestomach toxicity.

Acute administration of a single dose of ethyl acrylate (EA) to F344 rats by gavage caused time- and dose-dependent forestomach edema. Evidence from our laboratory and others suggested that EA is hydrolyzed to acrylic acid (AA) and ethanol both in vivo and in vitro. The major metabolites detected in teh urine of rats treated with EA were derivatives of the glutathione conjugates of EA and AA. The current work was undertaken to investigate the effects of sulfhydryl-depleting agents (diethylmaleate and fasting) and sulfhydryl-containing agents (cysteine and cysteamine) on EA-induced forestomach edema. Results presented in this report revealed that pretreatment of rats with sulfhydryl-containing chemicals such as cysteine or cysteamine has potentiated EA-induced forestomach edema. In contrast, depletion of indigenous sulfhydryls by fasting of rats or pretreatment with diethylmaleate (DEM) protected against EA-induced forestomach edema. Furthermore, repetitive daily administration of EA by gavage induced mucosal forestomach hyperplasia. Co-administration of cysteamine and EA resulted in a significant enhancement of the severity of EA-induced forestomach mucosal hyperplasia. In conclusion, current data suggest that modulation of indigenous sulfhydryls play a role in EA-induced forestomach toxicity; however, the exact mechanism underlying this role remains to be characterized.

Acrylates↗

PubMed2004

Novel epicatechin derivatives with antioxidant activity modulate interleukin-1beta release in lipopolysaccharide-stimulated human blood.

We examine the potential antioxidant activity and the immune function of new epicatechin conjugates obtained by depolymerization of grape polymeric flavanols in the presence of cysteamine or cysteine. When incubated with an erythrocyte suspension, flavanols protected the erythrocyte membrane from hemolysis induced by 2,2'-azo-bis(2-amidinopropane)dihydrochloride (AAPH), an azo free radical initiator. The inhibitory effect was concentration-dependent and the IC50 was 119.8 microM for epicatechin, and 74.9 and 89.4 microM for the cysteine and cysteamine derivatives, respectively. These compounds were tested for their antioxidant activity and their capacity to modulate interleukin-1beta (IL-1beta), which is currently considered to be the major cytokine factor influencing the acute phase of the inflammatory response. At concentrations up to 20 microM, epicatechin and its derivatives inhibited the production of IL-1beta in whole blood incubated in the presence of E. coli lipopolysaccharide (LPS), in a concentration-dependent manner. The most active compound was the cysteamine derivative.

Antioxidants↗

PubMed1979

Dopamine disorder in duodenal ulceration.

Cysteamine-induced duodenal ulcers in rats were prevented by the dopamine agonists bromocriptine, lergotrile, and apomorphine, whereas both the severity of duodenal ulcers and the mortality among cysteamine-treated rats were raised by the dopamine receptor antagonist, haloperiodol. Bromocriptine and lergotrile greatly reduced gastric-acid output in cysteamine-treated rats. A review of the literature shows a high incidence of duodenal ulcers in patients with Parkinson's disease (associated with dopamine deficiency) and a low occurrence in schizophrenics (associated with dopamine excess and/or hyperactivity). Thus, changes in peripheral and/or central dopamine concentrations and/or receptor activity may have a role in the pathogenesis of duodenal ulceration.

Animals↗

PubMed2004

Efficient one pot extraction and depolymerization of grape (Vitis vinifera) pomace procyanidins for the preparation of antioxidant thio-conjugates.

Antioxidant thio-conjugates were obtained from white grape pomace by a clean and efficient one pot extraction and depolymerization method using water and cysteamine hydrochloride. To evaluate the potential of grape pomaces of different origins as sources of proanthocyanidins and conjugates, we conducted varietal comparative studies of polyphenol content, antioxidant power, and procyanidin composition. Xarel.lo proved to be the richest source of polyphenols. The total conversion into the conjugates was as high as 8 g/kg of Xarel.lo grape pomace, with a 50-fold excess of cysteamine, and 3 g/kg, with a 5-fold excess of cysteamine. After purification by preparative cation exchange and reversed phase high-performance liquid chromatography, 17 g of 63% pure 4beta-(2-aminoethylthio)epicatechin (acetate salt) was obtained from 35 kg of moist pomace. The procedure described here will make the antioxidant thio-derivatives efficiently available directly from raw plant byproducts such as grape pomace.

Antioxidants↗

PubMed1988

The antioxidant action of taurine, hypotaurine and their metabolic precursors.

It has been suggested that taurine, hypotaurine and their metabolic precursors (cysteic acid, cysteamine and cysteinesulphinic acid) might act as antioxidants in vivo. The rates of their reactions with the biologically important oxidants hydroxyl radical (.OH), superoxide radical (O2.-), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) were studied. Their ability to inhibit iron-ion-dependent formation of .OH from H2O2 by chelating iron ions was also tested. Taurine does not react rapidly with O2.-, H2O2 or .OH, and the product of its reaction with HOCl is still sufficiently oxidizing to inactivate alpha 1-antiproteinase. Thus it seems unlikely that taurine functions as an antioxidant in vivo. Cysteic acid is also poorly reactive to the above oxidizing species. By contrast, hypotaurine is an excellent scavenger of .OH and HOCl and can interfere with iron-ion-dependent formation of .OH, although no reaction with O2.- or H2O2 could be detected within the limits of our assay techniques. Cysteamine is an excellent scavenger of .OH and HOCl; it also reacts with H2O2, but no reaction with O2.- could be measured within the limits of our assay techniques. It is concluded that cysteamine and hypotaurine are far more likely to act as antioxidants in vivo than is taurine, provided that they are present in sufficient concentration at sites of oxidant generation.

Antioxidants↗

PubMed1990

Swallowing dysfunction in nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis causes renal failure in most patients at approximately 10 years of age. This can be prevented or retarded by cystine-depleting therapy with oral cysteamine. Many patients who do not receive adequate cysteamine therapy undergo renal transplantation, but the accumulation of cystine continues in other organs, resulting in various clinical abnormalities. We report age-related swallowing dysfunction in patients with nephropathic cystinosis. METHODS: We studied 43 patients with cystinosis (24 who had received a renal transplant and 19 who had not), 3 to 31 years of age. Oral motor function was assessed by a cranial-nerve oral sensorimotor examination, and an oral motor index was calculated for each patient. The oral phase of swallowing was assessed by ultrasonography, and the pharyngeal and esophageal phases were evaluated by videofluoroscopy. RESULTS: Approximately half the patients were slow eaters. Oral motor dysfunction, reflected by a higher oral motor index, increased with age. Speech, oral structure and anatomy, and tongue and lip strength were particularly affected. Seven of nine patients 21 to 31 years old had abnormalities in all three phases of swallowing; the deficits were variable in younger patients. In 28 patients with cystinosis, the mean (+/- SD) duration of oropharyngeal swallowing for a dry swallow (3.06 +/- 1.06 seconds) was longer than in 14 normal subjects (1.89 +/- 0.57 seconds; P less than 0.001). This prolongation reflected impairment of the initiation phase of swallowing. CONCLUSIONS: Swallowing dysfunction is a late complication of nephropathic cystinosis, probably related to muscular dysfunction. Changes in the consistency of foods, swallowing exercises, and long-term cysteamine therapy should be considered for patients with cystinosis who have difficulty in swallowing.

Adolescent↗

PubMed1984

Radical reactions in aqueous disulphide-thiol systems.

Absolute rate constants have been measured for the reaction of (CH3SSCH3)+. and sulphur centred radical cations of lipoic acid, lip (SS)+., with various thiols including penicillamine, cysteamine and cysteine. Under pulse radiolysis conditions no reactions was observed between the disulphide radical cations and the neutral thiols, RSH, i.e. kappa less than or equal to 10(7) M-1 s-1. Rate constants in the order of 10(9) M-1 s-1, i.e. close to the diffusion controlled limit, were, however, found for the corresponding reactions with the thiolates, RS-. In systems containing lipoate and cysteamine the lip (S therefore S)+. induced oxidation of CyaS- proceeds via CyaS., (CyaS therefore SCya)- and lip (S S)- as intermediates, i.e. results in a cysteamine mediated conversion of an oxidizing lip (S therefore S)+. radical cation to a reducing lip (S S)- radical anion along the reaction route. In other cases the reaction of disulphide radical cations with thiolate anions was found to proceed via an optically absorbing transient (lambda max approximately 380 nm) which is suggested to be an adduct radical. The mechanism of the (RSSR)+. induced oxidation of thiolate appears to depend on the stability of the 3-electron bonded disulphide radical anion.

Cysteamine↗