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PubMed2001

Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures.

Polyamines are ubiquitous cations that are essential for cell growth, regeneration and differentiation. Increases in polyamine metabolism have been implicated in several neuropathological conditions, including excitotoxicity. However, the precise role of polyamines in neuronal degeneration is still unclear. To investigate mechanisms by which polyamines could contribute to excitotoxic neuronal death, the present study examined the role of the polyamine interconversion pathway in kainic acid (KA) neurotoxicity using organotypic hippocampal slice cultures. Treatment of cultures with N1,N(2)-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527), an irreversible inhibitor of polyamine oxidase, resulted in a partial but significant neuronal protection, especially in CA1 region. In addition, this pre-treatment also attenuated KA-induced increase in levels of lipid peroxidation, cytosolic cytochrome C release and glial cell activation. Furthermore, pre-treatment with a combination of cyclosporin A (an inhibitor of the mitochondrial permeability transition pore) and MDL 72527 resulted in an additive and almost total neuronal protection against KA toxicity, while the combination of MDL 72527 and EUK-134 (a synthetic catalase/superoxide dismutase mimetic) did not provide additive protection. These data strongly suggest that the polyamine interconversion pathway partially contributes to KA-induced neurodegeneration via the production of reactive oxygen species.

Animals↗
PubMedDate not supplied

Dimethylsilane polyamines: cytostatic compounds with potentials as anticancer drugs. II. Uptake and potential cytotoxic mechanisms.

Dimethylsilane tetramines are structural analogues of spermine with a (CH3)2 Si-group incorporated into the central carbon chain. They have potential as anticancer drugs. Their cytotoxic effect was considered to rely mainly on their polyamine antagonist property. In order to obtain new ideas about cellular mechanisms, which are potential targets of the dimethylsilane polyamines, the effects of these compounds on some basic cell functions, such as protein and DNA synthesis, and calmodulin antagonism were studied. In addition, their mode of accumulation in cells was investigated. It became evident that the intracellular accumulation of dimethylsilane polyamines is almost exclusively achieved via the polyamine transport system. However, the exchange of a part of the intracellular natural polyamines against dimethylsilane polyamines has only a small effect on polyamine uptake. Binding to the endoplasmic reticulum and inhibition of protein synthesis are presumably important for the cytotoxic action of bis(11-amino-4,8-diazaundecyl)dimethylsilane, a hexamine, but seem of no importance for the tetramines. Calmodulin antagonism, however, is likely to contribute to their cytotoxic effect.

Animals↗
PubMed1997

Polyamine metabolism in various tissues during pathogenesis of chloroquine-susceptible and resistant malaria.

The pathophysiological impact of infections with chloroquine-susceptible (CQS) and chloroquine-resistant (CQR) strains of Plasmodium berghei in Mastomys natalensis was studied with respect to changes in polyamine profiles in various tissues. Both CQS and CQR infections produced similar changes in polyamine profiles of various tissues. Maximum increase was recorded in spleen followed by liver and lungs. Renal, cardiac and cerebral tissues did not register significant changes. An increase in spermidine level was more prominent as compared to putrescine and spermine, leading to an overall increase in spermidine/spermine ratio. This ratio is an important index of cellular proliferation. Liver did not show considerable change in the activities of ornithine decarboxylase and S-adenosyl methionine decarboxylase, the regulatory enzymes of the polyamine biosynthetic pathway. Spleen however, registered marked induction of both the enzymes which was more prominent in the CQS infection than CQR. Normal erythrocytes contained traces of polyamine while the erythrocytes loaded with P. berghei parasites exhibited appreciably higher polyamine levels. Spermidine was detected in about five-fold higher concentrations than putrescine and spermine which were detected in equimolar levels. Again, CQS as well as CQR P. berghei, exhibited qualitatively and quantitatively similar polyamine profiles thus ruling out a role of polyamines in CQ-resistance in malaria.

Adenosylmethionine Decarboxylase↗
PubMed1993

Polyamines, chromatin structure and transcription.

Nucleosomes are the basic elements of chromatin structure. Polyamines, such as spermine and spermidine, are small ubiquitous molecules absolutely required for cell growth. Photoaffinity polyamines bind to specific locations in nucleosomes and can change the helical twist of DNA in nucleosomes. Acetylation of polyamines reduces their affinity for DNA and nucleosomes, thus the helical twist of DNA in nucleosomes could be regulated by cells through acetylation. I suggest that histone and polyamine acetylation act synergistically to modulate chromatin structure. On naked DNA, the photoaffinity spermine bound preferentially to a specific 'TATA' sequence element, suggesting that polyamines may be involved in the unusual chromatin structure in this region. Further work is needed to test whether the specificities shown by photoaffinity polyamines are also shown by cellular polyamines; such experiments are now feasible.

Affinity Labels↗
PubMed2004

Liquid chromatographic determination of polyamines in human urine based on intramolecular excimer-forming fluorescence derivatization using 4-(1-pyrene)butanoyl chloride.

A liquid chromatographic method for highly sensitive and selective fluorometric determination of polyamines (putrescine, cadaverine, spermidine and spermine) in human urine is described. This method is based on an intramolecular excimer-forming fluorescence derivatization with a pyrene reagent, 4-(1-pyrene)butanoyl chloride (PBC), followed by reversed-phase liquid chromatography. The method offers higher sensitivity for determination of spermidine and spermine than previously reported method utilizing 4-(1-pyrene)butyric acid N-hydroxysuccinimide ester as a derivatization reagent. Samples containing free polyamines in diluted human urine were directly derivatized with PBC and separated on an octyl column. The derivatives were detected at excitation 345 and emission 475 nm wavelengths. For determination of total polyamine content, the conjugated polyamines were first hydrolyzed in 4 M HCl. The detection limits (signal-to-noise ratio = 3) for polyamines in urine were 1.1-3.4 pmol/mL. At optimized derivatization and chromatographic conditions, interferences such as biogenic monoamines gave no peaks or the peaks did not interfere with the peaks of polyamine derivatives. In conclusion, the present derivatization method allows direct determination of polyamines in human urine samples without the need for sample clean-up procedures.

Butanes↗
PubMed1996

JAR human placental choriocarcinoma cells actively synthesize, take up and release polyamines.

Uptake of polyamines has been investigated extensively in many cells, but not in placenta, where the polyamine-polyamine oxidase system is supposed to have an immunoregulatory function in pregnancy. Due to the importance of the transfer in this tissue, we have started this study. JAR human placental choriocarcinoma cells in monolayer at confluency were used as a model for measuring the key enzymes of polyamine synthesis and interconversion, rate of uptake and efflux, and the polyamine content. Polyamines were taken up by JAR cells and released by an independent mechanism. Ornithine decarboxylase and spermidine acetyltransferase activities and the rate of transport in and out of the cell were much higher than in other cells, such as L1210 cells. However the systems used for uptake and release appear in many respects to be similar to those observed in L1210 cells, but different from others. The uptake appears to be regulated by an inhibitory protein. Moreover, protein kinase C appears to be involved in the process. The efflux also is regulated as in L1210 cells, through control of H+ and Ca2+ concentration. In conclusion, this study shows that, in JAR cells, ornithine decarboxylase and spermidine acetyltransferase activities were much higher than in other cells, and so was the rate of transport in and out of the cells. As a result, a much higher polyamine content was observed.

Animals↗
PubMedDate not supplied

Polyamine profiles in rat testis, germ cells and Sertoli cells during testicular maturation.

Polyamine cellular concentrations (putrescine, spermidine and spermine) in the rat testis and testicular cell types were determined by fluorescence spectroscopy of their dansyl derivatives. A method is described to separate dansylated polyamines by high performance liquid chromatography in less than 12 minutes. In rat Sertoli cells, polyamine concentrations (per mg DNA) were greater than those in germ cells and the testis. The concentrations of all three polyamines increased with age. Concentrations of spermidine and spermine in germ cells also increased with age and leveled off after 27 to 35 days. On the other hand, higher putrescine levels were found in the testis of young rats (13 to 22 days) while the greatest spermidine and spermine contents were observed in the testis from rats of 31 to 35 days old. Of great interest, Sertoli cells from all age groups studied released a relatively large quantity of putrescine and a smaller amount of spermidine, but no spermine, into culture media. The amount of polyamine released by Sertoli cells varied with the age of the animal. Sertoli cells from 27-day-old rats released the greatest quantity of putrescine on a per mg DNA basis. The release of putrescine increased after hypotonic treatment that removed contaminating germ cells from the remaining Sertoli cells. It is concluded that cellular polyamine levels in the rat testis, germ cells and cultured Sertoli cells and the amount of polyamines released by Sertoli cells were age-dependent during the first wave of spermatogenesis.

Aging↗
PubMed1990

Management of polyamine pools and the regulation of ornithine decarboxylase.

The management of polyamine synthesis and polyamine pools differs fundamentally from that of most other small molecular-weight endproducts. The polyamines are vital to growth and important cellular functions, but they are toxic in excess. I argue here that their multivalent cationic character, leading to binding to cell constituents, precludes fluent feedback inhibition of synthesis. This has led to the development of elaborate alternative regulatory mechanisms controlling ornithine decarboxylase, the key initial enzyme of the pathway. Poorly regulated polyamine synthesis and the toxicity of polyamines impose upon cells a need to control uptake and to dispose of excess polyamines. Recent data on polyamine transport suggest unorthodox mechanisms of accomplishing these functions.

Animals↗
PubMed1981

Induction of polyamine limitation in Chinese hamster ovary cells by alpha-methylornithine.

Chinese hamster ovary (CHO) cells in culture were limited for polyamines through the use of alpha-methylornithine (alpha MO), a competitive inhibitor of ornithine decarboxylase. Initial exposure of the cells to the inhibitor caused growth rate and intracellular polyamine content to decline continuously. Reseeding the alpha MO-treated cells into medium containing the inhibitor resulted in steady-state (exponential) growth at cell densities below 5 x 10(3) cells/cm2, at a rate approximately twofold slower than untreated cells. Under these conditions, putrescine and spermidine were undetectable and spermine remained relatively constant at a level approximately half that found in untreated cells. Addition of exogenous putrescine elevated the polyamine content and stimulated the growth of alpha MO-treated cultures. Thus, growth rate correlated with polyamine content in the alpha MO-treated cells. The growth of reseeded, alpha MO-treated cells became nonexponential at a density (5 x 10(3) cells/cm2) far below that at which untreated cells departed from exponential growth (1 x 10(5) cells/cm2). Medium obtained from high density, alpha MO-treated cultures inhibited the growth of cells at low density in the presence of alpha MO. Doubling the concentration of the defined components of conditioned medium did not markedly affect its capacity to inhibit growth. However, dialysis completely not markedly affect its capacity to inhibit growth. However, dialysis completely removed the inhibitory activity from conditioned medium. The results imply that a low molecular weight inhibitor of growth is produced by polyamine-limited cells. This is a variable that must be controlled in studies with polyamine-limited animal cells. Morphological studies indicated that subcellular organelles, including mitochondria, were largely unaffected by treatment with alpha MO. The maintenance of mitochondrial integrity in the presence of alpha MO demonstrates that the swelling of mitochondria observed previously in cells treated with methylglyoxal bis(guanylhydrazone) was not due to polyamine limitation. alpha MO-treated cells did, however, accumulate numerous cytoplasmic vacuoles. The identity of these vacuoles and their relationship to cellular physiology is not yet understood.

Animals↗
PubMed1977

Serum polyamine alterations in surgical patients with colorectal carcinoma.

Polyamines, by virture of their regulatory role in the cellular synthesis of DNA, RNA, and protein, are potential indicators of malignant growth. In view of this, serum polyamine levels of patients with colorectal carcinoma or benign bowel disease were examined. Of 53 patients with colorectal carcinoma, 35 (66%) showed elevations of 1 or more polyamines. Nine patients with benign bowel disease (villous adenoma, Gardner's syndrome, familial polyposis, and diverticulitis) showed normal serum polyamine levels except 1 patient with a villous adenoma. Patients with colorectal carcinoma were designated stage A, B, C, or D depending on the progression of their disease. All patients classified as D showed elevation of 1 or more polyamines. Serum polyamines became elevated following surgery in patients with colorectal carcinoma as well as those with benign bowel diseases, suggesting a relationship to the surgical procedure. Preliminary longitudinal studies of patients with colorectal carcinoma (B stage) undergoing curable surgical procedures show normal polyamine levels and no evidence of disease at 15 months.

Colonic Diseases↗
PubMed2006

Role of polyamines in arginine-dependent colon carcinogenesis in Apc(Min) (/+) mice.

We evaluated the role of polyamines in arginine-dependent intestinal tumorigenesis in Apc(Min) (/+) mice. Arginine is a substrate for ornithine synthesis and thus can influence polyamine production. Supplementing the diet with arginine increased intestinal and colonic polyamine levels and colonic carcinogenesis. Inhibiting polyamine synthesis with D,L-alpha-diflouromethylornithine (DFMO) decreased small intestinal and colonic polyamine pools. In mice provided basal diet, but not when supplemented with arginine, DFMO decreased small intestinal tumor number and burden, and increased intestinal apoptosis. In mice provided supplemental arginine in the diet, DFMO induced late apoptosis and decreased tumorigenesis in the colon. DFMO slightly reduced tumor incidence, number, and size while significantly decreasing tumor burden and grade. These changes in colon tumorigenesis did not occur in mice not provided supplemental arginine. Our study indicates that polyamines play unique roles in intestinal and colonic carcinogenesis in Apc(Min) (/+) mice. Inhibition of polyamine synthesis suppresses the arginine-dependent risk of colon tumorigenesis, resulting in apoptosis induction and decreased tumorigenesis, in this murine model.

Animal Feed↗
PubMed2003

Polymethylene tetraamine backbone as template for the development of biologically active polyamines.

The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of ligands for different biological targets. As a matter of fact, the insertion of different pharmacophores onto the polymethylene tetraamine backbone can tune both affinity and selectivity for any given receptor. The application of this approach provided a prospect of modifying benextramine (1). structure to achieve specific recognition of muscarinic receptors that led to the discovery of methoctramine (2). which is widely used as a pharmacological tool for muscarinic receptor characterization. In turn, appropriate structural modifications performed on the structure of methoctramine led to the discovery of new polyamines endowed with high affinity and selectivity for (a). muscarinic receptor subtypes, (b). G(i) proteins, and (c). muscle-type nicotinic receptors. Thus, polyamines tripitramine (9) and spirotramine (33), among others, were designed, which were shown to be highly selective for muscarinic M(2) and M(1) receptors, respectively. Several polyamines have been discovered, which inhibit noncompetitively a closed state of the nicotinic receptor. These ligands, such as 66, resulted in important tools for elucidating the mode and site of interaction of polyamines with the ion channel. It was discovered that reducing the flexibility of the diaminohexane spacer of methoctramine led to polyamines, such as 70, which are endowed with a biological profile significantly different from that of the prototype. Most likely, tetraamine (70) is a potent activator of G(i) proteins. Finally, the universal template approach formed the basis for modifying benextramine (1) structure to the design of ligands, which display affinity for acetylcholinesterase and muscarinic M(2) receptors. Thus, these polyamines, such as caproctamine (78), could have potential in the investigation of Alzheimer disease.

Muscarinic Antagonists↗
PubMed2000

Polyamines: mysterious modulators of cellular functions.

In recent years the functions of polyamines (putrescine, spermidine, and spermine) have been studied at the molecular level. Polyamines can modulate the functions of RNA, DNA, nucleotide triphosphates, proteins, and other acidic substances. A major part of the cellular functions of polyamines can be explained through a structural change of RNA which occurs at physiological concentrations of Mg(2+) and K(+) because most polyamines exist in a polyamine-RNA complex within cells. Polyamines were found to modulate protein synthesis at several different levels including stimulation of special kinds of protein synthesis, stimulation of the assembly of 30 S ribosomal subunits and stimulation of Ile-tRNA formation. Effects of polyamines on ion channels have also been reported and are gradually being clarified at the molecular level.

Animals↗
PubMed2001

Transglutaminase activity is involved in polyamine-induced programmed cell death.

Natural polyamines, i.e., putrescine, spermidine, and spermine, are ubiquitous molecules essential for cell proliferation and differentiation. In the present study, the effect of polyamines on primary cultures of bovine aortic endothelial cells (BAECs), rat aortic smooth muscle cells (RASMCs), and a human melanoma cell line was examined. While in the absence of fetal calf serum (FCS) polyamines had no effect on viability, in the presence of FCS spermidine and spermine, at concentrations close to physiologic levels, induced a dose-dependent cell death, whereas putrescine was ineffective. RASMCs were significantly more sensitive than other cells. FACS analysis, oligo-nucleosome ELISA, Hoechst nuclear staining, and Annexin V-FITC quantification showed that cell death was likely due to apoptosis. Cells exposed to spermidine showed a marked increase of intracellular transglutaminase (TGase) activity ( approximately 30-fold over control). Inhibitors of polyamine oxidation or inhibitors of TGase activity prevented polyamine-induced apoptosis. Moreover, tissue TGase overexpression significantly increased cell sensitivity to polyamine, suggesting that this effect is likely related to enhanced intracellular TGase activity. These data indicate that polyamines may modulate cell viability through a novel TGase-dependent process.

Animals↗
PubMed1988

The influence of polyamine-nucleic acid complexes on Fe2+ autoxidation.

Polyamines are able to affect Fe2+ autoxidation in the presence of suitable low molecular weight phosphorus-containing compounds; the inhibitory effect exerted by polyamines is directly related to their ability to bind phosphorus-containing compounds. It is well known that polyamines, as polycations at physiological pH, bind strongly to nucleic acids. In this paper it is shown that polyamines, also in the presence of nucleic acids, inhibit Fe2+ autoxidation and thus depress the generation of free oxygen radicals. Most of the nucleic acids tested inhibited Fe2+ autoxidation although the concentration which causes half maximal effect differs. Polyamine effect on Fe2+ autoxidation varies greatly depending on the single or double stranded nature of the nucleic acid. In the present of single stranded nucleic acids, spermine and spermidine potentiate the inhibition of Fe2+ autoxidation by these nucleic acids. A relationship exists between the ability of spermine to interact with single stranded nucleic acids and to inhibit Fe2+ autoxidation in their presence. When double stranded nucleic acids are present, polyamines reverse the inhibition of Fe2+ autoxidation exerted by these nucleic acids. Molecular mechanisms are proposed to explain these experimental results. The hypothesis that polyamines may inhibit oxidative damage caused to nucleic acids by Fe2+ autoxidation, is also discussed.

Animals↗
PubMed1997

Synthetic methods for polyamine linkers and their application to combinatorial chemistry.

Polyamines and polyamine conjugates display a diverse range of important biological functions, ranging from antibiotics to immunosuppressants and glutamate receptor antagonists. For these reasons, polyamines provide an excellent template/scaffold for combinatorial chemistry. In this paper we present methods for the solid-phase immobilisation of polyamines for use in synthetic and combinatorial chemistry and describe how they have been employed in the preparation of a number of important polyamine conjugates and polyamine libraries. Thus, we have designed, synthesised and utilised a number of polyamine linkers for both solution and resin screening combinatorial application.

Chemistry, Organic↗
PubMed1984

Anti-inflammatory effects of polyamines in serotonin and carrageenan paw edemata - possible mechanism to increase vascular permeability inhibitory protein level which is regulated by glucocorticoids and superoxide radical.

Serotonin paw edema of mice and carrageenan paw edema of rats were inhibited by subcutaneously or orally administered certain polyamines. They must be given at least 2 h before serotonin challenge to get inhibitions which were blocked by the concomitant injections of cycloheximide. Thirty percent inhibitory dose (ID30) of polyamines (s.c.) 3 h before serotonin (s.c.) were: spermidine (8 mg/kg), spermine 28 mg/kg) and putrescine (55 mg/kg). Agmatine, cadaverine, ornithine, citrulline, lysine and arginine were not inhibitory even at 200 mg/kg. Three inhibitory polyamines were effective by oral administration but were not inhibitory by local administration into the paws. Intravenous injections of spermidine also required 2 h of lag period for inhibitions. Serotonin edema was inhibited by dexamethasone (1 mg/kg), prednisolone (1 mg/kg) or by superoxide dismutase (SOD, 5 mg/kg) in lag period requiring manner (s.c. and i.v.). High dose of cyclo-oxygenase inhibitors indomethacin and diclofenac sodium, lipo-oxygenase inhibitor BW755C (30 mg/kg s.c., respectively) and phospholipase A2 inhibitor quinacrine (100 mg/kg s.c.) failed to inhibit serotonin edema, suggesting that arachidonate metabolites are not participating in this model. ID30 of polyamines which were administered (s.c. and oral) to rats 3 h before carrageenan and determined at 3 h by paw weight were: spermidine (28 and 100 mg/kg), spermine (18 and 90 mg/kg) and putrescine (both greater than 200 mg/kg). Adrenalectomized rats responded to polyamines just as normal rats. Local vascular permeability, irritancy and acute toxicity were also tested in mice. Polyamines were proved to be glucocorticoid-type anti-inflammatory drugs. Polyamines may be mediators of glucocorticoids for the synthesis of the postulated vascular permeability inhibitory protein (called as 'vasoregulin' for convenience). Anti-inflammatory effect of glucocorticoid is recently explained by its capacity to induce phospholipase A2 inhibitory protein(s) (macrocortin or lipomodulin). However, this hypothesis has not yet been proved by in vivo experiment and our data suggest that there is induction by glucocorticoid of another kind of protein which does not inhibit phospholipase A2 activity.

Adrenalectomy↗
PubMed1999

Endogenous polyamines modulate Ca2+ channel activity in guinea-pig intestinal smooth muscle.

The polyamines spermine and spermidine inhibit L-type Ca2+ channels in whole-cell recordings from guinea-pig ileum cells (Gomez and Hellstrand, Pflügers Arch, 430:501-507, 1995 [4]). To study whether they modulate channel activity under physiological conditions, we further investigated their actions on Ca2+ channels and the effects of altered cellular polyamine contents. In inside-out patches, spermine (0.1-1 mM) inhibited channel activity without affecting the amplitude of unitary currents. In cell-attached recordings, addition of spermine to the bath did not influence channel activity in the patch, indicating that its extracellular action is direct and not mediated via passage of the polyamine through the cell membrane. Cellular contents of spermidine and spermine were decreased by about 50% by organ culture of ileum strips for 5 days with the adenosylmethionine decarboxylase inhibitor CGP 48664 (10 microM). This caused enhanced channel activity in cell-attached recordings, suggesting a reduced level of channel block by endogenous polyamines compared with control cells. Whole-cell recordings in the perforated patch mode showed increased current in polyamine-depleted cells, while this was not seen when cells were dialysed with the pipette solution. We conclude that polyamines block Ca2+ channels from the inside as well as the outside of the cell membrane, and that endogenous polyamines in smooth muscle modulate Ca2+ channel activity.

Amidines↗