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PubMed2005

Adenosine deaminase enzyme levels, their relation with disease activity, and the effect of colchicine on adenosine deaminase levels in patients with Behçet's disease.

Behçet's disease (BD) is a systemic vasculitis. Although its clinical characteristics are well defined, the etiology and immune pathogenesis are not clear yet. Neutrophilic vasculitis, which is a consequence of immunological events, is suggested as the underlying pathophysiological mechanism. Adenosine deaminase (ADA) is a non-specific marker of T-lymphocyte activation. A total of 75 patients with BD (45 women and 30 men) and 25 age-matched and gender-matched healthy control volunteers (13 women and 12 men) were included in this study. BD patients were divided into three groups according to their clinical findings: inactive BD patients (group 1, n=25); active BD patients under colchicine treatment (group 2, n=25); and active BD patients without colchicine treatment (group 3, n=25). Plasma ADA (p-ADA) levels of all BD patients and the control group were measured and compared. The relationship between p-ADA levels and disease activity, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels was evaluated and correlated. Patients with BD had significantly higher p-ADA levels (20.6+/-6.3 U/l) than control subjects (12.8+/-1.8 U/l; P<0.001). The p-ADA levels of patients with active BD were significantly (for each, P<0.05) higher than those of inactive BD patients or controls. On the other hand, the difference was not significant (P>0.05) between active patients with or without colchicine use. In addition, there were significantly positive correlations between p-ADA, ESR and CRP levels in patients with BD (for each, P<0.05). However, disease duration or haemoglobin levels were not relevant. ADA level may be a valuable and supportive indicator of disease activity and is not affected by colchicine therapy in BD.

Adenosine Deaminase↗
PubMed1998

Colchicine-induced myoneuropathy in childhood.

UNLABELLED: Colchicine is used in the treatment of gouty arthritis, familial Mediterranean fever, amyloidosis, Behcet disease and dermatoses. Myoneuropathy is a rare side-effect reported either with intoxication or in elderly patients with chronic renal insufficiency causing elevated plasma drug levels. We report the first two cases of myoneuropathy in children, both taking appropriate doses of colchicine, and having normal renal function. The myoneuropathic changes were reversible after stopping treatment. The cause of colchicine myoneuropathy is unclear. CONCLUSION: In children treated with colchicine, neuromuscular phenomena of unknown aetiology may be related to the drug, even with a lack of intoxication or renal insufficiency.

Adolescent↗
PubMed2006

Colchicine-induced polyploidization depends on tubulin polymerization in c-metaphase cells.

The microtubule cytoskeleton plays a crucial role in the cell cycle and in mitosis. Colchicine is a microtubule-depolymerizing agent that has long been used to induce chromosome individualization in cells arrested at metaphase and also in the induction of polyploid plants. Although attempts have been made to explain the processes and mechanisms underlying polyploidy induction, the role of the cytoskeleton still remains largely unknown. Through immunodetection of alpha-tubulin, different concentrations (0.5 or 5 mM) of colchicine were found to produce opposite effects in the organization of the cytoskeleton in rye (Secale cereale L.). A low concentration (0.5 mM) induced depolymerization of the microtubular cytoskeleton in all phases of the cell cycle. In contrast, a high concentration (5 mM) was found to induce the polymerization of new tubulin-containing structures in c-metaphase cells. Furthermore, both treatments also showed contrasting effects in the induction of polyploid cells. Flow cytometric analysis and quantitative assessments of nucleolus-organizing regions revealed that only the high-concentration colchicine treatment was effective in the formation of polyploid cells. Our studies indicate that spindle disruption alone is insufficient for the induction of polyploid cells. The absence of any tubulin structures in plants treated with colchicine at the low concentration induced cell anomalies, such as the occurrence of nuclei with irregular shape and/or (additional) micronuclei, 12 h after recovery, pointing to a direct effect on cell viability. In contrast, the almost insignificant level of cell anomalies in the high-concentration treatment suggests that the presence of new tubulin-containing structures allows the reconstitution of 4C nuclei and their progression into the cell cycle.

Cell Nucleus↗
PubMed1984

Regulation of guinea pig macrophage collagenase production by dexamethasone and colchicine.

Previous studies have demonstrated that exposure of guinea pig macrophages to a primary signal, such as lipopolysaccharide (LPS), stimulates the synthesis of prostaglandin E2 (PGE2) which, in turn, elevates cAMP levels resulting in the production of the enzyme, collagenase. The potential of regulating the biochemical events in this activation sequence was examined with the anti-inflammatory agents dexamethasone and colchicine, which suppress the destructive sequelae in chronic inflammatory lesions associated with the degradation of connective tissue. The addition of dexamethasone with LPS to macrophage cultures resulted in a dose-dependent inhibition of PGE2 and collagenase production, which was reversed by the exogenous addition of phospholipase A2. Collagenase production was also restored in dexamethasone-treated cultures by the addition of products normally produced as a result of phospholipase action, such as arachidonic acid, PGE2 or dibutyryl-cAMP. Since the effect of dexamethasone was thus linked to phospholipase A2 inhibition, mepacrine, a phospholipase inhibitor, was also tested. Mepacrine, like dexamethasone, caused a dose-dependent inhibition of PGE2 and collagenase. In addition to corticosteroid inhibition, colchicine was also found to block collagenase production. However, this anti-inflammatory agent had no effect on PGE2 synthesis. Colchicine was effective only when added at the onset of culture and not 24 h later, implicating a role for microtubules in the transmission of the activation signal rather than enzyme secretion. The failure of lumicolchicine to inhibit collagenase activity provided additional evidence that microtubules are involved in the activation of macrophages. These findings demonstrate that dexamethasone and colchicine act at specific steps in the activation sequence of guinea pig macrophages to regulate collagenase production.

Animals↗
PubMed1975

Effect of colchicine on the osmotic water flow across the toad urinary bladder.

Osmotic water movement across the toad urinary bladder in response to both vasopressin and cyclic AMP was inhibited by 10(-5) to 10(-4) M colchicine on the serosal but not on the mucosal side. This inhibitory effect was found to be time- and dose-dependent. Colchicine alone did not change basal osmotic flow and a baseline of the short-circuit current (Isc) and also did not affect a vasopressin-induced rise of the Isc. The inhibitory effect was not prevented by the addition of pyruvate. The osmotic water movement produced by 360 mM Urea (mucosal), 360 mM mannitol (serosal) or 2 mug/ml amphotericin B (mucosal), was not affected by 10(-4) M colchicine. These results suggest that colchicine inhibits some biological process subsequent to the formation of cyclic AMP except a directional cytoplasmic streaming process where microtubules may be involved.

Amphotericin B↗
PubMed1977

Binding of [3H]ctyochalasin B and [3H]colchicine to isolated liver plasma membranes.

The binding to isolated hepatocyte plasma membranes of radioactively labelled inhibitors of microfilamentous and microtubular protein function ([3H]cytochalasin B and [3H]colchicine, respectively) was studied as one means of assessing the degree of association of these proteins with cell surface membranes. [3H]Cytochalasin B which behaved identically to the unlabelled compound with respect to binding to these membranes was prepared by reduction of cytochalasin A with NaB3H4. The binding was rapid, readily reversible, proportional to the amount of membrane and relatively insensitive to changes of pH or ionic strength. At 10(-6) M [3H]cytochalasin B, glucose of p-chloromercuribenzoate, an inhibitor of glucose transport inhibited binding by about 20%; treatment of membranes with 0.6 M KI which depolymerizes F actin to G actin caused about 60% inhibition of binding. These two types of inhibition were additive indicating two separate classes of binding sites, one associated with sugar transport and one with microfilaments. Filamentous structures with the diameter of microfilaments (50 A) were seen in electron micrographs of thin sections of the membranes. At concentrations greater than 10(-5) M [3H]cytochalasin B, binding was proportional to drug concentration, characteristic of non-specific adsorption or partitioning. Intracellular membranes of the hepatocyte also bound [3H]cytochalasin B, those of the smooth endoplasmic reticulum to a greater extent than plasma membranes. [3H]Colchicine bound to plasma membranes in proportion to the amount of membrane and at a rate compatible with binding to tubulin. However, other properties of the binding including effects of temperature, drug concentration and antisera against tubulin were different from those of binding to tubulin. Hence, no evidence was obtained for association of microtubular elements with these membranes. Despite this there appeared to be an interdependence between microtubule and microfilament inhibitors: vinblastine sulfate stimulated [3H]cytochalasin B binding and cytochalasin B stimulated 3H colchicine binding. [3H]Colchicine also bound to intracellular membranes, especially smooth microsomes.

Animals↗
PubMed1976

Lipid transport across the intestinal epithelial cell. Effect of colchicine.

Rats injected with colchicine (0.5 mg/100 g of body weight) 1 h before ingestion of a margarine emulsion (1 g in 2 ml of saline) do not show the rise in plasma triacylglycerol concentration found in controls during the subsequent hours. The effect of colchicine is more dramatic when the experiment is performed after prior administration of Triton WR-1339, a substance known to inhibit the catabolism of lipoproteins. Colchicine-treated rats also showed a five-fold increase in the content of triacylglycerol in proximal jejunum, when compared to controls. These results are consistent with the idea that colchicine interferes with the intracellular phase of fat absorption, suggesting that the microtubular-microfilamentous system could be involved in the release of chylomicrons from the intestinal cell into the circulation.

Animals↗
PubMed1990

Concanavalin A affects beta-tubulin mRNA expression during neuritic processes of mouse neuroblastoma N18TG2 cells in a different manner from colchicine.

Addition of concanavalin A (Con A) to mouse neuroblastoma N18TG2 cells cultured with dibutyryl-cAMP which can stimulate neurite outgrowth, stopped the neuritic processes effectively. The extended neurites showed a gradual retraction for at least 8 hrs after addition of Con A, while addition of colchicine caused rapid retraction of the neurites. Immunocytochemistry showed that the addition of Con A did not disorganize the microtubules but the addition of colchicine did. The increase in beta-tubulin mRNA expression which was observed after cell culture and after stimulation by dB-cAMP was suppressed by the addition of Con A. Con A did not affect the beta-tubulin mRNA expression when the cells had already been cultured, while colchicine drastically decreased it. Thus, Con A appeared to affect the beta-tubulin mRNA expression in a different manner from colchicine, probably through inhibition of cell movement.

Animals↗
PubMed1983

Effect of colchicine and S,S,S-tributyl phosphorotrithioate (DEF) on the biliary excretion of sucrose, mannitol and horseradish peroxidase in the rat.

The purpose of this study was to demonstrate the effect of colchicine and S,S,S-tributyl phosphorotrithioate (DEF) on vesicular transport of horseradish peroxidase (HRP) into bile at the same time that permeability changes occur in the canalicular membrane. Anesthetized Sprague-Dawley rats were surgically prepared with a bile duct cannulae. Four hours after colchicine pretreatment (10 mg/kg, i.p.), biliary excretion of intravenously injected sucrose and mannitol was increased, while that of HRP was decreased. Administration of these marker compounds from the bile side by segmented retrograde intrabiliary injection (SRII) (40 microliters washed in the 110 microliters saline) resulted in decreased biliary excretion of all three markers in colchicine-pretreated rats. Twenty minutes after DEF pretreatment by intrabiliary administration (40 microliters of DEF washed in with 31 microliters of saline and held in place for 0.5 min), the biliary excretion of intravenously injected sucrose and mannitol was decreased but that of HRP was increased; when administered by SRII, the biliary excretion of all three marker compounds was increased. These results demonstrate that colchicine, in addition to having blocked vesicular transport (HRP), also increased canalicular permeability to sucrose and mannitol. DEF, on the other hand, decreased canalicular permeability to sucrose and mannitol and enhanced vesicular transport of HRP.

Animals↗
PubMed1986

Colchicine selectively inhibits lactase expression by rat enterocytes.

One early aspect of enterocyte differentiation involves the appearance of digestive enzymes in the brush border membrane during cell migration from intestinal crypts onto villi. Present experiments describe how small amounts of colchicine selectively affect this particular aspect of enterocyte development. Oral ingestion of approximately 50 micrograms colchicine per day halves lactase activity in intestinal homogenates without affecting sucrase, maltase or alkaline phosphatase activities. This inhibition, which is completely reversible, takes about 48 hr to become complete. Further analysis of this effect by quantitative cytochemistry shows colchicine to reduce the maximal rate at which lactase activity appears in the brush border membrane. This reduction takes place without substantially affecting enterocyte migration rate or the time taken to fully complete lactase development. The possibility is discussed that small amounts of colchicine can selectively inhibit lactase biosynthesis in both crypt and mature villus enterocytes.

Animals↗
PubMed1986

Increased stimulation of alkaline phosphatase by small doses of colchicine entrapped in liposomes. A biochemical test to detect effective liposome-hepatocyte interaction.

The subcutaneous administration of colchicine encapsulated in small unilamellar vesicles reduced the initial toxicity peak and maintained for several days an adequate level of the drug in the liver. Colchicine is an excellent marker for effective liposome-hepatocyte interaction since it fulfills the following criteria: (a) When taken up by the hepatocytes within liposomes, it is active and induces the synthesis of alkaline-phosphatase two to three times over control values. The injection of at least ten times more free colchicine is necessary to attain a similar induction. (b) If released from extracellular liposomes, colchicine is cleared rapidly from the circulation. The results show that liposomes, in spite of their reduced aqueous compartment (approximately 1.0 microliter/mumole of lipid), can achieve clinical utility when administered subcutaneously because of their efficient interaction with parenchymal cells and their continual arrival from the injection site.

Alkaline Phosphatase↗
PubMed1986

Intraocular colchicine inhibits competition between resident and foreign optic axons for functional connections in the doubly innervated goldfish optic tectum.

After unilateral optic tectum ablation in the goldfish, regenerating optic axons grow into the optic layers of the remaining ipsilateral tectal lobe and regain visual function. The terminal arbors of the foreign fibers are initially diffusely distributed among the resident optic axons, but within two months the axon terminals from each retina are seen to segregate into irregular ocular dominance patches. Visual recovery is delayed until after segregation. This suggests that the foreign fibers compete with the residents for tectal targets and that the segregation of axon terminations is an anatomical characteristic of the process. Here we investigate whether inhibiting axonal transport in the resident fibers inhibits competition with foreign fibers. The eye contralateral to the intact tectal lobe received a single injection of 0.1 microgram colchicine, which does not block vision with the intact eye. We measured visual function using a classical conditioning technique. Segregation of axon terminations was examined shortly following visual recovery by autoradiography. The no-drug control fish showed reappearance of vision with the experimental eye at 9 weeks postoperatively and ocular dominance patches were well developed. Colchicine administered to the intact eye (resident fibers) several weeks postsurgery decreased the time to reappearance of vision with the experimental eye by several weeks. Autoradiography revealed some signs of axonal segregation but the labeled foreign axons were mainly continuously distributed. Administration of colchicine at the time of tectum ablation, or of lumicolchicine at two weeks postoperatively produced normal visual recovery times. Fast axonal transport of 3H-labeled protein was inhibited by 1.0 and 0.5 microgram but not by 0.1 microgram of colchicine or by 1.0 microgram of lumicolchicine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Comparison of the neurotoxic effects of colchicine, the vinca alkaloids, and other microtubule poisons.

Previous studies have revealed that colchicine is selectively toxic to certain neuronal populations in the CNS, particularly granule cells of the dentate gyrus. The present study evaluates whether other microtubule poisons exhibit similar neurotoxic effects. Equimolar solutions of colchicine, colcemid, podophyllotoxin, vinblastine, vincristine and lumicolchine, the non-binding analog of colchicine, were injected into the dentate gyrus. Neurotoxicity was evaluated histologically. As previously reported, colchicine selectively destroyed dentate granule cells with minimal damage to other neurons including hippocampal pyramidal cells. Vincristine was very toxic and was not selective for granule cells. Vinblastine was relatively selective in destroying granule cells, but was not as potent as colchine. Colcemid and podophyllotoxin had minimal toxic effects. Lumicolchine injections caused no more damage than injections of vehicle. This ordering appears to correlate with the reversibility of binding tubulin.

Animals↗
PubMed1989

Colchicine-induced alterations in receptor-stimulated phosphoinositide hydrolysis in the rat hippocampus.

Intradentate administration of colchicine has been reported to affect the cholinergic muscarinic system in the hippocampus, causing a reduction in quinclidinylbenzilate binding sites and an increase in choline acetyltransferase activity. Since the cholinergic muscarinic system is coupled to the formation of inositolphosphates in the brain, the effect of intradentate administration of colchicine on the agonist-induced turnover of inositollipid was studied in rats. The animals were sacrificed 12 weeks after injection, and the hippocampi removed and sliced. [3H]Inositol was incorporated into slices in the presence of lithium, and carbachol, a cholinergic muscarinic receptor agonist, was used to study the stimulated turnover of inositollipids. Hippocampal slices taken from colchicine-treated rats showed an increased carbachol-stimulated accumulation of inositolmonophosphate. Thus, intradentate colchicine appears to alter the signal transduction process for the muscarinic cholinergic receptor in the hippocampus, a change that may be associated with compensatory processes following damage to the hippocampus.

Animals↗
PubMed1989

GM1 ganglioside attenuates the behavioral deficits but not the granule cell damage produced by intradentate colchicine.

Bilateral injection of 3.5 micrograms of colchicine into the dentate gyrus produced hyperactivity, impaired retention of a passive avoidance task, and enhanced the motor stimulant effects of a dopaminergic agonist (apomorphine) and the analgesic effects of morphine. In contrast, there was no alteration in scopolamine-induced hyperactivity. These effects were associated with a decrease in the thickness of the granule cell layer in both the superior and inferior blade of the dentate gyrus and a coincident decrease in the size of the overlying dentate molecular layer. Intraperitoneal injection of monosialoganglioside GM1 (30 mg/kg) beginning 3 days prior to surgery and continuing for 25 days following surgery appeared to limit the extent and duration of these behavioral effects. GM1 facilitated recovery of motor activity and attenuated the impaired retention of the passive avoidance task and the alterations in pharmacological sensitivity following intradentate injection of colchicine. Despite the facilitative effects of GM1 on behavior histological analysis of the hippocampus did not reveal a protective effect of this compound on colchicine-induced granule cell destruction. The results of these studies suggest that intradentate injection of colchicine is a useful model of human diseases where only restricted populations of neurons are damaged. Furthermore, these studies indicate that the use of monosialoganglioside GM1 might be a useful primary or adjunct approach to the treatment of neurodegenerative disorders and their behavioral sequelae.

Animals↗
PubMed1990

Colchicine prevents recovery of nerve conduction at chronic demyelination.

A colchicine cuff was applied to rat sciatic nerve proximal to a demyelinating region produced by a focal injection of lysophosphatidylcholine (LPC). The colchicine cuff prevented the recovery of function normally seen within 6-8 days after LPC-induced demyelination. Colchicine blocked the delivery of sodium channels to the demyelinated region and induced their accumulation proximal to the cuff. The dual effect of colchicine in blocking both the recovery of impulse propagation through the demyelinated region and the delivery of sodium channels suggests a central role for fast axonal transport of sodium channels in the recovery of function at demyelination.

Action Potentials↗
PubMed1994

Effects of intrahippocampal colchicine administration on the levels and localization of microtubule-associated proteins, tau and MAP2.

Colchicine, a microtubule disrupting agent, has been used to model several aspects of Alzheimer's disease-related neuropathology. The formation of neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, involves the loss of tau (a low mol. wt. microtubule-associated protein) from axons and accumulation of abnormally phosphorylated tau in somatodendritic compartments. Other cytoskeletal proteins, such as microtubule-associated protein 2 (MAP2), disappear as tau accumulates. The present study was directed at evaluating the effects of colchicine on tau and MAP2, to determine if changes in their levels or distribution might be similar to those which precede the formation of neurofibrillary tangles in Alzheimer's disease. Six hours following intrahippocampal colchicine injection (3.5 micrograms injected into two rostro-caudal locations) tau-1 immunostaining was enhanced in CA1 s. radiatum and decreased in the outer molecular layer of the dentate gyrus. In addition, a shift in the relative abundance of tau isoforms was observed in Western blots. Both the immunocytochemical and immunoblot results are consistent with a dephosphorylation of tau. Loss of MAP2 was evident 3 days postinjection which coincided with a loss of Cresyl violet staining in granule cell, CA3, subicular and entorhinal neurons. Accumulation of tau or MAP2 in neuronal perikarya was not observed at any postinjection time points. Thus, intrahippocampal colchicine administration does not model the shift in tau localization, excessive tau phosphorylation, or other cytoskeletal alterations that are suggested to precede or accompany the formation of neurofibrillary pathology in Alzheimer's disease.

Animals↗
PubMed1980

Effect of colchicine on jejunal adenylate cyclase activity, PGE2 and cAMP contents.

The effect of colchicine on jejunal adenylate cyclase activity, prostaglandin E2 (PGE2) and cAMP contents, the enzyme and mediators involved in intestinal fluid secretion was tested in rats. Four h after the intraperitoneal injection of colchicine (0.5 mg/100 g body wt.) mucosal PGE2 content, adenylate cyclase activity and mucosal cAMP content were almost doubled. Pretreatment with indomethacin (4 mg/kg body wt., s.c./day x 2) or methyl prednisolone (3.0 mg/kg body wt.) decreased both the increase in mucosal PGE2 content and the stimulation of adenylate cyclase activity induced by colchicine. These results suggest that the stimulation of adenylate cyclase activity and an increase in mucosal PGE2 and cAMP contents might be among the mechanisms whereby colchicine induces a net accumulation of water manifested clinically as diarrhea. It is also suggested that the stimulation of adenylate cyclase activity is mediated by the increase in mucosal PGE2 content.

Adenylyl Cyclases↗