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PubMed1989

Selective decrease of duodenal phosphoprotein phosphatase activity is a general property of duodenal ulcerogens.

A phosphoprotein phosphatase (PPPase) is inhibited in rat duodenal mucosal cells very early after a single s. c. injection of the duodenal ulcerogens cysteamine, propionitrile and mepirizole. The effect seems to be independent of their effects on gastric acid secretion and on duodenal suppression of alkaline secretion. The enzyme inhibition is dose- and time-dependent under in vivo conditions. The inhibition of the PPPase activity is enzyme-selective at the level of mucosal cells in the duodenum. Under in vitro conditions, none of the duodenal ulcerogens inhibited PPPase activity. The results indicate that the effect of the ulcerogens on PPPase activity is probably exerted indirectly. When given simultaneously in vivo, propionitrile attenuated the inhibitory effects of cysteamine on the PPPase activity. However, both propionitrile and cysteamine potentiated the effect of mepirizole on PPPase depletion. These data indicate that cysteamine and propionitrile may act through the same mechanism when depleting PPPase activity. The mechanism of the decrease of duodenal protein phosphatase activity by mepirizole is probably different from the other duodenal ulcerogens.

Animals↗
PubMed1986

Protection against duodenal ulceration by somatostatins.

The purpose of our investigation was to study the effect of two somatostatin analogs (SMS 201-995 and 008) on duodenal ulcer disease induced by cysteamine in rats. Male Wistar rats were given cysteamine (28 mg/100 g body wt.) by rubber stomach tube three times in a single day. All animals of the test group were injected subcutaneously either with SMS 201-995 in different doses or with 008. On the 3rd day stomach, duodenum, and adrenal glands were macroscopically examined for lesions (duodenal ulceration, gastrointestinal bleeding, adrenal hemorrhage). Our results showed a dose-dependent effect of SMS 201-995 on the mortality, incidence, and intensity of cysteamine-induced duodenal lesions in rats. The incidence and the intensity of gastrointestinal bleeding and adrenal hemorrhage were also dose-dependently reduced by SMS 201-995. There was no definite effect of 008 on the mortality, incidence, or intensity of cysteamine-induced duodenal ulceration.

Adrenal Glands↗
PubMed1986

Gastric mucosal protection by somatostatins.

Somatostatin and somatostatin derivatives were tested for their ability to prevent gastric hemorrhagic erosions induced by ethanol. The somatostatin analogues were cyclohexapeptides with the rearranged amino acids 7-14 of somatostatin (S-14): Phe-Thr-Lys(Z)-Trp-Phe-D-Pro(I), Phe-Thr-Lys-Trp-Phe-D-Pro(II), Phe-Thr-Lys-D-Trp-Phe-Tyr(III) and Tyr-Phe-D-Trp-Lys-Thr-Phe(IV). In Spraque-Dawley rats receiving ethanol alone, the lesions involved 18.1 +/- 3.2% of the glandular stomach while after S- 14 (10(-7) mol/rat) the lesioned area was reduced to 6.3 +/- 1.1% (p less than 0.05). Peptide I and peptide II (doses 10(-7) -10(-9) mol/rat) decreased the area of erosions to less than 5%. Peptide III was less active and peptide IV was inactive. In rats with chronic gastric fistula S- 14 and peptide II decreased the cysteamine-stimulated acid secretion without affecting the pepsin output. We also continuously measured the intraluminal pH in the stomach of Wistar rats which develop gastric erosions after subcutaneous injection of cysteamine. The erosions were reduced by S- 14 or SMS while the intraluminal pH did not change under the influence of cysteamine or the combination of cysteamine plus S- 14 or SMS. Thus some of the peptides derived from S- 14 exert prominent gastric mucosal protection without influencing gastric secretion.

Animals↗
PubMed1987

Differential effects of radical scavengers on X-ray-induced mutation and cytotoxicity in human cells.

The cytotoxic and mutagenic effects of X irradiation on a human lymphoblast cell line were examined in the presence of two radioprotective agents which modulate damage to DNA. The cells were treated with X rays alone or in the presence of either dimethyl sulfoxide or cysteamine. Surviving fraction and mutation to trifluorothymidine resistance (tk locus) and to 6-thioguanine resistance (hgprt locus) were measured. Survival was enhanced when the cells were irradiated in the presence of dimethyl sulfoxide; the D0 rose from 58 to 107 rad. However, at both genetic loci the induced mutant fractions were identical in the presence or absence of dimethyl sulfoxide. Survival was enhanced to a greater degree when the cells were irradiated in the presence of cysteamine; the D0 rose from 58 to 200 rad. Cysteamine also protected the cells from X-ray-induced mutation; the frequencies of X-ray-induced mutation at both the tk and hgprt loci were reduced by 50-75%. No protective effects were observed unless dimethyl sulfoxide or cysteamine was present during irradiation. These findings are discussed in terms of the hypothesis that, unlike for cell killing, radiation-induced mutagenesis in human lymphoblast cells is not mediated by the actions of aqueous free radicals, but rather by the direct effects of ionizing radiation.

Cell Line↗
PubMed1985

Damage in DNA irradiated with 1.2 MHz ultrasound and its effect on template activity of DNA for RNA synthesis.

When aqueous DNA solution was irradiated with 1.2 MHz continuous ultrasound in the presence of cysteamine, the number of ultrasound-induced double-strand breaks of DNA was not influenced, but the number of ultrasound-induced single-strand breaks of DNA was reduced to about one-fifth that of the irradiated control. When the effect of cysteamine on the template activity of the ultrasound-irradiated DNA was investigated, the cysteamine was found to exert a leveling effect on the linear decrease of the template activity against ultrasonic intensity. Since cysteamine was known as an effective radical scavenger, the results of the experiment were regarded to suggest that (1) the double-strand breaks were exclusively induced by the mechanical effect of ultrasound, (2) the majority of single-strand breaks were produced by water radicals arising from cavitation, (3) the initial part in the decrease of the template activity was due to the double-strand breaks arising from mechanical effect, and (4) the further decrease of the template activity depended mainly on the single-strand breaks arising from water radicals.

Cysteamine↗
PubMed1984

Evidence for selective release of somatostatin-14 and somatostatin-28(1-12) from rat hypothalamus.

Cysteamine administration to rats results in a marked depletion of hypothalamic somatostatin-14 (SS14) and a decrease of the potassium-evoked in vitro release of SS14 without a significant change in the content or release of somatostatin-28(1-12)-like immunoreactivity (SS28(1-12)-L1). Furthermore, cysteamine enhances the spontaneous release and markedly potentiates the potassium-evoked release of SS14 in the in vitro slice preparation. However, in vitro-administered cysteamine does not alter the spontaneous or potassium-evoked release of SS28(1-12)-LI. Immunohistochemical visualization of hypothalamic neuronal cell bodies and fibers following cysteamine administration shows a disappearance of the SS14 immunoreactive fibers and cell bodies with no apparent change in the SS28(1-12) immunoreactive fibers and cell bodies. These data suggest that, in rat hypothalamus, selective release of SS14 and SS28(1-12) can occur. The results are discussed in relation to possible sites of storage and release of the somatostatin-related peptides from synaptic nerve terminals.

Animals↗
PubMed1984

Factors associated with the preincubation effect of hypoxic cell sensitizers in vitro and their possible implications in chemosensitization.

The enhancement of melphalan toxicity was observed by preincubation of V-79- 379A cells in spinner culture with multiple doses of misonidazole (miso) or SR-2508 under hypoxic conditions. Chemosensitization was shown to be a function of sensitizer concentration and duration of exposure to the alkylating agent. A preincubation exposure of cells with 5 mM miso reduced endogenous cell thiols to less than 5% of controls and enhanced melphalan toxicity by a factor of 4.7. Cells preincubated with miso not only had lower levels of nonprotein thiols, but also were shown to have altered levels of intracellular calcium and a lower threshold to oxidative stress as measured by toxicity to cysteamine or H2O2. Preincubated cells, hypoxic cells, and cells receiving moderate hyperthermia (42.5 degrees C for 3 hr) all showed increased sensitivity to either cysteamine or H2O2. The increased killing of preincubated cells by cysteamine was shown to be similar to that of H2O2, and the dramatic reduction of cysteamine toxicity by catalase indicated H2O2 was the major reaction associated with this effect. These results indicate that preincubated cells exhibit a variety of biological effects that may significantly influence their response to further treatment with drugs or radiation, especially where peroxidative and free radical mechanisms are involved. The depletion of endogenous thiols, calcium disturbance, and vulnerability to oxidative stress are factors to be considered when interpreting mechanisms of combined drug action and effects that may potentially be exploited in terms of therapeutic gains.

Animals↗
PubMed1984

Role of local secretory and motility changes in the pathogenesis of experimental duodenal ulcer.

Changes in gastric acid and pepsin secretions do not fully account for the duodenal ulcerogenic effect of cysteamine or propionitrile in the rat. We investigated the role of pancreatic and biliary secretions as well as motility changes in the duodenum. Bypass of bile to the jejunum and/or ablation of pancreatic secretion or drainage of these secretions through chronic duodenal fistula aggravated the cysteamine-induced duodenal ulcers. Biliary bypass to the proximal duodenum, on the other hand, decreased the incidence and intensity of experimental duodenal ulcers. An increased and dopamine-sensitive myoelectric activity caused by cysteamine or propionitrile was recorded in the proximal duodenum, indicating a state of hypermotility. Indeed, a decreased quantity of bilirubin was recovered through the chronic fistula in the proximal duodenum, suggesting an impaired delivery of bile to the ulcer area after cysteamine administration. Thus, duodenal hypermotility probably prevents the proper mix and neutralization of gastric acid and duodenal (mucosal, biliary and pancreatic) secretions, predisposing to ulceration in the proximal duodenum.

Animals↗
PubMed1984

Role of submandibular saliva and epidermal growth factor in gastric cytoprotection.

The role of submandibular epidermal growth factor in protection of the gastric mucosa was investigated in rats. Removal of the submandibular glands and thereby submandibular epidermal growth factor (EGF) caused rats to develop gastric lesions (ulcerations and ulcers) after administration of the duodenal ulcerogen cysteamine. The median output of EGF in gastric juice was reduced from 45.6 pmol/12 h (total range 17.5-65.0) in unoperated controls to less than 0.06 pmol/12 h (total range less than 0.06-1.82) in rats given cysteamine after extirpation of the submandibular glands. The contents of EGF in the submandibular glands was unchanged during cysteamine treatment. Furthermore, the effects of intragastric instillation of exogenous EGF, infusion of saliva without EGF, and infusion of saliva with a high concentration of EGF on the development of cysteamine-induced gastric lesions were investigated in rats without submandibular glands. Exogenous EGF and saliva with a high but still physiological concentration of EGF significantly reduced the median area in the stomach displaying ulcers and ulcerations, whereas saliva without EGF had no effect. Although EGF is a known inhibitor of gastric acid secretion, the dose used in the present study had no effect on gastric acid secretion in chronic gastric fistula rats; removal of the submandibular glands also did not have any such effect. We conclude that exocrine secretion of submandibular EGF has a cytoprotective function in the stomach, an effect that may be physiological.

Animals↗
PubMedDate not supplied

[Decrease of toxic effects of aminothiol radiation-protective agents and increase of chemical protection action against ionizing radiation by the use of unithiol].

It has been shown that unithiol diminishes toxic action of cysteamine, AET, and disulfide of WR-1065 on mice. This permits to enhance protection of animals against X-rays by increasing of protector doses. The effect of unithiol on cysteamine action in rats was the same. Antitoxic effect of unithiol on cysteamine was shown both at i.p. and p.o. protector administration. The effect was also revealed in Chinese hamster V-79 cell culture. Combined disulfide of cysteamine and unithiol was synthetized, which ensures effective prolonged protection against ionizing radiation.

Animals↗
PubMed1996

FK960 N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate ameliorates the memory deficits in rats through a novel mechanism of action.

With passive avoidance (PA), Morris water maze (WM) and eight-arm radial maze tasks, we evaluated the memory-enhancing action of FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a compound which we have found through rational drug screening based on our hypothesis that penile erection is a valid predictor of central cholinergic activation. Memory performance in the tasks was impaired in aged (24- to 26-months-old) rats as well as in rats with nucleus basalis magnocellularis lesions. Scopolamine (1 mg/kg i.p.) treatment induced memory impairment in PA and WM; treatment with cysteamine (200 mg/kg s.c.) induced memory impairment in PA but not in WM, whereas fimbria fornix lesioning affected the rats in the opposite manner. FK960 (0.1-10 mg/kg i.p.) ameliorated all the memory impairments except those induced by cysteamine or fimbria fornix lesion, and the dose-response curves were bell shaped with maximal response at 1 to 3.2 mg/kg. The effects of FK960 on the scopolamine-induced memory impairment in the PA and/or WM were abolished by cysteamine (200 mg/kg s.c.), dl-p-chlorophenylalanine methyl ester hydrochloride (150 mg/kg i.p. for 3 days) or raphe lesioning, but not by neonatal 6-hydroxydopamine (35 micrograms/head) treatment. Neurochemical analysis revealed that cysteamine and raphe lesions reduced brain somatostatin and serotonin contents, respectively. The treatment with FK960 (0.32-320 mg/kg p.o.) dose-dependently increased both serotonin and 5-hydroxyindoleacetic acid levels in the brain areas examined and significantly increased hippocampal somatostatin contents at the smaller doses. From these results, we conclude that FK960 ameliorates cognitive dysfunction through an activation of the somatostatinergic-serotonergic link.

Aging↗
PubMed1997

Mice's brain radioprotection: comparative efficacy of a series of aminothiols and aminothiol precursors.

A serie of radioprotective aminothiols was checked upon irradiation of the mice's brain. Cysteamine protects efficiently the brain as soon as 15 minutes after its administration. Among the tested aminothiols, it was the most effective compound. 2-isopropyl 1,3-thiazolane, rapidly hydrolysed, delivers a large amount of cysteamine in the brain and was nearly as potent as exogenous cysteamine. The other thiazolanes which delivered only progressively cysteamine or 2-mercaptopropylamine during a long period of time showed lesser efficacy. WR 2721 which did not penetrate the brain exhibited only a feeble radioprotection. The imperviousness to straight active aminothiols may be compensated by the diffusion of their precursors across the blood brain barrier and by their speed of hydrolysis, yielding active aminothiols during a short period of time between their administration and the irradiation.

Amifostine↗
PubMed1990

Update on nephropathic cystinosis.

The cystine that accumulates within cystinotic lysosomes comes primarily from proteins which have been degraded within this organelle. The individual amino acids have specific transport mechanisms to exit the lysosome. The lysosomal cystine transporter is defective in all types of cystinosis. When cells from patients with nephropathic and benign cystinosis were fused, the defect was not corrected and the cystine level remained elevated. This strongly indicates that the genetic defects are allelic (i.e., on the same chromosome). Cysteamine is a weak base which enters the cystinotic lysosome and reacts with cysteamine. forming a mixed disulfide of half-cystine and cysteamine. This mixed disulfide rapidly exits the lysosome via the transport system for cationic amino acids which is normal in cystinosis. Because of the success of renal transplantation, many cystinosis patients are alive in their twenties and even early thirties. Unfortunately, these patients have developed damage to other organs including thyroid, eye, central nervous system, pancreas, and muscle. Cysteamine and its analog, phosphocysteamine, are very beneficial to cystinosis patients, especially when started early in life. These drugs may prevent the need for transplantation. It is too early to know if they will prevent damage to other organs.

Cystinosis↗
PubMed2006

Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: implications for treatment of infantile neuronal ceroid lipofuscinosis.

Infantile neuronal ceroid lipofuscinosis (INCL, also known as infantile Batten disease) is a devastating neurodegenerative disorder caused by deficiency in the lysosomal enzyme palmitoyl-protein thioesterase (PPT, or CLN1), which functions to remove long-chain fatty acids from cysteine residues in proteins. A previous study suggested that the drug cysteamine, a simple aminothiol used in the treatment of cystinosis, may have utility in the treatment of INCL. In the current study, we compared the catalytic rate constants for the conversion of palmitoyl-CoA (a PPT substrate) and cystine (which accumulates in cystinosis) by cysteamine. We found that while cysteamine can react with palmitoyl-CoA, the rate constant is 10(3)-fold less than the reaction with cystine. Structure-activity studies suggested that it is the thiolate ion that is reactive in the cleavage reaction and that the amino group probably facilitates lysosomal entry. A modest effect of cysteamine (and two related aminothiols, WR 1065 and dimethylaminoethanethiol, DMAET) on PPT substrate accumulation in INCL lymphoblasts was observed. However, at optimum concentration a paradoxical increase in saposin immunoreactivity was seen, indicating possible lysosomal dysfunction. Improvements are needed in the design of small molecules for the treatment of INCL disease.

Cells, Cultured↗
PubMed2006

Cystine inhibits creatine kinase activity in pig retina.

BACKGROUND: Cystinosis is an autosomal recessive disorder associated with lysosomal cystine accumulation caused by defective cystine efflux. Visual deficit is a possible consequence of cystine accumulation in cornea and retina. Fibroblasts from cystinotic patients present ATP deficit with intact mitochondrial energy-generating capacity by an unknown mechanism. Considering that creatine kinase is a thiol enzyme crucial for energy homeostasis in retina, and disulfides like cystine may alter thiol enzymes, the main objective of the present study was to investigate the effect of cystine and cysteamine, the drug used for treatment of cystinotic patients, on creatine kinase activity in cytosolic and mitochondrial fractions of the retina from adult pigs. METHODS: Retina was isolated from 6-month-old Landrace pigs, homogenized and mitochondrial and cytosolic fractions separated by centrifugation. Cytosolic and mitochondrial creatine kinase activities were determined in the presence of different concentrations of cystine and/or cysteamine. RESULTS: Cystine inhibited the enzyme activity in a dose- and time-dependent manner and cysteamine prevented and reversed the inhibition caused by cystine, suggesting that cystine inhibits creatine kinase activity by oxidation of the sulfhydryl groups of the enzyme. CONCLUSIONS: Considering that creatine kinase is a crucial enzyme for retina energy homeostasis, in case cystine leaves lysosome these results provide a possible mechanism for cystine toxicity and also another beneficial effect for the use of cysteamine in patients with cystinosis.

Animals↗
PubMed1998

Inhibition of drug-naive and -resistant leukemia cell proliferation by low molecular weight thiols.

The aim of these studies was to investigate the ability of cysteamine and its congeners to arrest the proliferation of leukemic cells and to determine the physico-chemical properties responsible for this ability. Fifteen low molecular weight thiol-bearing compounds were shown to arrest the proliferation of CCRF-CEM cells and a methotrexate-resistant subline, with IC50 values between 10(-5) and 10(-4) M. Cysteamine arrested proliferation by slowing the passage of cells through S phase. These cells subsequently resumed cycling, although a proportion went on to die by apoptosis. The antiproliferative action of cysteamine was shown to depend, in part, on H2O2 production. This ability to generate peroxide is shared by many thiol compounds, and molecular modeling indicated that thiol groups were required for the antiproliferative actions of the congeners of cysteamine. Molecular modeling also revealed that the most efficacious antiproliferative agents were those that had their amino acid and thiol moieties separated by an intramolecular distance of 3.17 to 5.9 A, as exemplified by WR 1065 and the aminothiophenols. These findings indicate that thiol-bearing compounds may have some efficacy in the treatment of drug-naive and -resistant leukemia cells.

Cell Division↗
PubMed1996

Preparations of antigens and immunoadsorbents corresponding to the Streptococcus group A cell-wall polysaccharide.

The allyl glycosides of a tri-, penta- and hexasaccharide corresponding to the Streptococcus Group A cell-wall polysaccharide were coupled to solid or soluble supports to give immunoaffinity columns and neoglycoproteins, respectively. Cysteamine hydrochloride was added to the allyl glycosides and the resulting cysteamine adducts were used for subsequent coupling to linkers via the amine functionality. The tri- and penta-saccharide cysteamine adducts were coupled directly to the azalactone-derivatized 3M Emphase Biosupport Medium AB 1 to yield two affinity columns. The penta- and hexa- saccharides were coupled to bovine serum albumin or ovalbumin via the conjugate addition of the epsilon-amino groups of lysines on the proteins with the N-acryloylated sugars or the oligosaccharide-squarate adducts, derived in turn from the cysteamine adducts. The efficiency of the above methods is compared.

Antigens↗
PubMed1999

Re(V)=O(N(2)S(2)) Complexes with N(2)S(2) = Thio-Amido-Secondary Amine-Thio Chelate Ligands: Synthesis, Structure, and Characterization of Solution Forms.

Anti- and syn-ReO(L-cysteine-acetyl-cysteamine) (1 and 2, respectively), and the dimethyl derivatives anti- and syn-ReO(L-penicillamine-acetyl-cysteamine) (3 and 4, respectively), were synthesized. Anti and syn refer to the relationship of the oxo ligand and carboxyl group of the cysteine/penicillamine residue. In the structures of 1 and 4, determined by X-ray diffraction, the oxo/carboxyl relationship was anti in 1 and syn in 4. Such thio-amido-amine-thio (MAMA for monoamido monoamine) type complexes are being investigated as radiopharmaceuticals. The charge and the number of species present under physiological conditions influence biodistribution, and understanding factors influencing the pK(a) of the coordinated secondary amine is essential for successful design of such agents. Dissociation of the proton on the secondary amine alters the charge and structure. For both 1 and 2, the (1)H NMR spectra, monitored as a function of pH, exhibited changes in two pH regions: near pH 4 the signals (especially the H(alpha) of the cysteine residue) shifted, and from pH approximately 6-8 the signals shifted again and broadened. These shift changes are consistent with dissociation of the carboxyl proton to give a monoanion I, and of the amine proton to give a dianion II, respectively. The cysteamine chelate ring of 1 and 4, anchored by the amine donor, is highly puckered in the solid state. Torsion angles, calculated from (1)H NMR (3)J values at pH 3, 5 and 8, indicate that in solution the cysteamine chelate ring is also highly puckered in the neutral form and I, but relatively planar in II. Since five-membered chelate rings are more planar when an anchoring amine is deprotonated, the data are consistent with II being an NH-deprotonated form rather than an OH(-) axially ligated form. The high acidity of the amine in 1 and 2 compared to analogues with two amine donors indicates that the amido group is a modest donor. The signal broadening observed as I and II interconvert, an unusual effect for NH/N(-) exchange, is due primarily to the low rate of exchange at the OH(-) concentration needed to convert I to II. Making the metal (Re/Tc) more electron rich may decrease the acidity of the NH, but since the NH in 1 and 2 is particularly acidic, this approach is unlikely to work. Our results suggest that introduction of an electron-withdrawing group into the ligand may lower the NH pK(a) of the complex below the physiologically relevant range and give a species with a well-defined charge.

Journal Article↗