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PubMed1990

Effect of cysteamine on the lysosomal enzymes of the hyperprolactinaemic rat pituitary.

The effect of cysteamine on the activity of lysosomal enzymes and the prolactin content of isolated hyperprolactinaemic cells has been investigated. In broken cell preparations, cysteamine markedly stimulated acid prolactin protease activity. In intact cells, however, cysteamine inhibited acid prolactin protease activity and beta-galactosidase. Moreover, the activities of alpha-mannosidase, acid phosphatase, beta-glucuronidase, total arylsulphatase and hexosaminidase were not changed by the addition of cysteamine. Cysteamine significantly depleted the cells of prolactin, and this action was not compromized by the inclusion of either leupeptin, chloroquine or NH4Cl in the incubation media. Taken together, these results indicate that cysteamine does not promote degradation of prolactin and hence depletion of prolactin from the pituitary through a mechanism involving lysosomal enzyme degradation.

Animals↗
PubMed1995

Cysteamine attenuates iminodipropionitrile (IDPN) induced dyskinesia in rats.

The present investigation was undertaken to study the effect of cysteamine on experimental dyskinesia in rats. The movement disorders were produced by intraperitoneal administration of iminodipropionitrile (IDPN) in the dose of 100 mg/kg per day for 11 days. Cysteamine was administered (i.p.), daily 30 minutes before IDPN in the doses of 25 mg/kg, 50 mg/kg and 100 mg/kg bodyweight in three different groups of rats. Twenty four hours after the last dose of IDPN, animals were observed for neurobehavioural changes including vertical and horizontal head weaving, circling, backwalking, grip strength and righting reflex. Immediately after behavioural studies brain specimens were collected for analysis of vitamin E and total glutathione levels. The results of behavioural studies showed that co-treatment with cysteamine protected rats against IDPN-induced dyskinesia. Our biochemical studies showed that IDPN produced a depletion of vitamin E in cerebrum, cerebellum and brain stem. Concomitant treatment with cysteamine in doses of 50 and 100 mg/kg attenuated IDPN-induced decrease in vitamin E in cerebrum and cerebellum. There was a significant decrease in cerebral glutathione in IDPN treated rats, which was attenuated by cysteamine. No significant change was observed in the glutathione levels in cerebellum and brain stem. Further studies are deemed necessary to elucidate the mode of action of cysteamine and to determine therapeutic and/or prophylactic value of this drug in the treatment of movement disorders.

Animals↗
PubMed1980

Cysteamine-induced duodenal ulcer and acid secretion in the rat.

Duodenal ulcers can be produced in rats within 24 h by a single subcutaneous administration of cysteamine. To determine the role of gastric acid secretion in the pathogenesis of these ulcers, secretory and pathoanatomic studies were performed in chronic fistula rats ater an ulcerogenic dose of cysteamine. A prolonged increase of acid secretion was seen after cysteamine, reaching fourfold the basal level after 5 h. The acid response lasted for 10 to 11 h. After vagotomy cysteamine-induced acid secretion was markedly reduced. Ulcer formation was prevented by vagotomy and by drainage of the gastric juice before it entered the duodenum. When a gastric acid output equivalent to that produced by the ulcerogenic dose of cysteamine was induced by repeated injections of pentagastrin, no mucosal changes were seen in the duodenum. These results indicate that, although some acid in the duodenum is required for ulcer formation, the hypersecretion of acid induced by cysteamine is not the only factor responsible for the development of duodenal ulcer.

Animals↗
PubMed1999

Cysteamine: new preparation. Chronic treatment of cystinosis.

(1) Cysteamine bitartrate (also known as mercaptamine) is marketed for the treatment of cystinosis, a rare hereditary disease which, in its juvenile and infantile forms, progresses spontaneously to severe renal and ocular impairment, growth retardation with rickets, and involvement of many other organs. Only symptomatic treatments have been available until now. (2) The clinical file includes only non comparative trials. (3) Few children have been treated with cysteamine beyond the age of 10. Provided treatment is begun early, the main beneficial effects of cysteamine are maintenance of the growth curve and prevention of deterioration of renal lesions (an effect that varies from patient to patient). Oral cysteamine does not prevent the progression of ocular lesions. (4) Cysteamine has many potential adverse effects, some of which are serious (mainly gastrointestinal and neuropsychiatric disorders). Little is known of its long-term adverse effects. (5) The main disadvantage of this treatment is the need for four daily intakes (every 6 hours) and the sulphurous breath it causes. (6) Treatment with cysteamine is expensive.

Adolescent↗
PubMed2001

Effects of cysteamine on nociception in mice.

AIM: The present study was carried to study the effects of cysteamine on nociception in mice. METHODS: The pain assays were the hot plate and the tail flick test. RESULTS: When cysteamine, a drug well known as a somatostatin depletor, was administered 1 and 4 but not 24 h before the tests (hot plate, tail flick), the nociceptive threshold was elevated when the drug was administered at high doses (50 and 100 mg/kg) while at a lower dose (10 mg/kg), it was able to elevate the nociceptive threshold in the hot plate test only. In the hot plate as well the tail flick test cysteamine effects are reversed by naloxone administration and potentiated by morphine administration, whereas neither somatostatin nor cyclo-(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[Bzl], a reported somatostatin antagonist, changes cysteamine effects. CONCLUSION: These results suggest that cysteamine effects on the nociceptive threshold in the hot plate and tail flick test may be mediated by cysteamine interference with the opioid system.

Analgesics, Non-Narcotic↗
PubMed1991

[Inhibition of the cysteamine-induced gastric ulcer by the sympathoadrenal medullary system in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY)].

We previously reported that cysteamine induces severe gastric ulcers in WKY, but very mild in SHR. The aim of this study is to elucidate the role on the sympathoadrenal medullary system in the pathogenesis of the cysteamine-induced gastric ulcer. Catecholamine (CA) contents in the stomach and adrenal gland were significantly higher in the non-treated SHR than in the non-treated WKY, suggesting that the sympathetic nervous system is more facilitated in SHR. Cysteamine decreased the noradrenaline and adrenaline contents in these tissues in both strains, however the values of CA was still higher in the treated SHR than the non-treated WKY. Histologically the adrenal medulla was severely damaged by cysteamine administration in WKY than in SHR. In contrast an immunohistological study revealed that chromogranin reactivity of the adrenal medulla was significantly stronger in the treated SHR than in the treated WKY. The celiac plexus was well preserved morphologically even in the cysteamine treatment in both strains. These results suggest that the capacity of the sympathetic nervous system in both the adrenal medulla and the stomach plays an important role in preventing the cysteamine-induced gastric ulcer in SHR.

Adrenal Medulla↗
PubMedDate not supplied

Comparative studies of intracerebroventricularly administered cysteamine and pantethine in different behavioral tests and on brain catecholamines in rats.

In a passive avoidance test, intracerebroventricular administration (post-trial treatment) of the somatostatin-depleting compound cysteamine decreased the avoidance latency of the rats in a dose-related manner, while the effect of pantethine (which is metabolized to cysteamine) was less pronounced. In open-field studies, both compounds decreased the motor activity (ambulation, rearing) of the animals 15 min after the injection followed by a subsequent recuperation of the locomotor depression. Following pantethine, the ambulation increased during the later tests (60 min, 240 min, 24 hr). Cysteamine decreased the noradrenaline and increased the dopamine and dihydroxyphenyl acetic acid content in the hypothalamus, whereas the effects of pantethine were less expressed. Both compounds slightly decreased the striatal noradrenaline and increased the dihydroxyphenyl acetic acid levels at 15 and 60 min after administration. However, contrary to pantethine, 4 hr after treatment with cysteamine, there was a decrease in dihydroxyphenyl acetic acid concentration in this brain region. These findings suggest that both pantethine and cysteamine attenuate passive avoidance latency after intracerebroventricular treatment. The different efficiency of pantethine and its metabolite cysteamine might be connected to the low pantetheinase activity of the brain tissue; however, some direct effects of pantethine cannot be excluded. The different effects of the two compounds on the open-field activity are possibly associated with the diverse effects of the compounds on the striatal dopaminergic neurotransmission.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Cysteamine and pantethine effects on passive avoidance behavior, shuttle box learning, open-field activity, striatal catecholamines and somatostatin.

The effects of cysteamine and pantethine were compared on different behavioral tests and neurochemical parameters in rats. Cysteamine, administered in high dose (3.90 mM/kg s.c.), decreased the locomotor and rearing activities of rats, while it slightly but not significantly increased the avoidance latency in a passive avoidance test. Pantethine, 24 hr after its administration, significantly increased the dihydroxyphenyl acetic acid (DOPAC) levels in the striatum. Cysteamine slightly reduced the DOPAC level without influencing the catecholamine levels in this brain area. The striatal somatostatin concentration was reduced 24 hr after the administration of cysteamine, while pantethine did not influence it. After repeated daily injections of pantethine, the drug facilitated the shuttle box learning process and increased the intertrial and open-field activities of the animals. Cysteamine only slightly increased the locomotion and rearing and did not influence the shuttle box learning. Both pantethine and cysteamine slowed the rate of the "body weight increase" of the animals when compared to a saline-treated group. These findings suggest that the locomotor activation induced by pantethine 24 hr after its administration plays an important role in its behavioral effects. It might be that the striatal dopaminergic transmission, modified by administration of pantethine, plays some role in the higher locomotor activity induced by the substance.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Effect of cysteamine on secretion of gastrin and somatostatin from the rat stomach.

Cysteamine (beta-mercaptoethylamine HCl) administration to rats induces a hypergastrinemia and a reduction in gastric tissue somatostatin content. The possibility that this reduction may contribute to the elevated gastrin levels has been investigated in the isolated perfused rat stomach. Cysteamine (1 mM) rapidly increased immunoreactive gastrin release to levels ranging between 41% and 125% above basal. Increasing the dose to 10 mM caused a 1148% increase in immunoreactive gastrin. Secretion of somatostatinlike immunoreactivity did not change. Perfusion of gastric inhibitory polypeptide (1 nM) induced a sustained increase in somatostatinlike immunoreactivity secretion and a transient rise in gastrin. Addition of 10 mM cysteamine during gastric inhibitory polypeptide perfusion caused a 300% increase in immunoreactive gastrin. These levels were lower than in response to cysteamine alone. The results demonstrate that cysteamine can stimulate immunoreactive gastrin secretion without any change in somatostatinlike immunoreactivity release. When somatostatinlike immunoreactivity secretion is stimulated by an agent such as gastric inhibitory polypeptide, the cysteamine-induced release of immunoreactive gastrin is attenuated, suggesting the presence of a functional linkage between somatostatin and gastrin under these conditions.

Animals↗
PubMed1984

Gastric mucosal histamine, histamine formation capacity (HFC) and plasma gastrin after cysteamine administration.

Cysteamine administration is followed by stomach and duodenal ulcers in rats. We aimed to establish a time relationship between changes in gastric mucosal histamine, histamine formation capacity (HFC) and plasma gastrin after cysteamine administration. Up to 4 h after cysteamine s.c., no ulcers were found. Plasma gastrin rose after cysteamine and was higher than in controls 2h after injection. Mucosal histamine fell after 4h; no other significant changes were found in mucosal histamine and HFC. A direct correlation was found between plasma gastrin and HFC in both controls and after cysteamine. It is suggested that the changes indicate that cysteamine releases gastrin, which increases HFC and thus histamine. The fall in histamine seems to indicate utilization of histamine in acid production.

Animals↗
PubMed1981

Demonstration of an interaction of the radioprotector cysteamine with lecithin.

Cysteamine, a radioprotector belonging to the aminothiol class, interacts with nucleus DNA of mammalian or human cells to reduce the lethal effect of ionizing radiation. The transfer of this drug through cellular membranes has been studied, using as a model system an aqueous dispersion of lipid and cysteamine. The interaction of synthetic lecithin dipalmitoylphosphatidylcholine (DPPC) smectic mesophases with cysteamine was investigated by means of spectrophotometric and dielectric measurements. The thermal transitions of DPPC studied by spectrophotometry and dielectric Arrhenius diagrams showed that cysteamine deletes the pretransition of the lipid phase and does not modify the principal transition. This indicates a direct interaction between the lipid polar head with cysteamine; the aliphatic chains are not affected. Conductivity measurements confirmed these results and demonstrated an electrostatic interaction between the anionic phosphate site of the polar head and the cysteamine cation.

Chemical Phenomena↗
PubMed1993

[Inhibitory effect of cysteamine on nociceptive responses of dorsal horn neurons in spinal cord of cats].

The effect of somatostatin depletor cysteamine on the nociceptive responses of neurons in laminae IV-VI of spinal cord was studied in 16 pentobarbitone anesthetized and spinal cord transected (at L1) cats. Intravenous injection of cysteamine (50 mg/kg) markedly inhibited responses of the neurons produced by noxious heating (50 C) of glabrous skin of the plantar region, but not C fibre responses induced by electrical stimulation of unmyelinated fibers of the tibial nerve. However, C responses in 8/13 neurons tested were significantly inhibited by large dose cysteamine (100 mg/kg). Following micropressure ejection of cysteamine (20 psig) into the substantia gelatinosa where somatostatin-containing fibers terminate, heating responses were significantly inhibited in all laminae IV-VI neurons whereas C responses was only weakly inhibited in 7/13 neurons. The results suggest that depletion of spinal somatostatin may be involved in cysteamine-induced inhibition of spinal nociception. The possible mechanism underlying the stronger cysteamine-induced inhibition of heating response was discussed.

Animals↗
PubMed1984

Pantethine and cystamine deplete cystine from cystinotic fibroblasts via efflux of cysteamine-cysteine mixed disulfide.

Children suffering from cystinosis, a genetic disease characterized by high levels of lysosomal cystine, are currently being treated with cysteamine to lower the cystine levels in their cells. In fibroblasts from these patients, cysteamine and its disulfide, cystamine, are equally effective in lowering cystine levels. We recently reported that pantethine, a dietary precursor of coenzyme A, depletes cystine from cultured, cystinotic fibroblasts as effectively as cystamine. To determine the mechanism of action of pantethine, and of cystamine, we have compared the fate of [35S]cystine-derived metabolites in the presence and absence of these agents. The results indicate that the ability of pantethine to deplete cystine resides in its being a metabolic precursor of cysteamine. Furthermore, both pantethine and cystamine act by generating the mixed disulfide of cysteamine and cysteine in the lysosomes, which is then rapidly excreted from the cells. The fall in intracellular [35S]cystine caused by these agents was not accompanied by a comparable increase in any intracellular metabolite; rather, it could be accounted for by the appearance of mixed disulfide in the medium. There was no accumulation of mixed disulfide in the cells. Radioactivity in cytoplasmic glutathione was, however, increased by cystamine or pantethine. Thus, cysteamine (formed intracellularly in these experiments) undergoes thiol-disulfide exchange with cystine in the lysosomes, producing cysteamine-cysteine mixed disulfide and free cysteine, which enter the cytoplasm. The free cysteine is available to several pathways, including oxidation to the disulfide or the mixed disulfide, and synthesis of glutathione. The mixed disulfide is excreted from the cell, which ultimately depletes the cell of its excess cystine.

Cells, Cultured↗
PubMed1988

Inhibitory effect of prolonged administration of cysteamine on experimental carcinogenesis in rat stomach induced by N-methyl-N'-nitro-N-nitrosoguanidine.

The effect 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. Prolonged administration of 25 or 50 mg per kg body weight of cysteamine after treatment with MNNG for 25 weeks significantly reduced the incidence and number of adenocarcinomas of the glandular stomach. Histological examination showed that the adenocarcinomas that did develop in rats treated with these 2 doses of cysteamine had high mucin-producing activity. Furthermore, treatment with cysteamine caused significant increases in serum gastrin level and gastric acid secretion, together with significant decreases in the antral mucosal pH and the labelling indices of pyloric and oxyntic gland mucosae and gastric cancer. These findings indicate that cysteamine inhibits the development of gastric adenocarcinomas and that its effect may be related to decreasing proliferation of cells in the gastric mucosae.

Adenocarcinoma↗
PubMed1993

Effect of cysteamine on insulin release and exocrine pancreatic secretion in vitro.

Cysteamine is known to deplete somatostatin from pancreatic D cells. In the isolated perfused rat pancreas we investigated its effects on somatostatin and insulin release as well as exocrine pancreatic secretion in the presence of 16.7 mM glucose and 180 pM CCK-8. At a concentration of 0.1 mM, cysteamine had no significant effect on pancreatic endocrine and exocrine functions. At 10 mM, however, cysteamine released somatostatin (380 +/- 70 vs 100 +/- 20 fmol/20 min), inhibited insulin output (890 +/- 120 vs 13210 +/- 3260 mu units/20 min) and reduced exocrine pancreatic secretion (volume: 12 +/- 2 vs 20 +/- 2 microliters/20 min; lipase: 31 +/- 3 vs 60 +/- 7 units/20 min). We conclude that the complex changes induced by cysteamine are consistent with a physiological role of endogenous somatostatin in the regulation of insulin release. The reduction of exocrine pancreatic secretion, however, was at least in part, if not completely, mediated via the insuloacinar axis rather than a direct effect of cysteamine-released somatostatin on pancreatic acinar cells.

Animals↗
PubMed1984

Effect of cimetidine and carbenoxolone on cysteamine-induced ulcers: a study of gastric mucosal histamine and histamine formation capacity in rat.

Cysteamine-induced ulcers in rat were used to study the effect of ulcer-healing agents with different modes of action on ulcer formation and mucosal histamine. Male Wistar rats were divided into 5 groups. Group I had cysteamine injection; group II had cimetidine followed by cysteamine injection; group III had carbenoxolone before cysteamine injection; group IV had carbenoxolone as group III and cimetidine and cysteamine injections; group V had saline injections (controls). In group I 20/29; group II 17/30; group III 15/29; and group IV 23/30 developed ulcers. No significant differences were found. No ulcers were found in group V. Comparison between all groups and controls showed an increase in gastric mucosal histamine and HFC. The increase in histamine was related to ulcer formation. Duodenal and oesophageal histamine did not change significantly. Gastric mucosal histamine and HFC were directly correlated.

Animals↗
PubMed1987

Effect of cysteamine on somatostatin and neuropeptide Y in rat striatum and cortical synaptosomes.

Local injection of cysteamine into rat striatum results in a rapid but reversible reduction in somatostatin-like immunoreactivity (SLI). Since somatostatin and neuropeptide Y are co-localized in striatal and cortical neurons, we examined the effects of cysteamine in these areas. SLI and neuropeptide Y-like immunoreactivity (NPYLI) were measured following local injection of cysteamine into the striatum. In addition, we examined the effects of cysteamine on SLI and NPYLI in cortical synaptosomes. SLI was significantly reduced in both experiments, but NPYLI was unaffected. These results suggest that the mechanism by which somatostatin is depleted by cysteamine is one of specific biochemical modification, probably affecting the somatostatin disulfide bond, rather than one affecting neuronal metabolism.

Animals↗
PubMed1984

Effects of cysteamine on pain behaviour and on somatostatin- and substance P-like immunoreactivity in the substantia gelatinosa of the rat.

Immunohistochemical studies on rats showed cysteamine to deplete immunoreactive somatostatin, but not substance P, in the substantia gelatinosa of the spinal trigeminal nucleus and spinal cord. The effect of cysteamine treatment on chemical pain was investigated using capsaicin as the pain-producing stimulus. Thermal pain was assessed with a hot plate test after cysteamine treatment. It was found that cysteamine did not alter the hind paw lick latency in the hot plate test or the number of forepaw wipes after application of a drop of capsaicin into the cornea, compared to normal animals. In capsaicin-treated animals a significantly lower number of forepaw wipes were seen after corneal capsaicin application. However, in cysteamine-treated animals slower wiping was observed compared to untreated and capsaicin-treated animals. This suggests that somatostatin may be of importance for the modulation of nociceptive information, although it is not a major pain transmitter.

Animals↗