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PubMed1987

The effects of cysteamine on neurogenic responses in the stomach and small intestine of the rat.

The actions of the duodenal ulcerogen cysteamine in different regions of the rat stomach and small intestine were investigated utilizing isolated gut-bath preparations. Applied cysteamine caused concentration-dependent contractions of forestomach strips, primarily by direct actions at cholinergic muscarinic sites on the longitudinal muscle, and to a lesser extent indirectly via stimulation of intrinsic cholinergic motor nerves. In contrast to its gastric actions, applied cysteamine evoked nerve-mediated relaxations of segments of whole duodenum, jejunum and ileum. These actions were concentration-dependent and due to stimulation of the non-adrenergic, non-cholinergic (NANC) inhibitory nerves. In addition, cysteamine selectively inhibited nicotinic and GABA-ergic stimulation of the NANC inhibitory nerves, as well as electrically evoked cholinergic contractions. The interactions of cysteamine with the NANC inhibitory nerves appears to be via sites distinct from nicotinic or GABA receptors, and may have involved toxic effects.

Animals↗
PubMed1983

The effect of the duodenal ulcerogen cysteamine on somatostatin and gastrin cells in the rat.

Previous studies showed a rapid decrease of somatostatin concentration in the gut and an increase in serum gastrin levels after a single dose of the duodenal ulcerogen cysteamine. An attempt was made to identify morphologic changes that would correlate with these functional changes. Rats were killed 1, 4, 8, or 24 hr after a single dose of cysteamine and sections of gastric mucosa and pancreas were processed for electron and light microscopy. Subtle ultrastructural alterations were seen in D cells of the stomach (e.g., dilation of mitochondrial cristae and endoplasmic reticulum, and apparent increase in electron density of secretory granules) after cysteamine administration. The number of somatostatin-positive cells visualized by the immunoperoxidase technique using light microscopy was decreased in 1-4 hr but returned to normal by 24 hr. The alterations observed in the G cells after cysteamine administration are consistent with release of gastrin from mature granules and increased synthesis of the hormone. The lack of major morphologic changes in the D cells suggests that cysteamine affects somatostatin without causing cell necrosis or alteration in lysosome formation. The effect of the drug may thus be mediated at the biochemical level without marked morphologic alterations.

Animals↗
PubMed1990

Cysteamine induces cholecystokinin release from the duodenum. Evidence for somatostatin as an inhibitory paracrine regulator of cholecystokinin secretion in the rat.

To determine whether cholecystokinin secretion is regulated by endogenous somatostatin, somatostatin deficiency was induced in vivo with cysteamine (250 mg/kg body wt, IV) or anti-somatostatin antiserum in anaesthetized rats and in vitro with cysteamine (30 micrograms/mL) in a rat duodenum-incubation system. Cholecystokinin secretion was assessed in vivo by measuring amylase in duodenal perfusates collected at 10-minute intervals for 1 hour and in vitro by a carboxy-terminal radioimmunoassay. Cysteamine induced a marked decrease in duodenal immunoreactive somatostatin both in vivo (50%) and in vitro (60%). The rate of amylase secretion increased from 9.7 +/- 2.1 U (mean +/- SE) to 28.0 +/- 4.8 U at 20 minutes (P less than 0.001). The cholecystokinin-receptor antagonist CR-1392 abolished amylase response for 30 minutes, whereas the more potent antagonists Asperlicin (18.0 mg/kg body wt, IV) and L-364,718 (0.25 mg/kg body wt, IV) caused prolonged blockade. The rate of amylase secretion in gastrectomized animals increased from 7.2 +/- 2.0 U to 15.0 +/- 2.2 U 20 minutes after cysteamine administration (P less than 0.01), indicating that the effect was not due to the presence of gastrin. In vitro, cysteamine caused a nearly fourfold increase in cholecystokinin secretion compared with controls (63.1 +/- 4.9 vs. 15.2 +/- 3.7, respectively; P less than 0.001). In vivo immunoneutralization of circulating somatostatin with a high-affinity and high-capacity antiserum produced no significant change in the rate of amylase secretion. These results suggest that cholecystokinin secretion is tonically inhibited by somatostatin and that this effect is mediated by locally secreted (paracrine) but not by circulating somatostatin.

Amylases↗
PubMed1987

Pantethine lipomodulation: evidence for cysteamine mediation in vitro and in vivo.

Recent human studies suggest rapid in vivo hydrolysis of the lipid-lowering drug, pantethine, to the vitamin pantothenic acid and the small aminothiol compound, cysteamine. To test whether the active agent is a hydrolysis product, we repeated three experimental models of pantethine's effect with pantothenate and cysteamine. In vitro experiments with human fetal fibroblasts showed equivalent modulation of cholesterol and methyl sterol synthesis by pantethine, cysteamine, or cystamine (the disulfide of cysteamine), but pantothenate had no effect. Similarly, in vivo experiments with 0.5% cholesterol-fed rabbits showed oral pantethine or equimolar cystamine significantly lowered plasma cholesterol, while pantothenate, cystine, and 2-hydroxyethyl disulfide did not. Lastly, diabetic male rats (40 mg/kg streptozotocin) fed 0.1% pantethine and lower plasma free fatty acids after 2 weeks than controls, an effect not seen with pantothenate and largely duplicated by cystamine. The efficacy of pantethine has previously been attributed to altered vitamin metabolism and increased coenzyme A concentration. Pantethine did increase CoA levels 45% in rat liver homogenates while equivalent amounts of cystamine or pantothenate did not. However, a causal relationship between CoA levels and pantethine's action as a hypolipemic agent has never been shown. At least in 3 independent experimental models, the lipomodulating effect of pantethine appears instead to be mediated by the hydrolysis product cysteamine.

Animals↗
PubMed1982

Cysteamine reduces serum gonadotropin concentrations in adult male rats.

We have examined the effects of cysteamine on the hypothalamic-pituitary-gonadal axis of the adult male rat. A single subcutaneous injection of cysteamine (300 mg/kg) reduces significantly (p less than or equal to 0.05 serum concentrations of LH, FSH and T. Cysteamine blocked LH secretion induced by castration and administration of naloxone and LHRH. Neither acute nor chronic treatment (7 days) altered the hypothalamic LHRH content. These results suggest that cysteamine acts to reduce pituitary responsiveness to LHRH, resulting in lower mean serum gonadotropin and testosterone concentrations. It is possible, however, that cysteamine acts also at the hypothalamus to reduce LHRH secretion and/or at the testes to reduce testosterone release.

Animals↗
PubMed1989

Confirmation of the protective effect of cysteamine in in vitro ultrasound exposures.

Armour and Corry (Radiat. Res. (1982) 89 369-380) reported that ultrasound-induced damage to in vitro Chinese hamster ovary cells was significantly reduced in the presence of cysteamine. The objective of this study was to attempt verification of this result. Four series of experiments were undertaken using in vitro cell suspensions, namely: (1) determination of the effect of cysteamine concentration on cell growth; (2) determination of the temperature dependence of ultrasonically induced cell damage; (3) determination of a dose-response relationship for the cytotoxicity of cysteamine; and (4) assessment of cell integrity and reproductive capacity in the presence or absence of cysteamine during ultrasonic exposure. Ultrasound parameters included a resonance frequency of 1 MHz, a continuous wave exposure duration of 5 min, and intensities from 0 to 21.6 W cm-2. The results indicated a dependence of ultrasound's efficacy on the medium's temperature during insonation and a significant reduction of ultrasound efficacy in compromising cellular integrity in the presence of cysteamine.

Animals↗
PubMed1989

Suppressing effect of cysteamine on the TSH-stimulated mitotic activity of the rat thyroid follicular cells in vivo.

We have examined the effect of the thiol agent-cysteamine, known to deplete the hypothalamus, the pancreas, the gut of somatostatin--on the basal and TSH-stimulated mitotic activity of the thyroid follicular cells (TFC) in adult male rats in vivo. The animals of different groups were administered cysteamine alone (300 mg/kg BW, s.c.), TSH alone (2IU, i.p.), or cysteamine with TSH jointly, the former agent being injected 2 hrs prior to the latter. In order to evaluate the thyroid mitotic activity, the metaphase-arrest technique was used in the study. It was shown that: 1. TSH significantly increased the mitotic activity of TFC, as compared to controls, 2. cysteamine alone had no effect on the TFC proliferation, 3. unexpectedly, cysteamine, when administered 2 hrs prior to TSH, suppressed the stimulatory effect of TSH on the mitotic activity of TFC.

Animals↗
PubMed1988

Intra-cerebral cysteamine infusions attenuate the motor response to dopaminergic agonists.

Previous studies have suggested that somatostatin neurons in the basal ganglia may be involved in motor activity. In the present experiments, the effects of cysteamine, a drug which reduces somatostatin levels, on the basal and dopamine-mediated motor activities were examined in the rat. Neither intra-striatal nor intra-accumbens infusions of cysteamine had any effect on motor activity prior to the administration of dopamine agonists. However, intra-striatal cysteamine infusions reduced the duration of the stereotypic behavior induced by systemic apomorphine. In addition, intra-accumbens infusions of cysteamine produced a slight reduction in the locomotor response induced by amphetamine. The direct intra-cerebral infusion of cysteamine produced a significant depletion in the levels of somatostatin at the site of injections as measured by radioimmunoassay. These results indicate that somatostatin neurons in the basal ganglia may modulate the motor responses following dopaminergic activation, and further support the presence of a dopamine-somatostatin interaction in this region.

Animals↗
PubMed1989

Protective effect of oral cysteamine against induction of gastric cancer by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of oral administration of cysteamine (2-aminoethanethiol hydrochloride) on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in inbred Wistar rats. Oral administration of 0.4% cysteamine in food after treatment with MNNG for 25 weeks significantly reduced the incidence and number of adenocarcinomas of the glandular stomach in experimental Week 52. Histological examination showed that adenocarcinomas that did develop in rats fed on cysteamine had high mucin-producing activity. Furthermore, oral administration of cysteamine caused a significant increase in serum gastrin level and significant decreases in the antral mucosal pH and the labeling indices of the antral mucosa. These findings indicate that cysteamine inhibits the development of gastric adenocarcinomas when given orally. This effect may be related to its ability to decrease proliferation of antral mucosal cells.

Adenocarcinoma↗
PubMed1990

Effects of cysteamine administration on plasma concentration of metabolites, pancreatic glucagon and insulin in the chicken.

1. The effects of subcutaneous injection of cysteamine (2-mercaptoethylamine, 300 mg/kg) were investigated in 5-6 week-old chickens. 2. In the short term (1 hr), cysteamine increased plasma levels of glucose, free fatty acids and insulin, and decreased that of alpha-amino non protein nitrogen. 3. In a longer term (17-24 hr), cysteamine increased the plasma level of glucose, did not modify those of alpha-amino non protein nitrogen, insulin and glucagon and decreased that of free fatty acids. 4. The disposal of an oral glucose load was impaired and the glucose-induced inhibition of pancreatic glucagon and stimulation of insulin release were blunted 17 hr after cysteamine administration. 5. Therefore, cysteamine exerts multiple effects on chicken pancreatic islet cells.

Animals↗
PubMed1988

Simultaneous protective and damaging effects of cysteamine on intracellular DNA of leukocytes.

Incubation of human leukocytes with cysteamine can lead to the induction of DNA strand breaks. The induction of breaks is biphasic with increasing concentration of scavenger. The number of breaks increases in a dose-dependent manner to a maximum and then decreases at higher concentrations. Catalase has been shown to prevent the production of breaks, indicating an involvement of hydrogen peroxide. Cysteamine reacts with oxygen to generate hydrogen peroxide but at higher concentrations it also reacts with hydrogen peroxide. Thus, the biphasic effect of cysteamine on leukocyte DNA may be due to the sum of two separate reaction pathways. (i) Cysteamine reacts with oxygen to generate hydrogen peroxide which leads to DNA strand breakage. (ii) At higher concentrations, it eliminates hydrogen peroxide by reacting with it, thereby protecting the cellular DNA. Other antioxidant scavengers such as WR2721, acetylcysteine and ascorbate can also autooxidize to produce strand breaks. Thiourea and tetramethylurea do not. When tested for their ability to protect cells against DNA damage from added H2O2, the agent which most damaging by itself, cysteamine, was also the most protective.

Cysteamine↗
PubMed2004

Cysteamine alters redox state, HIF-1alpha transcriptional interactions and reduces duodenal mucosal oxygenation: novel insight into the mechanisms of duodenal ulceration.

Our recent studies demonstrated a critical role of enhanced transcriptional activity of early growth response factor-1 (Egr-1) in early stages of cysteamine-induced duodenal ulcer in rats. Since cysteamine is also a reducing agent, the aims of this study were to determine the effect of cysteamine on proximal duodenal mucosa: (a) redox status, (b) mucosal oxygenation, (c) expression of hypoxia-inducible factor 1 (HIF-1alpha) and its binding to DNA, and (d) HIF-1alpha interaction with Egr-1 and other redox-sensitive transcription factors. Here we demonstrate for the first time that cysteamine treatment reduced the duodenal oxygenation by 19% (vs. baseline) and markedly increased the redox status in duodenal mucosa (p<0.05). Cysteamine increased HIF-1alpha expression, its binding to DNA, and enhanced the HIF-1alpha interactions with Egr-1 and other transcription factors (e.g., AP-1, AP-2, L-III BP, NF-E1, NF-E2, STAT4, and MRE), their binding to DNA. Thus, these data demonstrate the involvement of the redox-dependent regulatory mechanisms in the early stages of duodenal ulceration.

Animals↗
PubMed2006

Cysteamine-related agents could be potential antidepressants through increasing central BDNF levels.

Major depressive disorder (MDD) is a common mental disease, but with an unknown etiology. Antidepressants are the main biological treatment for MDD. However, current antidepressive agents have a slow onset of effect and a substantial proportion of MDD patients do not clinically improve, despite maximal medication. Thus, the exploration for new antidepressants with novel strategies may help to develop faster and more effective antidepressant agents. Studies in the recent decades have demonstrated that antidepressants increase central brain-derived neurotrophic factor (BDNF) levels and activating the BDNF-signaling pathway may play an important role in their therapeutic mechanism. Cysteamine is a natural product of cells and constitutes the terminal region of the CoA molecule. Recent work has found that cysteamine and a related agent, cystamine, have neuroprotective effects in Huntington's disease (HD) mice, through enhancing central BDNF levels. Furthermore, cystamine or cysteamine injection could increase serum BDNF levels in wild-type mice as well as HD mice. Since activation of the BDNF-dependent pathway plays an important role in the mechanism of antidepressant therapeutic action, cystamine or its derivatives could have potential antidepressant therapeutic effects. Among these agents, pantethine may be one of the most promising agents. It is a naturally occurring compound which can be administered orally with negligible side effects, and is metabolized to cysteamine. Further evaluation of the therapeutic and toxic effects of these cysteamine-related antidepressant agents in MDD animal models is needed before any clinical application.

Animals↗
PubMed2006

Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy.

PURPOSE: Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by the intracellular accumulation of cystine. Treatment involves intracellular cystine depletion with oral cysteamine. A wide spectrum of ocular pathologic features has been associated with nephropathic cystinosis. We used the largest documented cohort of patients in the world to study the posterior segment manifestations associated with infantile nephropathic cystinosis and to determine retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities. DESIGN: Cross-sectional study of a series of patients. PARTICIPANTS: Two hundred eight patients with infantile nephropathic cystinosis were studied at the National Institutes of Health between 1976 and 2004. METHODS: All patients underwent an ophthalmic evaluation. Patients older than 11 years also underwent Humphrey static perimetry, and electrophysiological testing was performed when possible. MAIN OUTCOME MEASURES: Visual acuity, retina findings, visual fields, and electroretinographic (ERG) findings. RESULTS: Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated ERG responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy. CONCLUSIONS: Infantile nephropathic cystinosis has posterior segment complications that can contribute to significant visual handicap. Early initiation of oral cysteamine therapy can reduce the frequency of posterior segment complications in cystinosis patients.

Administration, Oral↗
PubMed2005

Influence of cysteamine supplementation and culture in portable dry-incubator on the in vitro maturation, fertilization and subsequent development of mouse oocytes.

The need to transport oocytes and embryos between two laboratories have prompted us to evaluate the effects of in vitro maturation of immature mouse oocytes in a CO2-deficient dry heat portable incubator and subsequent in vitro development of these fertilized mouse oocytes in a standard CO2 incubator. In addition, the effects of cysteamine supplementation on maturation rate and embryonic development during in vitro maturation (IVM) and culture of embryos in the portable incubator were also investigated. Germinal vesicle stage mouse oocytes, recovered at 40-h post-FSH from 6- to 8-week-old C57BL/6xCBA F1 healthy female mice, were matured in vitro in a modified TCM-199 supplemented with or without 100 microM cysteamine in a standard incubator (5% CO2; 37 degrees C) or cultured in a CO2-deficient dry heat portable incubator for 5 h at 37 degrees C and thereafter transferred to a standard incubator for further culture. The addition of cysteamine in the IVM medium significantly improved maturation rates of the GV mouse oocytes to metaphase II stage. However, cysteamine supplementation in the culture medium did not significantly improve fertilization and blastocyst formation rates of IVM and ovulated oocytes, and in vivo-derived zygotes. Culture conditions in a CO2-deficient dry heat portable incubator did not adversely affect the developmental competence of in vivo-derived zygotes and in vitro matured mouse oocytes after IVF or parthenogenetic activation. Cysteamine supplement in the IVM medium could enhance nuclear maturation of these immature oocytes during shipment.

Animals↗
PubMed2002

Cysteamine pre-treatment reduces pentylenetetrazol-induced plasticity and epileptiform discharge in the CA1 region of rat hippocampal slices.

The effects of prior treatment of cysteamine, a somatostatin inhibitor, on pentylenetetrazol (PTZ) induced epileptic and plastic changes in CA1 excitability were examined. Population spikes were evoked by activation of Schaffer collaterals with a range of stimulation intensities. Changes in the population spike and epileptiform amplitudes were used as indices to quantify the effects of PTZ exposure in the control and cysteamine pre-treated slices. Cysteamine pre-treatment decreased baseline CA1 population spike amplitude following high intensity stimulation of Schaffer collaterals. Following PTZ application directly to the slices, cysteamine diminished the increased population spike and epileptiform amplitudes which were normally observed following collateral stimulation. Magnesium-free medium induced epileptiform activity was also significantly reduced with cysteamine pre-treatment. It is concluded that somatostatin may be involved in PTZ-induced epileptic and plastic changes in CA1 excitability.

Action Potentials↗
PubMed1985

Duodenal ulcerogens cysteamine and propionitrile induce gastroduodenal motility alterations in the rat.

The effects of the duodenal ulcerogens cysteamine and propionitrile on gastroduodenal myoelectric activity and intraluminal pressure in the fasted rat as well as on contractility of isolated gut muscle strips were investigated. Duodenal ulcerogens, unlike the nonulcerogen but toxic analogue ethanolamine, caused an early disruption of the myoelectric migrating complex, a marked increase in the spiking activity, and a decrease in the frequency of the slow waves in the duodenum. Both the increased spiking activity and the decreased slow wave frequency were dose dependent for cysteamine. Manometrically recorded contractions at the stomach corpus, midantrum, and antropyloric region as well as in the proximal duodenum of the conscious rat showed decreased contractions at the corpus and midantrum and an increase at the pyloric and duodenal sites during an intravenous infusion of cysteamine. In vitro studies demonstrated that circularly or longitudinally cut muscle strips taken from different regions of the stomach and duodenum responded to cysteamine with increased contractility. In summary, the duodenal ulcerogens cysteamine and propionitrile rapidly induce motor abnormalities in the stomach and duodenum of the rat. In vitro studies suggest that a cholinergic mechanism may be involved. It is possible that motor changes play a role in the pathogenesis of the experimentally induced duodenal ulcers.

Acetylcholine↗
PubMed1965

The role of sulphur, sulphide and reducible dyes in the enzymic oxidation of cysteamine to hypotaurine.

1. Cysteamine is oxidized to hypotaurine by an enzyme extracted from horse kidney, with sulphur or sulphide acting as a cofactor. It has been now found that, when the enzyme is omitted, sulphur and sulphide are able to catalyse the oxidation of cysteamine to cystamine by molecular oxygen. 2. Methylene blue may be used in catalytic amounts as a cofactor in the enzymic oxidation of cysteamine to hypotaurine in the place of sulphur or sulphide. The effect of methylene blue is not light-dependent and is not abolished by catalase. Other redox dyes with E'(0) higher than that of methylene blue are also used as cofactors. 3. A property common to all the cofactors is that they are necessary for the enzymic process in catalytic amounts, though they depress the final amount of hypotaurine produced when added over a critical concentration. All the cofactors share also the property of being catalysts for the non-enzymic oxidation of cysteamine to cystamine. 4. Methylene blue is reduced by cysteamine under anaerobic conditions, and is reoxidized in the presence of air. The rate of the reduction is not accelerated by the enzyme, indicating that the dye does not act in this reaction as a hydrogen carrier from the enzyme to oxygen. The possible mechanism of action of methylene blue and of the other cofactors is discussed.

Animals↗