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At least 19 recordsLinked to original sources
PubMed1986

Cystamine-enkephalin dimer. Syntheses and biological activities of enkephalin analogs containing cystamine and cysteamine.

A cystamine-enkephalin dimer, containing two molecules of [D-Ala2, Leu5] enkephalin cross-linked at the COOH-terminal leucine residue with cystamine, (NH2-CH2-CH2-S-)2, has been synthesized in order to examine directly the dimerization effect of an enkephalin molecule on the opiate receptor interactions. In a comparison of potencies against [3H]-[D-Ala2,D-Leu5] enkephalin (3H-DADLE) and [3H]-[D-Ala2,MePhe4,Gly-ol5] enkephalin (3H-DAGO) as delta and mu tracers, respectively, enkephalin dimer showed a very high affinity, especially for the delta opiate receptors. Dimer was almost threefold more potent than DADLE, which is one of the most utilized delta ligand to date. When the binding affinity of cystamine-dimer was compared with that of its reduced thiol-monomer, namely [D-Ala2,Leu5,cysteamine6] enkephalin, the increment in affinity was four to fivefold for both delta and mu receptors. The results strongly indicate that the dimeric enkephalin is more potent presumably due to the simultaneous interaction with the two binding sites of the opiate receptors.

Animals↗
PubMedDate not supplied

Application of cystamine and N,N'-Bis(glycyl)cystamine as linkers in polysaccharide-protein conjugation.

Pneumococcal polysaccharide type 6B, 14, or 23F (35-70 kDa) was activated with cyanogen bromide and modified with cystamine. After reduction of the spacer, the thiol-containing (i.e. cysteamine-modified) polysaccharide obtained was added in a 5-10-fold molar excess to bromoacetylated tetanus toxoid to give thioether-linked polysaccharide-protein conjugates in a yield of 10-20%. This approach failed for preparing a type 19F polysaccharide-protein conjugate, possibly due to intramolecular elimination of cysteamine from the reduced 19F polysaccharide. When N,N'-bis(glycyl)cystamine was introduced as a spacer molecule, the elimination of the reduced spacer was suppressed, thus allowing preparation of a 19F polysaccharide-tetanus toxoid conjugate (15%).

Carbohydrate Conformation↗
PubMed1995

The uptake and metabolism of cystamine and taurine by isolated perfused rat and rabbit lungs.

Cystamine has been reported to be taken up and metabolized to taurine by the rat lung slices. The objectives of the present study were to compare the uptake and metabolism of cystamine and taurine in isolated perfused lungs of rats and rabbits and examine the action of glutathione (GSH) on these processes. The uptake and metabolism of [14C]cystamine and [14C]taurine were studied at 20 microM concentrations each in isolated, ventilated, perfused rat and rabbit lungs. In some experiments, 1 microM GSH was included in the perfusate prior to the addition of cystamine. The perfusate and lung homogenate samples were analyzed for cystamine and its metabolites. [14C]cystamine uptake with and without GSH was 13 and 14% in rat lungs and 37 and 32% in rabbit lungs. [14C]taurine uptake was 10% in rat and 37% in rabbit lungs. The levels of radiolabeled cystamine and its metabolites were (nmol/g lung): 20.0 +/- 10.0 and 11.5 +/- 7.0 cystamine, 4.7 +/- 0.5 and 3.2 +/- 0.5 hypotaurine and 56.0 +/- 16.0 and 49.4 +/- 6.0 taurine, for rat and rabbit lungs, respectively, when perfused without GSH; and 18.0 +/- 1.0 and 2.5 +/- 0.5 cystamine, 6.6 +/- 0.5 and 18 +/- 10 hypotaurine and 60.0 +/- 12.0 and 33.6 +/- 9.0 taurine, when perfused with GSH, for rats and rabbit lungs, respectively. Taurine did not undergo any further metabolism in either of the lungs. These studies show that cystamine is taken up and metabolized to taurine via hypotaurine by both rat and rabbit lungs in a manner similar to that seen in rat lung slices. However, rat lungs have much greater capacity to metabolize cystamine to taurine than rabbit. Inclusion of GSH did not significantly alter the ability of lungs to sequester cystamine from the perfusate but the metabolism of hypotaurine to taurine was markedly decreased in rabbit lungs. Taurine was not metabolized any further. It is concluded that rat and rabbit lungs take up cystamine from the systemic circulation, metabolize it via hypotaurine to taurine, and effuse most of the latter in to the circulation.

Animals↗
PubMed2005

Treatment of YAC128 mice and their wild-type littermates with cystamine does not lead to its accumulation in plasma or brain: implications for the treatment of Huntington disease.

Cystamine is beneficial to Huntington disease (HD) transgenic mice. To elucidate the mechanism, cystamine metabolites were determined in brain and plasma of cystamine-treated mice. A major route for cystamine metabolism is thought to be: cystamine --> cysteamine --> hypotaurine --> taurine. Here we describe an HPLC system with coulometric detection that can rapidly measure underivatized cystamine, cysteamine and hypotaurine, as well as cysteine and glutathione in the same deproteinized tissue sample. A method is also described for the coulometric estimation of taurine as its isoindole-sulfonate derivative. Using this new methodology we showed that cystamine and cysteamine are undetectable (< or = 0.2 nmol/100 mg protein) in the brains of 3-month-old HD transgenic (YAC128) mice (or their wild-type littermates) treated daily for 2 weeks with cystamine (225 mg/kg) in their drinking water. No significant changes were observed in brain glutathione and taurine but significant increases were observed in brain cysteine. Cystamine and cysteamine were not detected in the plasma of YAC128 mice treated daily with cystamine between the ages of 4 and 12 or 7 and 12 months. These findings suggest that cystamine is not directly involved in mitigating HD but that increased brain cysteine or uncharacterized sulfur metabolites may be responsible.

Animals↗
PubMed2002

Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormally expended polyglutamine domain. There is no effective treatment for HD; however, inhibition of caspase activity or prevention of mitochondria dysfunction delays disease progression in HD mouse models. Similarly administration of cystamine, which can inhibit transglutaminase, prolonged survival of HD mice, suggesting that inhibition of transglutaminase might provide a new treatment strategy. However, it has been suggested that cystamine may inhibit other thiol-dependent enzymes in addition to transglutaminase. In this study we show that cystamine inhibits recombinant active caspase-3 in a concentration-dependent manner. At low concentrations cystamine is an uncompetitive inhibitor of caspase-3 activity, becoming a non-competitive inhibitor at higher concentrations. The IC(50) for cystamine-mediated inhibition of caspase-3 activity in vitro was 23.6 microm. In situ cystamine inhibited in a concentration-dependent manner the activation of caspase-3 by different pro-apoptotic agents. Additionally, cystamine inhibited caspase-3 activity to the same extent in cell lines stably overexpressing wild type tissue transglutaminase (tTG), a mutant inactive tTG, or an antisense for tTG, demonstrating that cystamine inhibits caspase activity independently of any effects it may have on the transamidating activity of tTG. Finally, treatment with cystamine resulted in a robust increase in the levels of glutathione. These findings demonstrate that cystamine may prolong neuronal survival and delay the onset of HD by inhibiting caspases and increasing the level of antioxidants such as glutathione.

Caspase 3↗
PubMed2006

Cystamine and cysteamine prevent 3-NP-induced mitochondrial depolarization of Huntington's disease knock-in striatal cells.

Abstract Cystamine significantly improved motor deficits and extended survival in mouse models of Huntington's disease (HD); however, the precise mechanism(s) by which cystamine and the related compound cysteamine are beneficial remain to be elucidated. Using clonal striatal cell lines from wild-type (STHdhQ7/HdhQ7) and mutant huntingtin knock-in (STHdhQ111/HdhQ111) mice, we have tested the hypothesis that cystamine and cysteamine could be beneficial by preventing the depolarization of mitochondria in cell cultures. Treatment with 3-nitroproprionic acid (3-NP), a mitochondrial complex II inhibitor, induces mitochondrial depolarization and cell death of mutant HD striatal cells but not of wild-type cells. The 3-NP-mediated decrease in the mitochondrial membrane potential was attenuated by 50 microm cystamine and completely inhibited by 250 microm cystamine. Similar results were obtained using cysteamine (50-500 microm). In addition, both cystamine and cysteamine significantly attenuated the 3-NP-induced cell death. Treatment of mutant HD striatal cells with 3-NP resulted in a robust decrease in the cellular and mitochondrial levels of glutathione (GSH) compared with cells exposed to the vehicle alone. Pre-treatment of the cells with cystamine and cysteamine completely prevented the 3-NP-mediated decrease in cellular and mitochondrial GSH levels. Incubation with L-buthionine (S,R) sulfoximine (BSO) 250 microm in combination with cystamine (250 microm) or cysteamine (250 microm) prior to being treated with 3-NP completely prevented the beneficial effects of cystamine and cysteamine on the 3-NP-mediated mitochondrial depolarization. These results demonstrate that cystamine and cysteamine prevent the 3-NP-induced mitochondrial depolarization of HD striatal cell cultures.

Animals↗
PubMed1986

Cystamine induces toxicity in hepatocytes through the elevation of cytosolic Ca2+ and the stimulation of a nonlysosomal proteolytic system.

Infusion of cystamine into the isolated, perfused rat liver resulted in tissue damage preceded by the formation of cystamine-protein mixed disulfides which were mainly detected in the plasma membrane fraction. Hepatotoxicity was prevented when dithiothreitol was infused after cystamine or when the calcium antagonist, verapamil, was co-infused with the disulfide. In isolated hepatocytes, the formation of cystamine-protein mixed disulfides was associated with an inhibition of plasma membrane Ca2+-ATPase activity and a decreased rate of Ca2+ efflux from the cells. This resulted in intracellular Ca2+ accumulation which was followed by a stimulation of both phospholipid hydrolysis and proteolysis, as indicated by enhanced rates of release of radioactivity from hepatocytes prelabeled with [14C]arachidonate and [14C]valine, respectively. Preincubation of hepatocytes with the calmodulin inhibitor, calmidazolium, or with the phospholipase inhibitors, chlorpromazine and dibucaine, inhibited the stimulation of [14C]arachidonate release by cystamine. However, none of these agents prevented the onset of cystamine toxicity in hepatocytes. In contrast, pretreatment of the cells with antipain or leupeptin, two inhibitors of Ca2+-activated proteases, abolished the stimulation of proteolysis by cystamine and also protected the cells from cystamine toxicity. Our results suggest that the perturbation of intracellular Ca2+ homeostasis by cystamine is caused by the inhibition of Ca2+ efflux associated with the formation of cystamine-protein mixed disulfides in the plasma membrane and that subsequent cytotoxicity results from Ca2+-activation of a nonlysosomal proteolytic system.

Animals↗
PubMed1982

Cystamine-Sepharose. A probe for the active site of gamma-glutamylcysteine synthetase.

gamma-Glutamylcysteine synthetase, previously known to be potently inhibited by cystamine, has been found to bind covalently to cystamine-Sepharose. ATP facilitates, whereas glutamate plus magnesium ions inhibit, binding of the enzyme to cystamine-Sepharose. A large fraction of the enzyme applied to columns of cystamine-Sepharose binds by forming a disulfide bond between cysteamine-Sepharose and a sulfhydryl group at or near the active site of the enzyme. The enzyme may be released by treatment with dithiothreitol. Some of the enzyme applied to such columns is inactivated and not bound covalently to the column. That the enzyme does not bind to columns of S-(S-methyl)cysteamine-Sepharose, whereas free S-(S-methyl)cysteamine is a potent inhibitor, indicates that a cysteamine-S disulfide moiety derived from the external cysteamine residue of cystamine-Sepharose is the critical group recognized by the enzyme. The observed partitioning of the enzyme on columns of cystamine-Sepharose between covalently column-bound enzyme and nonbound inactivated enzyme suggests that the reactive enzyme sulfhydryl group forms a disulfide linkage with the sulfur atom at the immobilized end of cystamine to link the enzyme to the column and to liberate free cysteamine, and also that the enzyme interacts with the external cysteamine moiety of the bound cystamine. The latter may occur if the free cysteamine released is spontaneously oxidized to free cystamine followed by its inhibition of the enzyme, or if there is a direct reaction between the enzyme-reactive sulfhydryl group and the sulfur atom of the external cysteamine moiety of cystamine-Sepharose.

Animals↗
PubMed1996

Cystamine inhibits human immunodeficiency virus-1 replication in cord blood-derived mononuclear phagocytes and lymphocytes.

The effects of cystamine on the human immunodeficiency virus (HIV-1) expression in cord blood monocytes-derived macrophages (CBMDM) and lymphocytes were investigated. Cystamine suppressed HIV-1 expression in CBMDM and lymphocytes in a concentration-dependent fashion as determined by HIV-1 reverse transcriptase (RT) activity. This inhibitory effect of cystamine occurred with all five HIV-1 strains (both laboratory adopted and fresh isolates) tested in the study. The addition of cystamine to cultures of HIV-1 chronically infected CBMDM also suppressed 80% to 90% of RT activity in comparison with untreated controls. Cystamine also decreased HIV-1 protein expression in CBMDM as determined by indirect immunofluorescence assay. The inhibitory effects of cystamine on HIV-1 did not appear to be caused by toxicity to CBMDM or lymphocytes because there was no change in cell viability or cellular DNA synthesis as evaluated by trypan blue dye exclusion and [3H]-thymidine incorporation at doses of cystamine that inhibit the virus. HIV-1 infected CBMDM or lymphocyte cultures (without cystamine treatment) demonstrated giant syncytium formation or cytopathic effect (CPE), respectively, whereas cystamine-treated cultures lacked the giant syncytia or CPE induced by HIV-1 infection. Thus, these observations indicate that cystamine may have the potential to limit HIV-1 replication in monocytes/macrophages and lymphocytes in vivo and may represent a potentially useful compound in the treatment of pediatric HIV-1 infection and acquired immunodeficiency syndrome.

Antiviral Agents↗
PubMed1984

Cystamine augments the stimulation of DNA synthesis by peptide growth factors and microtubule-disrupting agents in cultures of 3T3 mouse fibroblasts.

Cystamine together with colchicine markedly enhanced the uptake of [3H]-thymidine into DNA of quiescent cultures of insulin-stimulated Swiss 3T3 mouse fibroblasts. Flow cytofluorometric analyses showed an increased rate of transition of cells from G0/G1----S + G2 in response to combinations of insulin, colchicine, and cystamine. Cystamine, the most effective of several thiol compounds, gave maximal augmentation at 200 microM and was toxic at 300-500 microM. Amplification of DNA synthesis by cystamine was also obtained with epidermal growth factor, vasopressin, and 0.5% fetal bovine serum. Combinations of cystamine and other microtubule-disrupting agents such as nocodazole, maytansine, and podophyllotoxin enhanced DNA synthesis in insulin-stimulated cells. In experiments involving sequential addition of agents, significant enhancement of DNA synthesis was observed when the addition of colchicine to cystamine-treated cells was delayed or conversely when the addition of cystamine to colchicine-treated cultures was delayed. This reciprocal interaction between cystamine and colchicine suggests that a prereplicative intermediate accumulates in response to the action of these dissimilar compounds. We consider the possibility that cystamine may act by forming mixed disulfides with thiol groups of unknown protein(s) that regulate DNA replication.

Animals↗
PubMed1986

Amelioration of carbon tetrachloride-induced hepatic necrosis by post-toxicant treatment with cystamine.

A quantitative animal model was developed to study amelioration of carbon tetrachloride-induced hepatic injury by post-toxicant administration of cystamine. Amelioration of CCl4-induced injury by post-toxicant cystamine treatment was compared to prevention of injury by cystamine pretreatment and possible mechanisms of the post-toxicant cytoprotective effect were investigated. Pretreatment of rats with cystamine dihydrochloride (300 mg/kg, p.o.) 30 min prior to CCl4 (0.25 ml/kg, i.p.) prevented CCl4-induced hepatic necrosis, plasma enzyme elevations, and hepatic calcium accumulation. When administered up to 12 h after CCl4, a single oral dose of cystamine inhibited necrosis in a dose-dependent manner, but did not reduce CCl4-induced plasma enzyme elevation or hepatic calcium accumulation. Cystamine post-treatment, therefore, does not appear to inhibit toxicant-induced influx of extracellular calcium into toxicant-damaged cells. This also suggests that the influx of extracellular calcium does not necessarily constitute an irreversible event leading to cell death. The mild hypothermia induced by post-toxicant treatment with cystamine did not delay the appearance of the lesion. Evidence for a slightly earlier regeneration of hepatic tissue was noted when cystamine was administered 12 h after CCl4. However, this effect was observed too long after exposure to the toxicant to account for the protection from necrosis observed 24 h after CCl4.

Administration, Oral↗
PubMed2006

Biodegradable cystamine spacer facilitates the clearance of Gd(III) chelates in poly(glutamic acid) Gd-DO3A conjugates for contrast-enhanced MR imaging.

Poly(L-glutamic acid) (PGA)-cystamine-[gadolinium (Gd)-DO3A] was prepared in high yield with a high Gd-DO3A conjugation efficiency. Approximately 55% of the carboxylic groups in PGA were loaded with Gd-DO3A via cystamine as the spacer. Cystamine can be readily cleaved by endogenous thiols to release the Gd(III) chelates from the conjugate facilitating Gd(III) excretion after the magnetic resonance imaging (MRI). The contrast-enhanced MRI with PGA-cystamine-(Gd-DO3A) was investigated in mice bearing MDA-MB-231 breast carcinoma xenografts. PGA-1,6-hexanediamine-(Gd-DO3A), a paramagnetic polymer conjugate of a nondegradable spacer, was used as a control. Both conjugates resulted in similar contrast enhancement in the heart, vasculature, liver and kidneys in the first hour post injection. More substantial signal intensity reduction was observed for PGA-cystamine-(Gd-DO3A) in these organs than PGA-1,6-hexanediamine-(Gd-DO3A) due to release of the Gd chelates from PGA-cystamine-(Gd-DO3A) after the cleavage of the disulfide spacer by the endogenous thiols. Both conjugates resulted in similar tumor enhancement with approximately 70% increased signal intensity in the tumor periphery and 10-40% increased signal intensity in tumor interstitium. No cross-reaction was observed between PGA-cystamine-(Gd-DO3A) and human serum albumin, a plasma protein containing a cysteine residue. PGA-cystamine-(Gd-DO3A) resulted in significantly lower Gd(III) tissue retention than PGA-1,6-hexanediamine-(Gd-DO3A) 10 days after the injection in the mice (P<.05). The conjugation of Gd(III) chelates to biomedical copolymers via the degradable disulfide spacer resulted in significant contrast enhancement in the blood pool and tumor tissue but minimal long-term Gd(III) tissue retention.

Absorbable Implants↗
PubMed1995

Cystamine inhibits HIV type 1 replication in cells of monocyte/macrophage and T cell lineages.

The effects of cysteamine (2-aminoethanethiol, MEA) and its disulfide, cystamine, on the human immunodeficiency virus (HIV-1) expression in chronically infected promonocytic cells (U1), T cell line (ACH-2), and peripheral blood monocyte-derived macrophages (MDM) were investigated. U1 and ACH-2 cells constitutively express low levels of virus, which is increased by the addition of tumor necrosis factor (TNF-alpha), interleukin 6 (IL-6), granulocyte-macrophage-colony-stimulating factor (GM-CSF), and other inducers. Cystamine, in noncytotoxic doses, suppressed in a concentration-dependent fashion the induction of HIV-1 expression mediated by TNF-alpha, IL-6, GM-CSF, and monokine-enriched monocyte culture supernatants in both U1 and ACH-2 cells as determined by HIV-1 reverse transcriptase (RT) activity. Similarly, HIV-1 expression was substantially reduced in the cystamine-treated primary MDM cultures compared with the untreated control cultures. The addition of cystamine into HIV-1 chronically infected MDM (12 days after infection was established) also suppressed 80-90% of RT activity in comparison to the untreated controls. HIV-1 (Bal) infected MDM cultures (without cystamine treatment) demonstrated giant syncytium formation, whereas cystamine-treated cultures lacked the giant syncytia induced by HIV-1 infection. Cystamine also inhibited LPS-induced TNF production in MDM. In contrast to cystamine, cysteamine showed no significant effects on either the monokine-induced HIV-1 expression in U1 or ACH-2 or acute and chronic HIV-1 infection in MDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗
PubMed2000

Cystamine transport in spheroplasts of Saccharomyces cerevisiae.

This work is the first demonstration that cystamine is actively accumulated in spheroplasts of Saccharomyces cerevisiae. We have identified and quantitatively determined the transported cystamine in extracts of spheroplasts that have been incubated over different time periods and in the presence of different amounts of cystamine. The method used, already reported in literature for the identification of natural aliphatic polyamines in biological fluids, consists of a derivatization of spheroplast extracts with dabsyl-chloride and subsequent chromatographic analysis in HPLC. Our results show that cystamine accumulation is a function of time, it increases up to 2.5 min then decreases. Transport is inhibited by natural aliphatic polyamines, which, at the same concentration of cystamine (1 mM), cause a decrease in cystamine transport of about 90% for spermidine, 50% for spermine and only 15% for putrescine. Furthermore, transport is energy-dependent as demonstrated by a significant decrease observed in the presence of 2,4-dinitrophenol, ouabain and vanadate. In particular 0.2 mM ouabain causes a decrease of more than 60% in cystamine transport. Our data suggest that cystamine is transported in Saccharomyces cerevisiae spheroplasts via the same polyamine transport system(s) known to be operating in higher eukaryotic cells.

Adenosine Triphosphatases↗
PubMed1989

The accumulation of cystamine and its metabolism to taurine in rat lung slices.

The objective of these studies was to determine the accumulation and fate of the disulphide, cystamine by rat lung slices. Cystamine was accumulated by two active uptake systems that obeyed saturation kinetics, with apparent Km values of 12 and 503 microM, and maximal rates of 530 and 5900 nmol/g wet weight/hr respectively. The high affinity system was competitively inhibited by the diamine, putrescine and the herbicide paraquat, which are themselves accumulated. Thus, this pulmonary uptake process appears to be identical for all three compounds. In contrast, the low affinity process was not inhibited by putrescine, and this process results from the diffusion of cystamine into the cell and its subsequent metabolism. Upon accumulation, cystamine was metabolised, predominantly to the sulphonic acid, taurine, with 10-20% of the intracellular label covalently binding to protein. Conversion to taurine was unaffected by amine oxidase inhibitors, but was decreased after GSH depletion, suggesting that pulmonary cystamine metabolism is glutathione-dependent, and is not mediated by diamine oxidase. Both cystamine and taurine have been implicated as antioxidants, and we suggest that cystamine is actively accumulated by the lung as part of the process to protect pulmonary tissue against oxidative stress.

Animals↗
PubMed2004

Different inhibition characteristics of intracellular transglutaminase activity by cystamine and cysteamine.

The treatment of cystamine, a transglutaminase(TGase) inhibitor, has beneficial effects in several diseases including CAG-expansion disorders and cataract. We compared the inhibition characteristics of cystamine with those of cysteamine, a reduced form of cystamine expect-ed to be present inside cells. Cystamine is a more potent inhibitor for TGase than cysteamine with different kinetics pattern in a non-reducing condition. By contrast, under reducing conditions, the inhibitory effect of cystamine was comparable with that of cysteamine. How-ever, cystamine inhibited intracellular TGase activity more strongly than cysteamine despite of cytoplasmic reducing environment, suggest-ing that cystamine itself inhibits in situ TGase activity by forming mixed disulfides.

Cell Line, Tumor↗