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PubMed1987

Prevention of cysteamine-induced myoclonus blocks the long-term inhibition of kindled seizures.

In kindled rats, the administration of cysteamine (CSH, 200 mg/kg, i.p.) 4 h prior to a kindled seizure leads to long-term (up to 10 days) inhibition of kindled seizures. CSH (200 mg/kg, i.p.) also induces myoclonic seizures in kindled rats. We suggest that the long-term inhibition of kindled seizures might be the result of the myoclonus, not the somatostatin depletion as previously suggested. Prior administration of the short-acting benzodiazepine midazolam (5 mg/kg, i.p.) eliminated the CSH-induced myoclonus and prevented the long-term inhibition of kindled seizures. These results suggest that the CSH-induced long-term inhibition of kindled seizures is the result of an interaction between the myoclonic seizure and a subsequent kindled seizure.

Animals↗

PubMed1993

Stress protein co-localization to autofluorescent astrocytic inclusions in situ and in cysteamine-treated glial cultures.

In the aging brain, a unique subpopulation of limbic and periventricular astrocytes accumulates red autofluorescent, peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. Cysteamine (CSH) exposure rapidly induces identical inclusions in cultured, immature astroglia. CSH induces a cellular stress response prior to astrocyte granulation. To determine whether stress proteins are actual constituents of the autofluorescent granules, 12-week-old rat brain sections and CSH-treated astroglial cultures were immunostained with various anti-stress protein antibodies and evaluated by laser scanning confocal microscopy. We observed intense co-localization of heat shock protein (HSP) 27 and ubiquitin (Ub) to the autofluorescent astrocyte granules in situ and in CSH-treated glial cultures. In both preparations, glucose regulated protein (GRP) 94 consistently exhibited partial co-localization to the granule periphery and adjacent cytoplasm. In contrast, HSP72 co-localization to these inclusions was only occasionally seen and the granules appeared entirely devoid of HSP90 and alpha B-crystallin. Acute exposure of cultured astroglia to CSH induced intense cytoplasmic Ub staining, suggesting that activation of the Ub pathway may be an early event in the biogenesis of these astrocytic granules. Taken together, our results support the notion that the autofluorescent astrocyte inclusions are stress or heat shock granules which progressively accumulate in the aging periventricular brain. Moreover, CSH greatly accelerates the appearance of this senescent astrocyte phenotype in primary culture.

Animals↗

PubMed1993

Isolation of pseudoperoxidase-positive astrocyte granules from intact rat brain and cysteamine-treated neuroglial cultures.

A subpopulation of astrocytes in periventricular regions of aging brain and in cysteamine (CSH)-treated glial cultures contain autofluorescent cytoplasmic granules that exhibit an affinity for Gomori's chrome alum hematoxylin (CAH), and non-enzymatic peroxidase activity. Although shown to be histochemically distinct from lipofuscin, the lack of pure preparations of these glial inclusions has hindered the elucidation of their precise chemical constituents. Using sucrose gradient fractionation and density centrifugation on percoll, we obtained enriched preparations of astrocyte cytoplasmic granules from intact rat brain and CSH-treated astrocyte cultures. The presence and relative purity of these inclusions were confirmed by laser scanning confocal microscopy for red autofluorescent granules, diaminobenzidine histochemistry for non-enzymatic peroxidase activity and chrome alum hematoxylin (Gomori) staining. In the enriched fractions, the smaller granules (0.5-4.0 microns) were spherical and weakly autofluorescent, whereas larger inclusions (5.0-10.0 microns) tended to be intensely autofluorescent and pleomorphic. As in situ, the purified material was argyrophilic and did not stain for lipids. Isolation of these astrocytic inclusions should permit a more thorough characterization of their biochemical contents.

3,3'-Diaminobenzidine↗

PubMed1993

Effects of a new sigma ligand, JO 1784, on cysteamine ulcers and duodenal alkaline secretion in rats.

BACKGROUND: The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-yl amine, hydrochloride], a new specific and highly selective sigma ligand, were examined in rats. METHODS: Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied. RESULTS: JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784. CONCLUSION: These results show that JO 1784, a selective sigma ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.

Animals↗

PubMed1991

High-performance liquid chromatography of thiazolidinic compounds obtained by condensation of pyridoxal 5'-phosphate or pyridoxal with aminothiols (L- or D-cysteine, cysteamine, L-cysteine ethyl ester).

We investigated six thiazolidine 4-carboxylic acids of biological interest, obtained by condensation of pyridoxal 5'-phosphate or pyridoxal with L- or D-cysteine, cysteamine or L-cysteine ethyl ester. A reversed-phase high-performance liquid chromatographic method, using a C18 column for their separation, was developed by sequential optimization of the pH and the gradient of the mobile phase. Resolution of the compounds was obtained with an analysis time of less than 20 min.

Chromatography, High Pressure Liquid↗

PubMed1986

Cysteamine, zinc, and thiols modify detectability of rat pituitary prolactin: a comparison with effects on bovine prolactin suggests differences in hormone storage.

Little is known about the structure of prolactin (PRL) within secretory granules. Evidence from our previous studies in bovine tissue preparations suggests that control of secretion may reside, in part, in the conversion of storage hormone to releasable PRL. The conversion can be monitored by measuring changes in immunodetectability since the oligomeric, storage form is poorly recognized by antisera raised against monomeric PRL. Since many investigators use rats to study the secretory process and changes in detectability of rat pituitary PRL occur during lactation ("depletion-transformation"), we undertook the present immunodetectability studies to gain insight into the storage structure of rat (r) PRL. Cysteamine and zinc inhibited tissue PRL immunoassayability in male rat pituitary homogenates and also in partially purified secretory granules as they had inhibited bovine (b) PRL; however, zinc inhibited the rodent hormone less potently than the bovine. In vitro incubation of rat tissue samples without additions resulted in increases in rPRL detectability of up to 84% after 180 minutes; such incubation of bovine samples had no significant effect. A striking additional difference between the species was that exposure to reduced glutathione (GSH), cysteine, homocysteine, mercaptoethanol, and dithiothreitol inhibited rPRL by up to 44%. This compared to thiol stimulation of bPRL by as much as 450%. The inhibitory GSH effect on rPRL was abolished when 0.5% sodium dodecyl sulfate (SDS) was included; in contrast, the stimulatory GSH effect on bPRL did not change with added SDS. SDS alone had no effect on rat homogenate PRL, and only increased rat granule rPRL by 23% compared to its ability to increase bPRL assayability by 44%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Effect of cysteamine on levels of somatostatin-like immunoreactivity and catecholamines and on electroencephalogram in the rat brain.

Cysteamine (CYS) is known to be a quite specific depletor of somatostatin in the rat brain. In the present study we investigated the effect of CYS (100 mg/kg, 300 mg/kg, subcutaneously) on levels of somatostatin-like immunoreactivity (SLI) in the brain and cerebrospinal fluid, on catecholamines in the cortex, and on spectral cortical electroencephalogram (EEG) of rat. SLI was decreased in both the cortex and the striatum (p less than 0.05) of CYS-treated rats, but no change was seen in SLI of CSF. Cortical levels of dopamine, noradrenaline and homovanillic acid were decreased (p less than 0.05) following administration of either dose of CYS. In EEG, during mobility both the frontal and occipital peak (Fp) and mean (Fm) frequencies were slowed (p less than 0.05). Frontally, the amplitude of the frequency bands 1.5-3Hz and 3-5Hz was increased (p less than 0.05). During immobility the Fp and Fm were also slowed. In frequency bands of 3-5Hz, 5-10Hz and 10-20Hz the amplitude was decreased (p less than 0.05), indicating that, in addition to theta frequency, the low voltage fast activity is also affected by CYS. According to our results, both the cortical intrinsic neurons containing somatostatin and also the ascending catecholaminergic systems are affected after the single administration of CYS concomittantly with, but not necessarily related to, changes in different frequency bands in EEG.

Animals↗

PubMed1989

Effect of cysteamine on somatostatin-like immunoreactivity in the amygdala-kindled rat brain.

Previous studies have shown that a somatostatin-depleting drug, cysteamine (CYS), suppresses kindled seizures. However, no data is available concerning the levels of somatostatin-like immunoreactivity (SLI) in the kindled rat brain after CYS administration. In the present study, we used radioimmunoassay to measure SLI in the frontal cortex, amygdala + piriform cortex, hippocampus, striatum and hypothalamus: 1) in control rats, 2) in amygdala-kindled rats decapitated 14 days after the last stimulus, and 3) in amygdala-kindled rats decapitated 14 days after the last stimulus but treated either 11 days or 4) 4 hours before decapitation with CYS (100 mg/kg, subcutaneously). The results showed that, compared to controls, in kindled rats SLI was elevated both in the ipsi lateral (28%, p = 0.0372) and contralateral (17%, p = 0.0078) frontal cortex. Compared to kindled rats, CYS given 4 hours before decapitation decreased SLI in the frontal cortex (to 71%, p = 0.0066) and hippocampus (to 72%, p = 0.0027), but compared to the controls, only in the hippocampus. In rats given CYS 11 days before decapitation, SLI did not differ from either the controls or from the kindled rats. In conclusion, the somatostatinergic system is affected in amygdala-kindling; but the relationship of anatomical localization and the magnitude of CYS-induced decrease of SLI to elevated seizure threshold needs to be studied further.

Amygdala↗

PubMed1990

Gomori-positive astrocytes in primary culture: effects of in vitro age and cysteamine exposure.

Gomori-positive astrocytes have been identified in the periventricular brain in situ and in diencephalic explants on the basis of their endogenous peroxidase activity, affinity for chrom alum hematoxylin, and orange-red autofluorescence. To facilitate analyses of their functional properties, we sought to identify these cells in dissociated fetal rat brain cultures. Astrocytes containing cytoplasmic inclusions with the above tinctorial and fluorescent properties represented less than 1% of cultured astrocytes at day 10 in vitro (DIV). There was a marked increase in the fraction of Gomori-positive astrocytes and their granule content between 10 and 46 DIV. As in situ, the peroxidase activity appeared to be non-enzyme-mediated insofar as it catalyzed diaminobenzidine oxidation over a wide range of pH (3-11) and could not be inhibited by tissue preheating or the catalase inhibitor, aminotriazole. Metalloporphyrins probably mediate both the pseudoperoxidase activity and autofluorescence in these cells. Cysteamine and cystamine, but not ethanolamine or L-cysteine, induced a massive accumulation of Gomori-positive astrocytes when administered from DIV 6-18. Alterations of the redox microenvironment or induction of porphyrin/heme biosynthetic enzymes may be the mechanisms responsible for this cyst(e)amine effect. Dissociated rat brain culture enriched for Gomori astroglia should provide ample opportunity to investigate the functional properties of these cells.

Animals↗

PubMedDate not supplied

Cysteamine protection of SCEs induced by UV and fluorescent light.

CHO cells were grown for 36 h in the presence of BUDR. 12 h before harvesting, the cells were irradiated with UV or with fluorescent (FL) light. Part of the cultures were treated with cysteamine (Cys) during irradiation. Metaphase spreads were stained by the Hoechst-plus-Giemsa method, and the frequency of SCEs per chromosome was determined in second-mitosis cells. The basal frequency of SCEs (1.07 +/- 0.073) was not increased by Cys treatment (1.15 +/- 0.048). On the other hand, UV and FL induced a 3-4-fold increase in the frequency of exchanges (4.18 +/- 0.2 and 3.32 +/- 0.12 resp.). Cys, when present during irradiation, markedly reduced the frequency of UV- and FL-induced SCEs (2.7 +/- 0.14 and 2.29 +/- 0.11 resp.). It is assumed that Cys prevents the formation of radiation-induced breakages in the BUDR-substituted DNA. The residual increase over the basal levels of SCEs which remains after the treatment with Cys may be due to the persistence of some open breaks, to the presence of protein-DNA crosslinking, or to the combined action of both types of lesion.

Animals↗

PubMed1986

Enhancement by cysteamine of N-methyl-N-nitrosourea mutagenesis in E. coli.

Cysteamine (MEA) is comutagenic to methylnitrosourea (MNU) in E. coli AB 1157 but not in the nonadaptable mutant derivative ada-6 of that strain. The comutagenic action of MEA was eliminated by cysteine at low concentrations, which also lowered mutation frequencies in AB1157 but not in ada-6. In model experiments it was shown that cysteine counteracted the inhibition by MEA of beta-galactosidase induction in both bacterium strains. The comutagenic action of MEA is interpreted as being due to an inhibition of induction of methyltransferase during treatment with MNU.

Bacterial Proteins↗

PubMed1991

Cysteamine can induce duodenal ulceration in rats without depletion of immunoreactive somatostatin.

Single subcutaneous administration of cysteamine (2-aminoethanethiol, CSH) produces duodenal ulceration in rats within 24 h. Depletion of circulating and tissue somatostatin (SOM), hypergastrinemia and gastric acid hypersecretion have all been postulated as the pathophysiological response to CSH leading to ulceration. The purpose of this study was to analyze the synthesis, storage and secretion of gastrin and SOM as well as structural changes in SOM peptide after CSH treatment. Injection of 300 mg/kg (s.c.) of CSH caused macroscopic duodenal ulcers in seven out of eight rats at 24 h. Hypergastrinemia was seen within 30 min (from 23 +/- 4 to 74 +/- 20 pmol/l), and persisted for 4 h. Antral gastrin content was elevated at 30 min (2539 +/- 114 pmol/g) when compared to saline controls (1589 +/- 101 pmol/g). Plasma SOM did not change over the 24 h but antral SOM increased at 30 min (from 120 +/- 3 to 230 +/- 23 pmol/g) and remained elevated at 2 h (374 +/- 48 pmol/g) and 4 h (357 +/- 37 pmol/g). Fundic and duodenal SOM followed a similar pattern. Antral SOM mRNA was also elevated over the first 4 h (3-fold increase, P less than 0.05). HPLC analysis of antral tissue extracts revealed the presence of additional molecular forms of SOM which, however, differed from the major products of in vitro reduction with either CSH or dithiothreitol. Thus, the in vivo effect of CSH on SOM cannot be solely explained by a reductive opening of the disulphide bond. These results suggest that duodenal ulceration in rats treated with CSH is not related in a simple fashion to depletion of immunoreactive SOM. Early induction of hypergastrinemia may be important in the onset of ulceration. The value of CSH as a SOM depleting tool in gastrointestinal tissue must remain in doubt.

Animals↗

PubMed1994

Cysteamine-induced reduction in tissue somatostatin immunoreactivity is associated with alterations in somatostatin mRNA.

The drug cysteamine (CHS) induces a profound loss of somatostatin-14 (SS-14) biological and immunological (SS-14 LI) activity from somatostatin cells in vivo and in vitro. The present study was designed to determine (i) whether CHS induced loss of somatostatin is accompanied by secondary increases in SS-mRNA perhaps through loss of autoinhibition of somatostatin cells; (ii) whether CHS exerts additional direct effects on SS gene regulation. CHS was administered to rats in vivo or applied in vitro to primary cultures of rat islet cells, rat islet somatostatin-producing tumor cells (1027 B2), and endogenous or in vitro synthesized SS-mRNA. In vivo administration of CHS led to 80% reduction in tissue SSLI by 4 h. These changes were accompanied by significant alterations in SS-mRNA that were both tissue-specific and time-dependent. The pattern in brain and intestine was typified by a significant 60% increase in SS-mRNA at 2 h followed by a gradual reduction to approximately 55% of control at 8 h. Stomach showed a significant 95% increase in SS-mRNA at 4 h followed by a 37% decrease by 8 h. Pancreatic SS-mRNA displayed a sustained 25-65% reduction for 8 h. Pretreatment of islet cell cultures with CHS reproduced the in vivo findings with pancreas viz. decreased SSLI (80-90% of control) accompanied by a parallel reduction in SS-mRNA (40-50% of control) sustained from 2-72 h. CHS also induced a reduction in immunoreactive insulin and insulin mRNA in cultured islet cells. As with normal islet cells, CHS treatment of 1027 B2 islet tumor cells led to a profound and sustained decrease in SSLI and SS-mRNA. These changes occurred in the absence of any alteration in intracellular cAMP levels. CHS was without effect when incubated directly with SS-mRNA isolated from 1027 B2 cells or with in vitro synthesized SS-mRNA. We conclude that in addition to its effect on SSLI, CHS also induces time- and tissue-dependent alterations in SS-mRNA. The mechanism of CHS action on SS-mRNA is complex and may involve both an indirect effect secondary to loss of somatostatin autoinhibition (to account for SS-mRNA increases) and/or a direct inhibition of SS gene expression (to explain SS-mRNA reduction). The precise site of direct CHS action on SS gene regulation remains to be defined.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Differential effects of cysteamine on heat shock protein induction and cytoplasmic granulation in astrocytes and glioma cells.

The sulfhydryl agent, cysteamine (CSH), promotes the accumulation of autofluorescent, peroxidase-positive cytoplasmic granules in cultured astroglia akin to those which naturally accumulate in astrocytes of the aging periventricular brain. Both in vitro and in situ, CSH rapidly induces various heat shock proteins (HSP) in astrocytes long before granulation occurs. In the present study, we determined that CSH treatment resulted in an increase in HSP 27, HSP 90 and heme oxygenase (HO-1) at both the protein and mRNA level. We also showed that C6 glioma cells, unlike primary astrocytes, constitutively express HSP 27, HSP 90 and HO-1 at low levels. Moreover, CSH is incapable of eliciting further HSP expression or inducing granulation in the glioma cells. Our results support the hypothesis that the biogenesis of redox-active astrocytic inclusions in CSH-treated glial cultures and in the aging periventricular brain is dependent on an antecedent cellular stress response.

Animals↗

PubMedDate not supplied

The effects of cysteamine and capsaicin on somatostatin and substance P in medullary nuclei.

Administration of the thiol reagent, cysteamine, reduced the somatostatin content (70-80%) in each of the discrete medullary nuclei assayed without altering the substance P content of the same nuclei. In contrast, capsaicin, the putative neurotoxin for primary sensory afferent neurons had no effect on the somatostatin content of any of the medullary nuclei assayed while depleting the substance P content of the spinal trigeminal nucleus in the same animals.

Animals↗

PubMedDate not supplied

Protection against cis-dichlorodiammine Pt (II) cytotoxicity in vitro by cysteamine.

EMT6/SF cells exposed to cis-dichlorodiammine Pt(II) (DDP) for 1 hr in the presence of 10 mM cysteamine (MEA) survived better than cells treated with DDP alone (DMF-3.1). MEA added to cultures after removal of DDP also protected, even when the two exposures were separated by as long as 4 hr. Protection by MEA was concentration dependent: no significant protection was observed below 1 mM and maximum protection required 5 mM. When cells were incubated with 10 mM MEA immediately after removal of DDP, survival increased as a function of the length of exposure to MEA, reaching a maximum at 2 hr.

Animals↗

PubMed1984

Modification of radiation and dihydroxyanthraquinone-induced cell lethality by cysteamine and N-ethylmaleimide.

The effect of alteration of sulfhydryl levels on the cell lethality induced by ionizing radiation and dihydroxyanthraquinone (DHAQ) was investigated in cultured Chinese hamster V79 cells. DHAQ produces a potentiation of radiation-induced cell lethality, both by increasing the slope and decreasing the shoulder of the survival curve. It has been suggested that DHAQ functions through the production of free radicals which then produce DNA strand breaks and crosslinks, resulting in cytotoxicity. If this mode of action predominates, then one would expect to be able to change the degree of cell kill by modifying conditions such that free radical processes were altered. This was accomplished by the addition of N-ethylmaleimide (NEM) or Cysteamine (CYS) to the culture medium during treatment with DHAQ. It was observed that the combination of DHAQ and NEM did not produce more cytotoxicity than would be expected from an additive interaction. Likewise, CYS did not reduce the cytotoxicity induced by DHAQ. When cells were treated with DHAQ and radiation plus either NEM or CYS, the resultant survival was consistent with an additive interaction between the potentiation of DHAQ for radiation-induced cell kill and the extra effect of NEM or CYS. These results indicate that alterations of sulfhydryl levels do not produce changes in the cytotoxicity induced by DHAQ, nor in the enhancement by DHAQ of radiation-induced lethality. More investigation is required before definite conclusions can be reached as to the mechanisms of action by which DHAQ, alone or in combination with ionizing radiation, induces mammalian cell lethality.

Animals↗

PubMed1985

Radioprotection of EMT6 tumor by a new class of radioprotectors based on a pseudo-peptide cysteamine combination.

Although WR-2721 preferentially protects normal tissues against irradiation, it seemed desirable to find other drugs presenting a lower toxicity and the same radioprotective properties. A new compound, I 102, was selected; it was characterized on one hand by a coupling between cysteamine and an amino-acid, and on the other hand by an acetyl-group, which protects the thiol function. The effects of WR-2721 and of I 102 were studied on EMT6 tumors grafted on BALB/c mice. Whatever the size of the tumor, the cell survival increased as a function of the time elapsed between the injection of I 102 and the end of the irradiation (TI). In contrast, the radioprotection afforded by WR-2721 was found to be independent of TI. The survival curves suggest that, like WR-2721, I 102 protects essentially oxygenated cells.

Amifostine↗