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PubMed1991

Differential response of striatal dopamine and muscarinic cholinergic receptor subtypes to the loss of dopamine. II. Effects of 6-hydroxydopamine or colchicine microinjections into the VTA or reserpine treatment.

In the previous paper it was demonstrated that striatal dopamine (DA) D1 and D2 receptor subtypes and muscarinic M1 and M2 receptor subtypes show differing responses to lesions of the mesostriatal DA system. To examine this differential regulation further rats were given unilateral injections of 6-hydroxydopamine (6-OHDA) or colchicine into the ventral tegmental area (VTA), or treated chronically with reserpine or saline. Two weeks later the animals were tested for their behavioral response to a subthreshold dose of apomorphine and 24 h later their brains were removed and processed for quantitative autoradiography or for analysis of DA levels by high-performance liquid chromatography. The 6-OHDA-lesioned animals showed a supersensitive rotational response to apomorphine. The loss of DA, loss of DA uptake sites, regulation of DA D1 and D2 receptors and regulation of the muscarinic cholinergic system was similar to the previous paper. Injection of colchicine in the VTA resulted in incomplete loss of striatal DA (50%), [3H]mazindol binding (50%), and no behavioral supersensitivity to apomorphine. There was a small loss of presynaptically located D2 receptors (13%). Similar to the 6-OHDA lesions there was a loss of D1 (12%) and M1 receptors. Reserpine treatment produced an 86% decrease in DA levels, an enhanced stereotyped responsiveness to apomorphine, and an increase of both D2 (28%) and D1 receptors (26%). There was a loss of muscarinic M1 but not M2 receptors. Thus removal of DA terminals or blockade of transport of proteins in the mesostriatal axons can lead to a reduction in D1 receptor density in the striatum. In contrast, loss of DA without removal of DA terminals leads to a significant up-regulation of the D1 receptor. D2 receptors show increases following removal of DA or of DA terminals. Alteration in the muscarinic cholinergic system following damage to the mesostriatal DA system is a complex response not mimicked by either reserpine or colchicine treatment.

Animals↗
PubMed1988

Colchicine acts as a progression factor to initiate DNA synthesis in quiescent Balb/c 3T3 cells.

In quiescent Balb/c 3T3 cells, competence factors such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and platelet-derived growth factor (PDGF) synergize with progression factors such as insulin to initiate DNA synthesis. In this study, we found that colchicine, a microtubule-disrupting agent, acted synergistically with TPA, but not with insulin, to induce the maximal stimulation of DNA synthesis. Colchicine also synergized with PDGF in the presence of epidermal growth factor to elicit nearly the optimal induction of DNA synthesis. Moreover, it acted synergistically with fibroblast growth factor, another competence factor. These results suggest that colchicine acts as a progression factor like insulin in quiescent Balb/c 3T3 cells.

Animals↗
PubMed1988

The importance of the phenyl-tropolone 'aS' configuration in colchicine's binding to tubulin.

Measuring ellipticities of (+/-)-colchicine and (+/-)-deacetamidocolchicine in the presence of tubulin afforded net positive CD bands with maxima at 340 nm resulting from reduction of the negative ellipticities upon binding of (-) enantiomers to the protein. Results of optical studies together with earlier NMR conformational analysis of these molecules substantiate the hypothesis that colchicinoids bind to tubulin with the phenyl-tropolone moiety in the 'aS' configuration. Natural colchicine which binds to tubulin, therefore, should be referred to as (-)-(aS,7S)-colchicine.

Animals↗
PubMed1992

Analysis of the colchicine-binding site of beta-tubulin.

Comparison of the beta-tubulin sequences with the equilibrium colchicine Ka and the Ki for inhibition by podophyllotoxin suggests that residue beta:316 is directly involved in binding the common trimethoxyphenyl-(or A-) ring. By contrast, the analysis indicates that the local hydrophobicity affects the rate of one of the two conformational changes associated with colchicine binding but does not determine the affinity of the colchicine-binding site.

Amino Acid Sequence↗
PubMed1987

Granulocytopenia complicating colchicine therapy for primary biliary cirrhosis.

A case is presented of a 76-yr-old woman with primary biliary cirrhosis and adult polycystic liver disease who developed bone marrow toxicity associated with chronic low-dose colchicine therapy. Two months after starting colchicine therapy (0.6 mg b.i.d. p.o.), the patient developed hematologic toxicity as evidenced by transient but profound granulocytopenia which promptly reversed 4 days after the drug was stopped. Bone marrow examination revealed moderate hypocellularity of all cell lines and striking dysplastic changes in the late myeloid and erythroid series. There was no apparent toxicity involving other organ systems. The patient fully recovered. This case is compared with previous descriptions of colchicine toxicity.

Aged↗
PubMed1992

Tauro-beta-muricholate preserves choleresis and prevents taurocholate-induced cholestasis in colchicine-treated rat liver.

In recent clinical and animal experimental studies, ursodeoxycholic acid (UDCA) has been noted to have marked choleretic and cytoprotective actions. To define the mechanism and determine whether such favorable influence is specific to UDCA, the choleretic action of beta-muricholic acid (beta-MCA), which has a similar chemical structure, was studied using an isolated rat-liver-perfusion system. As a result, beta-MCA and taurine-conjugated beta-MCA (T beta-MCA) stimulated bile flow accompanied by elevation of bile acid output and phospholipid output, and beta-MCA caused an elevation in biliary HCO3- concentration in normal rat livers. After colchicine treatment, taurocholic acid (TCA) administration was associated with marked cholestasis while both beta-MCA and T beta-MCA still increased bile flow under the same conditions. Furthermore, simultaneous administration of beta-MCA or, more markedly, T beta-MCA reversed the effects of TCA alone in colchicine-treated rat liver; significant preventive effects against the cholestasis could be shown. These data suggest that beta-MCA and especially T beta-MCA can support choleresis even under conditions of colchicine-dependent microtubule dysfunction. The effects of T beta-MCA on organelle lipids and their intracellular transport may differ from those of TCA, presumably because of the anticholestatic and cytoprotective effects of T beta-MCA.

Animals↗
PubMed1988

Dissociation by colchicine of the wet weight and the cGMP responses to estradiol in immature rat uterus.

We previously reported on a positive correlation between two effects of estrogen on rat uterus, namely the early increases in cGMP and in water content of the organ suggesting that they were under the control of the same hormone sensitive regulatory process or linked by a cause to effect relationship. Up to now we were unable to find experimental conditions that would dissociate the two responses. In this work, immature Wistar rats were treated with colchicine (50 micrograms/animal) given at the same time as estradiol-17 beta (1 microgram/animal) or with estradiol alone. The experiments showed: (1) that the estradiol induced increase in uterine wet weight that occurs during the first 8 h after hormone injection was completely suppressed in the presence of colchicine indicating that it might depend on an intact microtubular system and (2) that, by contrast, the estrogen-induced increase in uterine cGMP remained unaffected by the colchicine presence. These data allow to conclude that the cGMP response to estradiol can be dissociated from the wet weight response and, therefore, that it is not controlled by the latter. From this and from data in the literature the hypothesis is proposed that the increase in uterine cGMP content might trigger the wet weight response, this possibly through a positive action on some microtubular function.

Animals↗
PubMed1979

Degenerative changes at the neuromuscular junctions of red, white, and intermediate muscle fibers. Part 2. Responses to long stump nerve section and colchicine treatment.

The ultrastructure at the neuromuscular junction (NMJ) of red, white, and intermediate skeletal muscle fibers undergoes specific changes following either unilateral severance of the phrenic nerve or unilateral topical treatment of the phrenic nerve with colchicine. Both procedures were performed in the cervical region and produce similar rates of muscle fiber degeneration. The severity of degeneration appears to be related to muscle fiber type with white fibers being most severely affected and red fibers least affected. Degeneration rates of the axon terminal also correlate with fiber type in the orderwhite, intermediate, red. However, the rates of degeneration of the specific axon terminals are more rapid with surgical severance than with colchicine treatment. Statistical analysis of morphometric data indicates that hemidiaphragms denervated surgically exhibited significant axon terminal degeneration before significant muscle degeneration. Conversely, diaphragmatic muscle fibers of colchicine-treated phrenic nerves exhibit significant degeneration before loss of the axon terminal. Despite reversal of the temporal sequences for loss of axonal and muscular components between the two preparations, degenerative characteristics of muscle fiber structure are similar. This suggests that the presence of fiber-specific neurotrophic substances transmitted from the neuronal cell body to the axon terminal and released at the NMJ may be an important factor in the maintenance of normal muscle fiber morphology.

Animals↗
PubMed1975

Colchicine: effects upon urinary hydroxyproline excretion in patients with scleroderma.

Three patients with scleroderma were given intravenous infusions of colchicine (2-4 mg/day) for 3 days. Twenty-four-hour urine collections were assayed for total hydroxyproline (HYPRO), an index of collagen resorption, and for nondialyzable polypeptide HYPRO, an index of collagen synthesis. During the colchicine infusions there was a fall in total urinary HYPRO and a slight increase in the per cent nondialyzalbe HYPRO in each patient. The hydroxylysyl-galactosyl-glucose (HGG) to hydroxylysyl-galactose (HG) ratios were not strikingly different in two samples, with the greastest differences in HYPRO excretion. Our results suggested that total body collagen catabolism had diminished without a concomitant decrease in synthesis. In contrast to provocative reports in the literature, these data do not support the hypothesis that administration of colchicine in doses tolerated in man can either inhibit synthesis of new collagen, increase degradation of mature collagen, or be of use in treatment of fibrotic states.

Adult↗
PubMed1989

Colchicine administered into the area of the nucleus basalis decreases cortical nicotinic cholinergic receptors labelled by [3H]-acetylcholine.

Lesions in the nucleus basalis in the rat are known to decrease presynaptic markers for acetylcholine, including levels of cholineacetyltransferase (CHAT), high affinity uptake of choline and levels of acetylcholinesterase. Effects of lesions of the nucleus basalis on populations of nicotinic and muscarinic receptors are less well understood. After bilateral injection of the neurotoxic agent, colchicine into the nucleus basalis in the rat, levels of CHAT in the cerebral cortex were reduced 44%. Muscarinic cholinergic [( 3H]QNB) and dopaminergic [( 3H]spiroperidol) binding was not changed in the cortex, hippocampus or striatum. However, significant decreases in nicotinic binding sites, labelled by [( 3H]acetylcholine), were observed in the frontal cortex of nucleus basalis treated animals; scatchard plot analysis indicated a significant decrease in the number, but not affinity, of nicotinic binding sites. Colchicine injected into the nucleus basalis had no effect on the binding of [3H]acetylcholine in the hippocampus, but decreased binding of [3H]acetylcholine in the striatum. Subsequent experiments, in which colchicine was administered into the striatum at a site above the nucleus basalis had no significant effect on nicotinic binding in the striatum or frontal cortex. These results support the hypothesis that degeneration of the nucleus-basalis-cortical cholinergic pathway results in a loss of presynaptic nicotinic binding sites in the cortex as well as in the striatum (through transsynaptic degeneration of the cortico-striatal pathway).

Acetylcholine↗
PubMed1981

Effect of the microtubule disrupting agents, colchicine and vinblastine, on seminiferous tubule structure in the rat.

Injections of colchicine or vinblastine were given intratesticularly and rats sacrificed 6 and 12 hr later. Colchicine and vinblastine produced identical morphological patterns of response in the seminiferous tubules resulting in arrest of germcell mitoses and meioses and a rapid depletion of the microtubules normally found within the Sertoli cell. Sloughing of cells into the lumen of seminiferous tubules was the most prominent feature noted. Germ cells and portions of the apical Sertoli cells were frequently sloughed together where they remained in close association. Usually germ cells and associated Sertoli cell fragments were cleaved from the wall of the seminiferous tubule at a level between dissimilar generations of germ cells, e.g. between spermatocytes and spermatids. This selective sloughing probably occurred as the result of the support normally provided by intercellular bridges which link clones of like germ cell types. Sequential steps in the process leading to sloughing of Sertoli-germ cell associations could be inferred from observations made in plastic 1 micrometer sections. Cell sloughing at 12 hr post-injection was generally more extensive. It was frequently noted that germ cells and the apical portions of Sertoli cells had been extruded to the level of the most adluminal tight junctions forming the blood-testis barrier. It was concluded that disruption of Sertoli microtubules was responsible for sloughing of Sertoli fragments and associated germ cells, and that the cytoskeletal support, of the Sertoli cell was, at least in part, dependent upon the integrity of Sertoli microtubules. The Sertoli cell could not round-up after loss of its cytoskeletal support, due to the numerous attachment devices known to link it with various apically positioned germ cells. Thus, the cell was severed at some point along its delicate apical processes, as the consequence of forces produced by the 'rounding-up' process. Long-term sacrifice after vinblastine or colchicine treatment allowed the Sertoli cells to regain microtubules and long processes but not their typical configuration. Spermatogenesis remained severely impaired.

Animals↗
PubMed1984

Cytoskeleton and differentiation: effects of cytochalasin B and colchicine on expression of the differentiated phenotype of rabbit costal chondrocytes in culture.

Cytochalasin B changed the shape of cultured rabbit costal chondrocytes from polygonal to nearly spherical and stimulated glycosaminoglycan synthesis, which is a differentiated phenotype of chondrocytes, whereas colchicine changed them from polygonal to flattened and inhibited glycosaminoglycan synthesis. These morphological changes occurred parallel with the changes in glycosaminoglycan synthesis. Induction of ornithine decarboxylase by parathyroid hormone, which is a good marker of differentiated chondrocytes, was markedly potentiated in the spherical cells which had been pretreated with cytochalasin B, whereas pretreatment with colchicine inhibited the induction of the enzyme. Both cytochalasin B and colchicine inhibited DNA synthesis. The inhibitions were observed after the appearance of changes in the morphology of the cells and glycosaminoglycan synthesis. These findings suggest that intactness of microtubules and disruption of microfilaments are involved in regulating the expression of the differentiated phenotype of chondrocytes in culture.

Animals↗
PubMed1988

Redistribution of lipofuscin in aged neurons induced by colchicine.

The effect of a single, 40 micrograms, intracerebroventricular injection of colchicine on the distribution of neuronal lysosomes and lipofuscin granules in aged mice was studied. At the light microscope level we observed that colchicine induced a redistribution of dipeptidyl aminopeptidase II (Dpp II), a lysosomal and lipofuscin granule marker enzyme, from the cell bodies of neurons to the dendrites; cell bodies became depleted of Dpp II while dendrites became enriched with this enzyme. Quantitation of this phenomenon at the electron microscope level demonstrated that colchicine induced a rapid and significant decrease in the density of lysosomes and lipofuscin granules from the somata of neurons whereas in dendrites we observed a significant increase in the density of these organelles.

Aging↗
PubMed1982

Effects of colchicine and vinblastine on platelet contractility and release.

Pre-incubation of normal platelet-rich plasma for 30 minutes at 37 degrees C with concentrations of colchicine (2.5 x 10(-4)M) or vinblastine (1.1 x 10(-4)M) which disrupt platelet microtubles did not inhibit aggregation induced by ADP or collagen. Even following pre-incubation of platelets with a 10-fold higher concentration of colchicine (2.5 x 10(-3)M), platelets released 14C-serotonin and aggregated in response to collagen. In the presence of a 10-fold higher vinblastine concentration (1.1 x 10(-3)M), platelets lysed and released 51Cr. Dynamic viscoelastic measurements on recalcified platelet-rich plasma in a Weissenberg rheogoniometer demonstrated that neither colchicine (2.5 x 10(-4)M to 5 x 10(-3)M) nor vinblastine (1.1 x 10(-4)M) interferes with the initiation, rate of generation, or extent of contractile force produced in platelet-fibrin clots. These results indicate that polymerized tubulin is not essential for collagen-induced release of platelet dense granule contents. In addition, intact tubulin polymers are not required to support the platelet surface configuration necessary for platelet-fibrin adherence and the platelet contractile events which result in platelet-fibrin clot retraction.

Blood Platelets↗
PubMed1988

Effects of taxol and colchicine on platelet membrane properties.

The effects of the assembly-disassembly of microtubule on the membrane lipid fluidity, the fragmental motion of sulfhydryl groups of membrane proteins, and the functions of shape change and hypotonic shock response (shrinkage ratio) in human platelets were studied. We have employed electron spin resonance (ESR) utilizing spin labels for bilayer lipids or membrane proteins and microtubule reactive reagents to change microtubule assembly. Both, taxol, a microtubule stabilizing agent, and colchicine, a microtubule disrupting agent, did not affect the platelet membrane lipid fluidity detected by 5- or 16-doxylstearate. On the other hand, the mobility of sulfhydryl groups detected by 4-maleimide-tempo increased by taxol treatment and decreased by colchicine. Moreover, the temperature sensitivity of platelets below 20 degrees C decreased by taxol treatment, but unchanged by colchicine treatment. This behavior was similar to the shape change ability or the shrinkage ratio of platelets pre-treated with taxol, in which microtubule disassembly was inhibited due to taxol binding to microtubule. Therefore, it is confirmed that the assembly-disassembly state of microtubule which may control the ability of platelets to change shape, influences the mobility of sulfhydryl groups in platelet membrane proteins and its temperature sensitivity.

Adult↗
PubMed1987

Effect of rioprostil and colchicine on CCl4-acute liver damage in rats. Relationship with plasma membrane lipids.

The effects of colchicine (10 g/day p.o. for 7 days) and rioprostil (2-decarboxy, 2-hydroxymethyl-15-deoxy-16-RS-hydroxy-16-methyl-prostaglandin-E1) (20 g/kg s.c., a single dose) on the enzymatic and histological markers of acute liver damage were studied in rats intoxicated with a single oral dose of CCl4. The rats were sacrificed 24 h after CCl4. The lipid composition of the liver plasma membranes was also determined. The increase in Alk. Phosp., GGTP and GPT activities and bilirubin concentration in serum as well as the histological images produced by CCl4 were equally prevented by the treatments with colchicine or rioprostil. CCl4 changed the lipid composition of the liver plasma membrane by increasing PI and PC and decreasing SM, PS and PEA. There was a decrease in the cholesterol/phospholipid ratio at the expense of a reduction of cholesterol/protein ratio and elevation in phospholipid/protein ratio. Colchicine and rioprostil also prevented these lipid alterations. The results suggest that the plasma membrane is an important site of action of CCl4 and of the 2 drugs studied. We postulate that the plasma membrane rather than other organelles is the target for the cytoprotective actions of prostaglandins.

Alanine Transaminase↗
PubMed1991

Microtubule disruption and cognitive defects: effect of colchicine on learning behavior in rats.

Neuropathological findings in Alzheimer's disease (AD) suggest a possible involvement of microtubule dysfunction in neurodegenerative process pathogenesis. Because microtubules have a major role in neuronal plasticity, microtubule disruption could be also directly responsible for cognitive defects in AD. We report that in rats, continuous microtubule disruption induced by chronic colchicine administration results in a dose-dependent learning deficit. In addition, retention is also impaired. These cognitive defects are specific, as chronic colchicine induces no other behavioral toxicity within the study dose range. Colchicine-induced cognitive defects resemble those of AD, which are characterised by amnesia of recent learning and loss of formerly established memories. This new procedure of pharmacologically induced cognitive impairment may prove useful, both towards understanding AD pathogenesis and towards drug screening.

Animals↗
PubMed1991

Chemistry of colchicine.

Chemical structures of colchicine and related analogs, including allo-compounds with a six-membered ring, are presented here with correct absolute configurations, showing the natural representatives as a S-atropisomers. Spectral data, synthesis, biosynthesis, and metabolism of colchicine are discussed. Structural requirements required for these compounds to inhibit polymerization of tubulin and binding of radiolabeled colchicine in vitro are presented.

Animals↗