Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cysteamine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources
PubMed1988

A novel non-H1, non-H2 histamine antagonist protects against cysteamine-induced duodenal ulcers in rats.

A newly synthesized para-diphenylmethane derivative, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE), binds with high affinity to the microsomal anti-estrogen binding site (AEBS). Recent data suggest that the DPPE/AEBS binding site is closely related to a novel low-affinity, non-H1, non-H2 histamine site which may be associated with a calcium channel. We previously have shown that DPPE markedly reduces stress-induced and ethanol-induced gastric ulcers and attenuates gastric acid secretion. We now show that DPPE also profoundly reduces cysteamine-induced duodenal ulcers in rats.

Animals↗
PubMed1985

Effects of cysteamine and antibody to somatostatin on islet cell function in vitro. Evidence that intracellular somatostatin deficiency augments insulin and glucagon secretion.

In this study we have characterized the effects of cysteamine (CHS) on the cellular content and release of immunoreactive somatostatin (S-14 LI), insulin (IRI), and glucagon (IRG) from monolayer cultures of neonatal rat islets. Incubation of cultures with 0.1-10 mM CHS for 1 h led to an apparent, dose-dependent reduction of cellular S-14 LI that was 50% of control at 0.3 mM, 87% at 1 mM, and 95% at 10 mM. IRI content was unaffected by CHS up to 1 mM, but at 10 mM 90% loss of IRI occurred. All concentrations were without effect on IRG content. The loss of S-14 LI and IRI was completely reversible with time, but with different recovery rates for the two hormones (48 h for S-14 LI, and 72 h for IRI). Released S-14 LI rose progressively with increasing doses of CHS from 21 +/- 2.5 pg/ml per hour to 41 +/- 1.4 pg/ml per hour at CHS concentrations of 5 mM and 10 mM. IRI and IRG secretion were both also significantly enhanced (by 55% and 88%, respectively), despite the elevated medium S-14 LI. Since CHS reduced cellular S-14 LI but augmented medium S-14 LI, the relative effects of CHS (1 mM) and immunoneutralization with antibody to S-14 LI on IRI and IRG secretion were tested. Anti S-14 LI alone stimulated basal IRG (67%) but not IRI. Cultures rendered S-14 LI deficient with both CHS and anti-S-14 LI exhibited threefold and 2.3-fold potentiation of IRG and IRI secretions, respectively, greater than that expected from the separate effects of the two agents. Increasing medium glucose from 2.8 mM to 16.7 mM stimulated IRI release by 86% and suppressed IRG by 53%. CHS (1 mM) and anti-S-14 LI further augmented stimulated IRI release, by 30%; although 16.7 mM glucose suppression of IRG was still maintained under these conditions, the quantitative IRG response was significantly greater. These results suggest that CHS induces an apparent loss of islet S-14 LI, and at high doses, of IRI as well, but has no effect on A cells. Complete islet S-14 LI deficiency augments IRI and IRG secretion over a wide range of glucose concentrations, suggesting a physiological role of D cells on B cell and A cell regulation. D cell modulation of B cells requires cellular but not extracellular S-14 LI, being mediated probably though direct intracellular communication, whereas the A cells seem to be regulated by both direct contact as well as through locally secreted S-14 LI.

Animals↗
PubMed1983

The effects of cysteamine on thyrotropin and immunoreactive beta-endorphin secretion in the rat.

We examined the effects of the thiol agent cysteamine (CSH), which is known to deplete the hypothalamus of immunoreactive somatostatin, on physiological TSH and beta- endorphin secretion in the adult male rat. CSH at doses of 90 and 300 mg/kg CSH produced a rapid decline in plasma TSH, whereas a dose of 30 mg/kg did not alter plasma TSH levels. After the higher doses of CSH, TSH levels in the blood remained lower than control values on day 2, but returned to normal by 1 week. This decrease in TSH within the plasma was not associated with a reduction in hypothalamic TRH concentrations. The TSH response to 500 ng/kg TRH was normal in CSH-treated animals. Blockade of norepinephrine synthesis with diethyldithiocarbamate (500 mg/kg) or fusaric acid (100 mg/kg) inhibited TSH secretion in a manner similar to that of CSH. beta-Endorphin-like immunoreactivity (bet-End-LI) was elevated in the plasma immediately after CSH (300 mg/kg) administration. This was associated with a 58% reduction in anterior pituitary beta-End-LI and no change in hypothalmic beta-End-LI. Plasma beta-End-LI returned to normal on day 2. The increase in plasma beta-End-LI induced by immobilization stress was not compromised by CSH treatment. The observed effects of CSH on both TSH and beta-End-LI are consistent with a reduction in central norepinephrine neurotransmission through the known actin of CSH to inhibit dopamine-beta-hydroxylase. Acute stress may play a role as well in the observed changes in TSH and beta-End-LI secretion.

Animals↗
PubMed1983

Cysteamine induces depletion of both immunological and biological prolactin activity in the anterior pituitary and blood of the rat.

Previous studies have shown that cysteamine [2-aminoethanethiol (CSH)], given in vivo or in vitro, rapidly but reversibly depletes immunoreactive PRL from the anterior pituitary (AP) through a mechanism which, in vitro, does not appear to involve the dopamine (DA) receptor. In the present investigation, these effects of CSH were explored further with emphasis on determining whether CSH; (1) depletes biological as well as immunological PRL activity from the AP and blood, (2) has effects on plasma PRL in chronically cannulated male rats, (3) alters the PRL response to drugs which stimulate the secretion of the hormone, and (4) acts in vivo via DA receptors to deplete PRL. CSH produced a dose-dependent depletion of both immunological and biological PRL activity from the AP and blood. In chronically cannulated animals, PRL levels in the plasma were undetectable 90 min after CSH administration and remained so for 4 h. However, by 24 h plasma PRL in treated animals had returned to control levels. The PRL response to both domperidone and morphine was virtually abolished in CSH-treated animals. Blockade of DA receptors by pretreatment with domperidone did not alter the ability of CSH to reduce AP PRL stores. These results indicate that CSH: 1) alters both biological and immunological PRL activity by a rapid but reversible effect, and 2) circumvents the DA receptor to deplete pituitary PRL content. Thus, CSH or similar compounds may serve as a prototype for a new class of drugs which can be used in the treatment of hyperprolactinemia.

Animals↗
PubMed1984

Effects of cysteamine on pituitary, MTTW15 tumor, and serum prolactin levels measured by rat lymphoma cell bioassay and radioimmunoassay.

Cysteamine (CSH), a sulfhydryl compound, reduces both serum and anterior pituitary (AP) PRL measured by RIA. We have used the Nb2 lymphoma cell bioassay (BIO) for PRL to evaluate possible CSH-related changes in PRL levels in sera and tissues of male and MtTW15 mammosomatotropic tumor-bearing female rats. Experimental animals received a single sc injection of CSH (300 mg/kg), and samples were collected 0.5-24 h later. Since CSH and serum from CSH rats were toxic in BIO, samples were dialyzed before assay. All samples were evaluated for PRL and GH by RIA as well. A significant decrease (P less than 0.05) in BIO serum PRL was evident in male rats 0.5 h after CSH; levels remained low for 24 h. Serum PRL by RIA was significantly depressed at 4 h but not at 0.5 h or 24 h. PRL in AP extracts was decreased (60-90%) at all times by BIO and RIA. Significant decreases of BIO- and RIA-detectable PRL were recorded in serum and tissues (AP and tumors) at 4 h in tumor rats. Sequentially bled (0.5-4 h) CSH-treated tumor-bearing rats showed 50% and 80% reductions in serum PRL at 1 and 4 h by both BIO and RIA. CSH had no effect on GH levels in sera and tissues of any animal studied at any time interval. Our results substantiate earlier reports on CSH-induced decreases in RIA-detectable PRL. They show that such changes cannot be attributed to assay effects alone, as significant decreases in circulating and stored PRL (both AP and tumor) were evident by BIO. Results with tissue extracts were the most dramatic. They suggest an action of CSH or a metabolic intermediate with stored PRL which reduces both extractable PRL and hormone release. Such an effect of CSH on PRL extraction has been suggested by others. Whatever the mechanism, it appears to be relatively specific, since GH cells were not affected.

Animals↗
PubMed1984

Cysteamine inhibition of bovine pituitary secretory granule prolactin immunoassayability and release.

Cysteamine [2-mercaptoethylamine (CySH)] displays a variety of neuroendocrine effects, the most potent being the depletion of immunoassayable tissue PRL. The present study used bovine adenohypophysial secretory granules to characterize this inhibition of measurable hormone (assayability). CySH decreased assayability in a dose-dependent manner at pH 7.4, with 50% inhibition observed close to 2 mM. Maximal inhibition was found between pH 6.0 and 6.5, whereas diminished (or no) inhibition occurred under alkaline conditions, depending on the buffer. In contrast, reduced glutathione (without CySH) increased assayability at pH 8-8.5, had little potency near neutrality, and inhibited assayability under acidic conditions. Electrophoretic studies under nondenaturing conditions demonstrated that CySH exposure of standard PRL resulted in additional charged species. With granules, CySH markedly decreased the staining of the major PRL band, no new bands were evident, and this effect was abolished by glutathione. Sodium dodecyl sulfate-electrophoretic patterns indicated that CySH resulted in higher apparent mol wt species of granule and standard PRL. This effect was nullified by mercaptoethanol. Never was there evidence for species smaller than monomeric. Depletion of PRL might involve interference with the conversion from oligomeric storage PRL to assayable PRL; 44-fold increases in PRL oligomer immunoactivity after alkali and thiol treatment were reduced to 6-fold increases when CySH was present. Reactions involved in production of assayable hormone appear relevant to secretion, since CySH also inhibited PRL release from granules, with maximal inhibition occurring under acidic conditions. Thus, CySH may be useful in investigating the physicochemical properties of tissue PRL and may also represent an approach to treatment of hyperprolactinemic states.

Animals↗
PubMed1984

Cysteamine inhibition of prolactin immunoassayability and secretion: studies with aminothiophenols and other analogs.

Analogs of the aminothiol cysteamine (CySH) have been studied to clarify the structural features required for exertion of inhibitory effects on PRL. The inhibited functions examined were the detectability of PRL by RIA and the release of PRL from suspensions of isolated secretory granules. The influence on GH assayability and release was also tested. The aromatic compounds 2-aminothiophenol, 3-aminothiophenol, and 4-aminothiophenol shared with CySH the ability to inhibit PRL assayability and release, but were all more potent. Derivatization of the thiol, as in 4-aminothioanisole, was associated with a substantial loss of inhibitory potency, whereas derivatization of the primary amine, as in N-dimethylaminoethanethiol, had no influence. Thiols such as mercaptoethanol, cysteine, glutathione, and others without nearby amino groups were stimulators of PRL assayability and release. The inhibitory effects of the aminothiols were highly pH dependent, being marked at pH 5.5, 6.5, and 7.5, but modest or marginal at 8.5. After CySH exposure, inhibition was reversible in part by extraction of samples with reduced glutathione or at pH 10.5. Though CySH and 4-aminothiophenol induced changes in the electrophoretic migration of granule PRL, similar changes occurred in the migration of standard purified hormone despite the known absence of immunochemical effects. There was close quantitative correlation between the potency of a compound to inhibit PRL assayability and its potency to inhibit PRL release. We conclude that the inhibitory aminothiol action on PRL requires the thiol rather than the sulfide form and involves a reversible interaction which diminishes the immunochemical recognition of granule PRL. This change also results in diminished secretion.

Aniline Compounds↗
PubMed1984

Cysteamine-induced depletion of brain somatostatin is associated with up-regulation of cerebrocortical somatostatin receptors.

Cysteamine (CSH) administered as a single sc injection to rats produced rapid depletion of cerebrocortical Somatostatin-14 like immunoreactivity (S-14 LI) with a significant 48% reduction occurring within 5 min and maximum (72%) decrease at 4 h. The depletion of S-14 LI was associated with a 1.7 fold increase in Bmax of the cerebrocortical S-14 receptors 5 min after CSH administration and a concomitant but slower increase in the affinity of these receptors [dissociation constant (Kd) being 1.8- and 1.6-fold lower than the control at 30 and 60 min, respectively, post CSH]. Incubation of intact synaptosomes with 1 mM CSH at 37 C in vitro for 60 min also caused a rapid depletion of S-14 LI, but in contrast to the in vivo data, there was no change in the Bmax or Kd of the S-14 receptors for up to 30 min beyond which time a 2.8-fold decrease in the affinity of S-14 receptors was observed. Higher concentrations of CSH (greater than or equal to 10 mM) added during the incubation of synaptosomes in vitro completely abolished the specific binding of these receptors. The pituitary S-14 receptors were studied 30 min after CSH administration and unlike the cerebrocortical S-14 receptors at this time did not exhibit any change in Bmax or affinity. When added at the time of the binding assay CSH (1 mM) was without a direct effect on cerebrocortical as well as pituitary membrane S-14 receptors. Furthermore, addition of CSH at the time of binding assay did not destroy the integrity of [125I-Tyr11]S-14. It is concluded that administration of CSH to rats in vivo depletes brain S-14 LI and up-regulates synaptosomal S-14 receptors. Exposure of synaptosomes to CSH in vitro for 30 min also depletes S-14 LI but has no effect on S-14 receptors suggesting that S-14 receptor regulation by S-14 is an in vivo phenomenon or requires the intact cell. CSH has a direct inhibitory effect on S-14 receptor binding after prolonged in vitro incubation. Pituitary S-14 receptors unlike those in the brain are unaffected by S-14 LI depletion at least acutely.

Animals↗
PubMed1985

The mechanism of action of cysteamine in depleting prolactin immunoreactivity.

The thiol reagent cysteamine (CSH) depletes anterior pituitary cells of immunoreactive PRL both in vivo and in vitro. We examined the hypothesis that CSH affects either the solubility or immunoreactivity of PRL through a mechanism involving thiol-disulfide exchange. Adult female rats were treated with either CSH (300 mg/kg, sc) or an equimolar dose of ethanolamine as a control. Anterior pituitary glands were extracted in 0.1 M sodium borate buffer, pH 9.0. Treatment of pituitary extracts with beta-mercaptoethanol (BME) destroys the immunoreactivity of PRL. However, extraction in the presence of reduced glutathione or CSH of pituitaries of rats treated with CSH restores immunoreactive PRL to control levels. Extracts were also subjected to polyacrylamide gel electrophoresis (PAGE). On gels of pituitary extracts of CSH-treated rats, the band that comigrates with purified PRL is diminished compared to that in ethanolamine-treated controls. This is found regardless of whether the borate extracts are treated with BME. However, extraction of the pituitaries in sodium dodecyl sulfate-containing buffer followed by chemical reduction with BME restores the PRL band. Therefore, CSH acts on PRL through a thiol-related mechanism to yield a product that is poorly soluble in aqueous buffer at pH 9 and is poorly immunoreactive. Dispersed anterior pituitary cells in tissue culture were incubated with L-[35S]methionine to radiolabel newly synthesized peptides. These cultures were incubated in the presence of either CSH or ethanolamine. PAGE followed by autoradiography confirmed the above results obtained in vivo. Also, extracts of CSH-treated cultures were subjected to gel permeation chromatography. As determined by PAGE, at least some of the radiolabeled PRL can be recovered from void volume fractions by reduction with BME, indicating that CSH induces the formation, through disulfide exchange, of a high mol wt form of PRL, possibly PRL oligomers.

Animals↗
PubMed1987

Somatostatin-14-like antigenic sites in fixed islet D-cells are unaltered by cysteamine: a quantitative electron microscopic immunocytochemical evaluation.

Exposure of somatostatin cells to cysteamine (CSH) produces a marked reduction in somatostatin-14-like immunoreactivity (S-14 LI) in cell extracts. In the present study we have evaluated the effects of CSH on S-14-like sites in fixed islet D-cells using immunofluorescence and quantitative electron microscopic immunocytochemistry. Monolayer cultures of rat islet cells exposed to CSH (10 mM) for 1 h and subsequently extracted in 1 M acetic acid exhibited a severe reduction in S-14 LI from 6.6 +/- 0.48 to 0.7 +/- 0.06 ng/dish. CSH-induced reduction in S-14 LI persisted when cells were fixed in Zamboni's solution for 16 h and subsequently extracted and assayed. By immunofluorescence, however, the relative numbers of somatostatin-positive cells as well as the fluorescent intensity were identical in control and CSH-treated cells. CSH did not produce any identifiable abnormality in the ultrastructural appearance of D-cells. Protein A-gold labeling of the islet cells showed a uniform distribution of gold particles in both control and CSH-treated cultures. The density of gold particles over D-cell secretory granules from CSH-exposed cultures (36.6 +/- 3.5 particles/micron2) was not different from that in control D-cell granules (42.2 +/- 5.9 particles/micron2). These data clearly indicate that despite a profound reduction by CSH of S-14 LI in tissue extracts, there is no detectable decrease in the same antigenic sites in tissue sections when assessed immunocytochemically.

Animals↗
PubMed1987

The effect of cysteamine, cystamine, and the structurally related compounds taurine, N-acetyl-cysteine, and D-penicillamine on plasma prolactin levels in normal and estrogen-primed hyperprolactinemic rats.

Studies were undertaken to evaluate the effects of cysteamine (CSH), cystamine (CS-S), N-acetyl-cysteine, D-penicillamine, and a major metabolite of CSh, taurine, on plasma PRL levels in normal and estrogen-primed hyperprolactinemic rats. Both CSH and CS-S caused a marked decrease in plasma PRL concentration in hyperprolactinemic rats. The effects of CSH and CS-S lasted for at least 6 h but returned toward pretreatment levels 24 h later. In normal rats a fall in basal plasma PRL concentration was not readily observed but after stimulation with TRH or metaclopramide, PRL secretion elicited by these stimuli was markedly inhibited by CSH and CS-S. The response to TRH or MCP 24 h after treatment with CSH was variable with CS-S appearing to cause an unexpected increase in PRL release in response to TRH or metaclopramide. The structurally related compounds, taurine, N-acetyl-cysteine, and D-penicillamine did not cause any reduction of plasma PRL levels in hyperprolactinemic rats. This may be due, in the case of taurine, to a loss of the free sulfydryl group, in the case of N-acetyl-cysteine, a change in basicity because of a carboxyl group and derivatization of the amino group and D-penicillamine, again a change in basicity due to a free carboxyl group as well as an altered structural relationship between the free amino and sulfydryl groups. These studies indicate that CSH and CS-S by possible reduction to CSH cause a reversible depletion in plasma PRL in normal and hyperprolactinemic rats. Because both substances inhibit different receptor-mediated stimuli, their mechanism of action is likely to be mediated at a common locus involved with the synthesis and release of PRL.

Acetylcysteine↗
PubMed1987

Cysteamine-induced decrease of somatostatin in rat brain synaptosomes in vitro.

The mechanism of somatostatin depletion induced by cysteamine [2-mercaptoethylamine (CySH)] was studied in isolated nerve endings (synaptosomes) from rat brain in vitro. A dose-dependent reduction of somatostatin-like immunoreactivity (SLI) was observed which reached its maximal extent (41%) at a concentration of 300 microM CySH after 1-5 min. There was no release of somatostatin into the incubation medium. CySH at concentrations of up to 10 mM did not interfere in the RIA. Among a variety of compounds, structurally related to CySH 4-aminothiophenol, 2-aminothiophenol and N,N-dimethylaminothiol exhibited the highest efficacy in decreasing somatostatin (60%, 50%, 30%, respectively, at 10 mM and 10 min). The disulfide form of CySH cystamine and dimercaprol resulted in about 15% reduction after 10-min incubation, whereas taurine, alanine, cysteine, and mercaptoethanol were inactive. A saturable, sodium-dependent uptake process was found for the disulfide form of [35S]CySH cystamine [Michaelis-Menten constant (Km) = 18.6 microM, maximum velocity (Vmax) = 2.3 nmol/mg protein X 3 min) which was inhibited by cysteine (87% at 1 mM). [35S]CySH, at concentrations of 20 microM or less, was not stable in buffer solution. It underwent considerable nonenzymatic conversion into its dimeric form (60% at 37 C and 3 min), however it exhibited the same kinetic data for its uptake. Size exclusion HPLC of purified hypothalamic synaptosomes revealed a major SLI peak coeluting with synthetic somatostatin-14 and two minor peaks representing somatostatin-28 and a 13,000 mol wt protein. The three molecular forms of somatostatin were reduced to varied extent by CySH (somatostatin-14 by about 70%, somatostatin-28 by 15%, and the high mol wt form by 30%). Our experiments suggest that high affinity uptake of CySH may precede its action in decreasing somatostatin levels. Increased release or inhibition of synthesis of somatostatin have been excluded as possible mechanisms. It is suggested that SLI is equally affected in nerve endings and in perikarya.

Animals↗
PubMed1989

A critical evaluation of cysteamine as a tool to deplete somatostatin in the rat central nervous system.

The wide central nervous system (CNS) distribution of somatostatin (SRIF) as well as the well documented reduction in SRIF concentration in the cerebral cortex in patients with Alzheimer's disease have served as an impetus for studies of this peptide's neurobiological role in the brain. These studies were designed to evaluate the efficacy of centrally administered cysteamine (CYS) as a tool to deplete SRIF in the hypothalamus (HYP) and extrahypothalamic brain areas. Somatostatin was measured by RIA in the frontal cortex (COR), hippocampus (HIP), and HYP in rats after seven daily infusions of CYS into unilateral cannulae stereotaxically positioned into either the lateral ventricle (LV; 300 micrograms/2 microliters) or the dorsal HIP (100 micrograms/2 microliters), and after single (300 mg/kg) or daily (100 mg/kg) sc injections; rats were killed 4 or 24 h after the last injection. After LV infusions, the SRIF concentration was significantly reduced only in the HYP (35% at 4 h and 27% at 24 h). After HIP infusions, the SRIF concentration was significantly reduced only in the HYP at 4 h (23%); no reductions were observed at 24 h. Both a single and repeated sc administrations of CYS reduced SRIF in the HYP only 24 h after treatment (54% and 50%, respectively). Acute sc CYS reduced SRIF in the COR (23%) and the HYP (29%) 4 h after treatment; repeated sc CYS reduced SRIF in the COR (25%) and the HYP (63%). Although the reduction of SRIF in the HYP was increased by repeated sc dosing, the reduction of extrahypothalamic SRIF by sc CYS was relatively small in magnitude and was not enhanced by repeated dosing. These results suggest that CYS is not an ideal tool for depletion of extrahypothalamic SRIF after sc or CNS administration and, moreover, raise serious questions about studies in which behavioral or endocrine alterations after CYS treatment were attributed to specific actions on SRIF-containing neurons.

Animals↗
PubMed1990

Cysteamine-induced enhancement of growth hormone-releasing factor (GRF) immunoreactivity in arcuate neurons: morphological evidence for putative somatostatin/GRF interactions within hypothalamus.

The episodic secretion of GH is regulated through the reciprocal release into the hypophyseal portal circulation of two hypothalamic peptides, SRIF and GRF. Recent physiological evidence suggests that, in addition to exerting their well documented opposite actions at the level of the anterior pituitary, SRIF and GRF may interact within the central nervous system to modulate GH secretion. The aim of the present study was to provide morphological evidence to support the concept that SRIF exerts an influence on the GRF-containing neuronal system within the hypothalamus. To accomplish this, we used the thiol agent cysteamine (CSH; 300 mg/kg sc) to manipulate endogenous hypothalamic SRIF and examined its effects on the immunoreactivity and mRNA content of GRF-containing arcuate (ARC) neurons, using immunohistochemistry and semi-quantitative in situ hybridization, respectively. Hypothalamic SRIF content and pulsatile GH secretion were also monitored. CSH treatment reduced hypothalamic immunoreactive SRIF concentrations (to 60% of vehicle-injected control values) and severely suppressed the spontaneous surges of GH release (mean GH peak amplitude: 24.2 +/- 2.7 vs. 168.0 +/- 27.8 ng/ml in H2O-injected controls; P less than 0.001). CSH treatment also resulted in a striking increase in the number and labeling density of GRF-immunoreactive cells detected in the ARC nucleus. Cell counts revealed an overall 126% increase, over controls, in the mean number of detectable GRF-positive ARC neurons. This increase (P less than 0.01) was apparent over all rostrocaudal levels of the ARC nucleus, but was most pronounced within the caudal tier. Administration of CSH also produced a massive qualitative increase in the intensity and extent of staining of GRF-positive terminal elements in the external zone of the median eminence. Conversely, CSH treatment resulted in a decline in GRF mRNA-associated signal in cells of the ARC nucleus, with this decline being most evident in the caudal third of the nucleus. The finding of an increase in GRF immunoreactivity in ARC neurons in association with a decrease in plasma GH, as well as with a decline in relative GRF mRNA content, suggests that CSH leads to an overall decrease in GRF release from the median eminence. These results provide morphological evidence to support the concept of a SRIF-mediated central influence on the GRF-containing ARC neuronal system. Such central regulation of GRF by SRIF may be an important mechanism in the physiological control of pulsatile GH secretion.

Animals↗
PubMed1992

Effects of cysteamine administration on somatostatin biosynthesis and levels in rat hypothalamus.

A single injection of cysteamine (CSH; 2-aminoethanethiol; 300 mg/kg, sc) into male rats produced a rapid decline in immunoreactive somatostatin (IR-SRIF) levels in the hypothalamus (to 20% of preinjection values within 12 h) which persisted for several days. The levels of both somatostatin-14 (SRIF-14) and somatostatin-28 (SRIF-28) were reduced. In contrast, the levels of somatostatin-28(1-12) were unaffected. Most (80-90%) of the lost SRIF molecules (both SRIF-14 and SRIF-28) could be recovered from CSH-injected rats by subjecting hypothalamic samples to denaturing, reducing, and reoxidizing conditions. These results suggest that CSH does not deplete the hypothalamus of SRIF molecules, but, instead, alters their chemical structures, rendering them undetectable using a SRIF-14-directed RIA. CSH injection also caused a rapid and complete suppression (within 1 h) of [35S]cysteine incorporation into SRIF-14 and SRIF-28. This reduction, however, was short-lived; normal incorporation rates returned within 10 h of drug administration. CSH did not influence [35S] cysteine incorporation into acid-precipitable protein or [35S]cysteine specific activity in the hypothalamus. In addition, [35S]SRIF molecules were not recovered from hypothalami of CSH-treated rats by subjecting samples to denaturing, reducing, and then reoxidizing conditions. These findings indicate that CSH injection causes a true, but short-lived (1- to 10-h), suppression of hypothalamic SRIF-14 and SRIF-28 formation. Finally, biosynthesis studies of longer duration revealed no prolonged effects of CSH. The drug produced no changes 4, 24, or 72 h postinjection in hypothalamic levels of the prepro-SRIF mRNA. Moreover, two injections of CSH, separated by 3 days, which continuously suppressed IR-SRIF levels for almost 1 week, caused only a transient suppression of [35S]SRIF-14 and [35S]SRIF-28 synthesis after each injection. These results indicate that the SRIF biosynthetic pathway is not activated by the prolonged CSH-induced depletion of IR-SRIF stores.

Animals↗
PubMed1986

Huntington's disease: effect of cysteamine, a somatostatin-depleting agent.

Somatostatin levels in the basal ganglia are elevated in Huntington's disease. A controlled therapeutic trial of the somatostatin-depleting agent, cysteamine, was therefore conducted in five patients, including one with the rigid-akinetic form. Maximum tolerated dosage for 2 weeks produced no consistent change in extrapyramidal or dementia scores. Somatostatin concentrations were not significantly altered in plasma or CSF. Growth hormone levels, on the other hand, more than doubled, suggesting a functionally significant decrease in central somatostatin levels.

Adult↗
PubMed1987

Roles of gastric motility changes in cytoprotection induced by acetazolamide and cysteamine in rats.

The present study was undertaken using acetazolamide (AZ) and cysteamine (Cys) to investigate the relationship between gastric motor activity and the phenomenon of "cytoprotection" in rats. Both AZ (10-100 mg/kg) and Cys (10-100 mg/kg), given either p.o. or s.c., significantly reduced the formation of gastric mucosal injury caused by HCl-ethanol (1 ml of 60% ethanol in 150 mM HCl, p.o.). The protective effect of Cys appeared within 10 min, reached the maximal levels 30 min later, while that of AZ appeared from 30 min after administration and became potent with a latency period after treatment. Neither indomethacin (IM: 5 mg/kg, s.c.) nor N-ethylmaleimide (NEM: 5 mg/kg, s.c.) significantly affected the protective effect of Cys, whereas that of AZ was almost totally antagonized by IM. Both AZ and Cys, given either intragastrically or s.c., significantly inhibited gastric motor activity measured as intraluminal pressure recordings, but had minimal effect on acid and alkaline secretion. IM significantly attenuated the inhibitory effect of AZ on the motor activity, while NEM did not affect the inhibited motor responses caused by AZ and Cys. A significant relationship was found between the inhibitory effects of these two drugs on gastric motor activity and HCl-ethanol-induced mucosal injury, the correlation coefficient being 0.819 (P less than 0.01). When the mucosal folds were visualized with Gentian Violet (1 ml of 0.5% v/v, p.o.), both AZ and Cys significantly prevented the localized staining along the mucosal folds, suggesting dissolution of the folds. These results suggest that both AZ and Cys protect the gastric mucosa against injury caused by HCl-ethanol, probably through a dissolution of mucosal folds due to inhibition of gastric motor activity.

Acetazolamide↗
PubMed1985

Rapid depletion of somatostatin in isolated mouse pancreatic islets after treatment with cysteamine.

Cysteamine (CSH; beta-mercaptoethylamine) is known to deplete pancreatic somatostatin without affecting the insulin or glucagon content. It may therefore be useful for studies of intra-islet regulation of hormone release. In the present study injection of CSH (60 mg/kg body weight) to mice decreased the somatostatin content of their isolated pancreatic islets to 50% in 1 h and 30% in 4 h as compared to islets of non-injected controls. Exposure of isolated mouse islets to CSH (100 micrograms/ml) for either 0.5 h followed by incubation in control medium for 3.5 h, or continuously for 4 h, decreased the somatostatin content to about 40% of the controls. There was no change in the islet content of insulin or glucagon. Islets pretreated with CSH (100 micrograms/ml) for 1 h in vitro showed a decreased glucose stimulation of both oxygen consumption and glucose oxidation. Measurements of insulin release after a similar preincubation of the islets indicated an increased basal release and an attenuated glucose stimulation. It is concluded that CSH rapidly decreases islet somatostatin both in vivo and in vitro. This depletion may lead to a loss of tonic inhibition by islet somatostatin on basal insulin release. It is, however, more plausible that the increased basal insulin release reflected a direct effect of CSH on the islet beta-cells.

Animals↗