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PubMed1988

Radial-arm maze deficits produced by colchicine administered into the area of the nucleus basalis are ameliorated by cholinergic agents.

Rats were given bilateral injections of colchicine into the area of the nucleus basalis. Colchicine produced dose-dependent alterations in the acquisition of a food-reinforced working-memory task. Colchicine-induced deficits in maze performance were attenuated by cholinergic agents, including physostigmine, RS-86 (2-ethyl-8-methyl-2,8-diazospiro-(4,5)-decan-1,3-dione-hydro bromide) and nicotine. Naloxone and vasopressin did not affect radial-arm maze performance of colchicine-treated rats. Subsequent neurochemical analysis showed that colchicine decreased choline acetyltransferase (ChAT) activity and levels of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid in the neocortex. However, ChAT activity and other neurochemical measures were not altered in the hippocampus or corpus striatum. Histological assessment indicated damage limited to the injection in the area of the nucleus basalis and enlarged cerebrolateral ventricles. These data suggest the possible utility of the colchicine model in the study of cognitive deficits associated with neurodegenerative diseases.

Animals↗

PubMed1991

Colchicine-induced deafferentation of the hippocampus selectively disrupts cholinergic rhythmical slow wave activity.

It has been proposed that hippocampal rhythmical slow wave activity (RSA or theta-rhythm) induced by sensory stimulation (atropine-sensitive theta) is generated by the cholinergic septo-hippocampal system. Although ablations of the septum or its projections to the hippocampus disrupt hippocampal RSA, such non-selective lesions damage both cholinergic and non-cholinergic septo-hippocampal inputs. The present study assesses the effects of a selective septal neurotoxic lesion on hippocampal electrical activity. Colchicine, which has been reported to be selectively toxic to cholinergic neurons in the medial septum, was injected into the right lateral ventricle, and electrodes were implanted bilaterally into the dorsal hippocampus of female Sprague-Dawley rats. Hippocampal electrical activity was recorded 10-14 days later from the ipsilateral (colchicine-treated) and contralateral (control) hemispheres during locomotor activity or immobility. RSA ranging from 6.3 to 8.7 Hz was evoked in both hippocampi during mobility. Following i.p. administration of an anesthetic dose of urethane, hippocampal RSA at a frequency of 4 Hz could be elicited in the control hemisphere (n = 12) of all animals by pinching the tail. RSA was absent in 6 of 9 animals in the colchicine-treated hemisphere. RSA from control and treated hemispheres persisting after urethane administration was abolished by 5 mg/kg of scopolamine, thus verifying its cholinergic nature. A decrease in the number of choline acetyltransferase (ChAT)-immunoreactive neurons in the medial septum and a depletion of acetylcholinesterase (AChE)-staining in the hippocampus were evident in the hemisphere ipsilateral to colchicine administration. These data support the septal pacemaker hypothesis of hippocampal theta-rhythm and further demonstrate the neurotoxic effect of colchicine on septo-hippocampal cholinergic neurons by the induction of a functional alteration. The selective disruption of cholinergic neurons in the medial septum by colchicine provides a means to dissociate the contribution of septal cholinergic and non-cholinergic components to hippocampal electrical activity.

Acetylcholinesterase↗

PubMed1988

Effect of colchicine on collagen synthesis by liver fibroblasts in murine schistosomiasis.

Colchicine, an antimicrotubular agent, was shown to block the transcellular movement of certain structural macromolecules such as collagen. In the present study, the effect of colchicine on collagen synthesis and secretion by monolayer cultures of fibroblasts from livers of mice infected with Schistosoma mansoni was investigated. The effect of colchicine on proliferation of these fibroblasts was studied as well. Collagen and non-collagen protein synthesis was measured by incubating cultures with [14C]proline and measuring the incorporation of radioactivity into these protein fractions in both culture media and cell layers. Proliferation was measured by [3H]thymidine uptake. The isolated fibroblasts actively formed collagen and secreted most of it into the culture medium; 10-20% of the collagenase-sensitive radioactive protein remained in the cell layer. The addition of colchicine to culture medium led to selective inhibition of collagen formation with negligible effects on non-collagen protein synthesis. Fibroblast proliferation was also reduced by colchicine treatment. Both inhibition of collagen synthesis and inhibition of fibroblast proliferation were dose-dependent. Comparison of medium and cell layer collagen radioactivity confirmed inhibition of synthesis rather than only inhibition of secretion. These data suggest that colchicine has a specific effect on synthesis of collagen and proliferative activity by fibroblasts from S. mansoni-infected liver and may, therefore, be useful in modulating schistosomal hepatic fibrosis.

Animals↗

PubMed1983

The effect of colchicine on the rate of formation of aqueous humour and the gross outflow facility in the albino rabbit.

Colchicine, a naturally occurring plant alkaloid which prevents the polymerisation of cytoplasmic microtubules, lowers the intraocular pressure after topical administration or intravitreal injection. In this study we have examined the effect of topically administered colchicine on the rate of formation of aqueous humour and the gross outflow facility in the albino rabbit eye. The disappearance of [14C]inulin from the anterior chamber was measured to calculate the rate of aqueous humour formation and in a separate group of animals the gross outflow facility determined using a constant pressure perfusion technique. Topically administered colchicine (10, 20 and 40 micrograms/eye) inhibited the rate of aqueous humour formation dose-dependently. The mean rate of formation in control eyes was 3.68 +/- 0.09 microliters/min (n = 16) decreasing to 1.8 microliter/min (n = 9) in eyes treated with 40 micrograms colchicine. Furthermore, the gross outflow facility of colchicine treated (10 micrograms/eye) eyes (0.49 +/- 0.03 microliter/min/mmHg) was significantly greater (P less than 0.05) than that of contralateral control eyes (0.39 +/- 0.03 microliter/min/mmHg). The pharmacological evidence available indicates that colchicine is acting via mechanisms of microtubule disruption to produce an ocular hypotensive response, suggesting that microtubules may be involved in the formation of aqueous humour and possibly the maintainance of cell shape and form in the outflow vessels of the anterior chamber.

Animals↗

PubMed1983

Mechanisms of colchicine neurotoxicity in the dentate gyrus: dissociation of seizures and cell death.

Extracellular field potentials and the EEG were studied in the dentate gyrus of the rat after intrahippocampal injections of colchicine, which is a relatively selective neurotoxin for dentate granule cells. Injection of colchicine (0.5 microliters of a 5-mg/ml solution of colchicine in deionized water) resulted in granule cell hyperexcitability manifested by multispike field potentials in response to stimulation of the excitatory projections from the entorhinal cortex. In anesthetized rats, this state of granule cell hyperexcitability was occasionally accompanied by interictal epileptic spiking or brief electrographic seizures, but granule cell death was observed even in the absence of epileptic activity. Injection of colchicine into the CA1 area of the hippocampus also resulted in multispike field potentials in response to stimulation of the CA3 commissural pathway, but CA1 pyramidal cells were not destroyed by colchicine. Colchicine has been reported to act as a convulsant agent in the dentate gyrus, but it is a relatively selective neurotoxin for dentate granule cells even in the absence of epileptic activity.

Animals↗

PubMed1991

Ganglioside AGF2 prevents the cognitive impairments and cholinergic cell loss following intraventricular colchicine.

Ganglioside AGF2 prevented the cognitive and locomotor alterations induced by intraventricular colchicine. Adult male rats were initially trained to perform a standard radial arm maze (RAM) task. Following training, they were injected intraperitoneally with 10 mg/kg AGF2 (COL/AGF2), cerebrospinal fluid (CSF/AGF2) or the saline vehicle (COL/SAL, CSF/SAL) for 3 days prior to and for 14 days following the bilateral injection of colchicine (7 micrograms/0.5 microliters) or artificial CSF into the lateral ventricles. Colchicine (COL/SAL) impaired performance of the standard RAM task as well as a working memory version of the task in which various delays were imposed between the fourth and fifth arm choices. Colchicine also produced a transient hyperactivity which subsided within 10 weeks following surgery. In contrast, AGF2 (COL/AGF2) prevented the impairments in RAM performance and the alterations in locomotor behavior. Colchicine also produced significant decreases in hippocampal ChAT activity and high affinity choline uptake that were prevented by prior treatment with AGF2. Finally, colchicine produced a 35% decrease in the number of acetylcholinesterase-positive (cholinergic) neurons in the medial septum and vertical limb of the diagonal band (MS/VLDB) which was also prevented by AGF2. Thus, the behavioral and neurochemical protection afforded by AGF2 was paralleled by a prevention of the loss of hippocampal cholinergic parameters and cholinergic neurons in the MS/VLDB.

Animals↗

PubMed1990

Failure of colchicine to improve short-term survival in patients with alcoholic hepatitis.

Colchicine treatment was used in this randomized placebo-controlled trial in patients with severe acute alcoholic hepatitis [serum bilirubin greater than or equal to 5 mg/dL (85.5 mumol/L) mean, 17.5 +/- 7.5 mg/dL (299.25 +/- 128.25 mumol/L)]. Hospitalization mortality and morbidity and the effect on biochemical test results were the end points of the treatment. Patients in the two groups were evenly matched by demographics and laboratory test results. Mean time to study entry was less than 7 days from admission. The duration of the trial was 30 days. Thirty-six patients (24 men, 12 women) received colchicine (1 mg orally every morning) and 36 (25 men, 11 women) received an identical placebo. Seven (19%) colchicine-treated and six (17%) control patients died during the index hospitalization after a mean of 17.4 +/- 10.8 and 17.8 +/- 5.3 days, respectively (NS). During a 4-month follow-up period from entry into the trial, there were two additional deaths in each group. No differences between placebo- and colchicine-treated patients were observed in any of the laboratory parameters (serum bilirubin, aspartate transaminase, alanine transaminase, prothrombin activity, albumin, white blood cell count, hemoglobin, and creatinine) that were followed up over the 30-day treatment period. The frequency of complications did not differ statistically between the two groups. This study showed no effect of colchicine treatment on mortality and morbidity of severe alcoholic hepatitis. Colchicine cannot be recommended for the treatment of patients with alcoholic hepatitis.

Acute Disease↗

PubMed1987

Effects of colchicine on sulfated glycosaminoglycan production and cell detachment in pre-capillary pulmonary endothelial cells.

The effects of colchicine on the morphology, substrate adhesiveness, and production of glycosaminoglycan (GAG) macromolecules by cultured pre-capillary pulmonary endothelial cell were studied. Colchicine-treated cells demonstrated altered morphology and decreased substrate adhesiveness compared to untreated cells. In addition, [35S]sulfate incorporation into glycosaminoglycans was decreased 33% after treatment with colchicine. Spectrophotometric measurement of total cellular GAG revealed a similar GAG reduction in colchicine-treated cells. The composition of [35S]sulfate radiolabelled GAG was similar in cultures with and without colchicine, consisting of approximately 56% chondroitin sulfate and the remainder heparin/heparan sulfate. The results indicate that colchicine influences the biological behavior of pre-capillary endothelial cells, in part by altering the amount of glycosaminoglycan molecules produced.

Animals↗

PubMed1990

A clinical and immunologic study of colchicine in asthma.

A double-blind, randomized, crossover chronic study was done to determine the efficacy of colchicine in 10 atopic patients with asthma. A constant dose of sustained-release theophylline and albuterol by inhalation, as needed, was administered. Compared to placebo, colchicine, 0.5 mg twice daily, significantly reduced the mean (+/- SEM) daily clinical score from 2.18 +/- 0.34 to 1.64 +/- 0.32 (p less than 0.05), and the daily number of inhalations of albuterol from 5.89 +/- 1.48 to 4.01 +/- 1.26 (p less than 0.02). Colchicine significantly (p less than 0.05) increased the concanavalin A-induced suppressor cell function from 16.2 +/- 4.6% to 39.0 +/- 10.7%, which was similar to healthy volunteers (41.1 +/- 3.5%). Furthermore, colchicine significantly (p less than 0.05) decreased serum IgE from 248 +/- 63 to 188 +/- 46 IU/ml. Colchicine had no significant effect on pulmonary function tests, the early phase reaction of antigen-induced bronchial inhalation challenge, and immediate skin test responses. Thus, colchicine has immunomodulatory effects that may perhaps have a mild benefit in the treatment of asthma.

Adolescent↗

PubMed1990

Induction of micronuclei by mitomycin C and colchicine in the marine mussel Mytilus galloprovincialis.

The frequencies of micronuclei (MNi) in the gill cells of the mussel Mytilus galloprovincialis were determined over a long period (up to 28 days) following a 48-h treatment with colchicine. The frequency of MNi at the end of treatment was significantly higher than in controls and 24 h later it had increased even more. After this period, the frequency of MNi rapidly declined until a plateau level was reached on day 2-3, which was significantly higher than the control baseline level, and persisted until the end of the experiment (28th day). In the same cell system we previously reported a persistence of an increased frequency of MNi after treatment with mitomycin C (MMC) (Majone et al., 1987). In order to establish the origin of MNi, the difference between their size distribution in MMC- and colchicine-treated animals was determined at the end of treatment as well as during the plateau phase. The difference was statistically significant (P less than 0.001) at the end of treatment, the MNi induced by MMC being smaller than those induced by colchicine. However, the difference during the plateau phase was not statistically significant. Human CREST antikinetochore fluorescent antibodies reacted with chromosome centromeres of Mytilus and were applied to gill cells at the end of a 48-h treatment with MMC or colchicine. About 60% of the MNi induced by colchicine but only 30% of those produced by MMC reacted positively with the fluorescent antibodies. This result indicates that the majority of MNi observed at the end of a 48-h treatment with MMC or colchicine originate, respectively, from acentric chromosome fragments and from whole lagging chromosomes.

Animals↗

PubMed1981

Colchicine improves the alterations in the liver adenylate cyclase system of cirrhotic rats.

The adenylate cyclase system and the number and affinities of receptors for insulin and glucagon were studied in rats treated with CCl4 and in rats that received colchicine in addition to CCl4. Liver glycogen, cAMP and total collagen content were also measured in those animals. Rats received only mineral oil or only colchicine were used as controls. In this latter group, all parameters measured were normal. Differences in liver collagen content between groups treated with CCl4 and CCl4 + colchicine were not statistically significant. Basal adenylate cyclase activity was 2-fold increased in the CCl4 group. In the animals receiving CCl4 and colchicine, adenylate cyclase activity was normal. Adenylate cyclase activity stimulated by fluoride or by glucagon was also increased in the CCl4 group. However, this increase was due to to the enhanced basal activity. The number of receptors and the affinities of the receptors of glucagon and insulin were normal in all groups. cAMP levels were found increased in the CCl4 treated animals and this was accompanied by a 90% reduction in liver glycogen. In the group treated with CCl4 + colchicine, cAMP was normal and liver glycogen was only reduced 25%. These results suggest that part of the clinical and biochemical improvements observed in the colchicine treated animals were due in part to a reversal of the alterations of the adenylate cyclase system induced by CCl4.

Adenylyl Cyclases↗

PubMed1978

Effect of colchicine on estrogen action. II. Translocation of 17 beta-estradiol cytosol receptor complex into the nucleus.

Colchicine has previously been shown in our laboratory to inhibit 17 beta-estradiol stimulation of uterine water uptake in the immature rat measured 6 h after administration of the agents. We sought to determine whether this effect was mediated through colchicine action on translocation of estradiol receptor complex into the uterine cell nucleus. The time course of estradiol effect on uterine water uptake was followed with and without concurrent colchicine administration up to 6 h after administration. At no time during this period did there appear to be any influence of colchicine on translocation of the estradiol receptor complex into the nucleus. Examination of physical chemical characteristics of the nuclear estradiol receptr complex after estradiol and estradiol plus colchicine treatments revealed no observable differences. Thus, colchicine inhibition of estradiol-stimulated uterine water retention does not appear to be mediated through inhibition of nuclear translocation of estradiol-receptor complex nor to be due to any reduced retention time of estradiol-receptor complex in uterine nuclei.

Animals↗

PubMed1981

An effect of colchicine on galactosyl- and sialyltransferases of rat liver Golgi membranes.

Colchicine inhibited the activity of the galactosyl- and sialyltransferases of rat liver Golgi membranes. The sialyltransferase was more sensitive to the drug than galactosyltransferase since it was inhibited to a greater extent and at lower concentrations of colchicine than the galactosyltransferase. Two soluble enzymes, i.e. that from rat serum and that isolated from bovine milk, were not inhibited by colchicine. Even with very high concentrations of colchicine a marked stimulation of activity was observed. The data suggest that the inhibition observed in the Golgi membranes is in some way related to the arrangement of the enzymes in the lipid bilayer. In support of this hypothesis, the milk galactosyltransferase became very sensitive to colchicine after incorporation of the enzyme into lipid vesicles. The incorporation of colchicine into Golgi membranes was shown to decrease the order parameter as determined by electron spin resonance which reflects an increased fluidity of the Golgi membranes. A change in fluidity may be responsible for the inhibition of enzyme activity at least in part.

Animals↗

PubMed1979

Differences in microtubule stability to colchicine in extracts of guinea pig, rat and rabbit brain.

1. Microtubules (MT) from a guinea pig brain 25,000 g supernatant are not depolymerized by colchicine in contrast to MT from similar preparations of rat and rabbit. 2. The colchicine-stability was lost if the guinea pig brain homogenate was centrifuged at a higher g-level, further purified or if only the grey matter was used. 3. The association constant of colchicine to tubulin did not differ between a stable and a labile guinea pig brain preparation. 4. The GTP-hydrolysis was higher in the guinea pig preparation containing stable MT, than in the preparation containing labile MT. Additional GTP added to the polymerized MT before colchicine exposure, labilized the MT. Preincubation with NaF decreased the GTP-hydrolysis and caused a colchicine depolymerization. 5. The results indicate species differences in colchicine sensitivity of in vitro polymerized MT, probably depending on differences in GTP-hydrolysis.

Animals↗

PubMed1982

Inhibition of axoplasmic transport in the developing visual system of the rat-L Structural changes in the retina and optic nerve with graded doses of intraocular colchicine.

In order to study the role of axonal transport in the mediation of transneuronal metabolic stimulations upon a population of differentiating neurons, colchicine, a potent inhibitor of rapid and slow phases of axonal transport, was injected into the eye of albino rats at 1, 3, 5, 10, 15 and 20 days postnatal in concentrations ranging from 10-5 M to 2 X 10-2 M and in quantities of 0.3 to 0.5 microliter. Quantitative light and electron microscopy were subsequently employed to assess reactive alterations in the developing retina and optic nerve. Application of colchicine severely retarded the development of the sensory elements, with disappearance of synaptic ribbons of sensory cell axons, a significant reduction in the thickness of the inner plexiform layer, due to the presence of numerous shruken synaptic elements and the appearance of rosettes of sensory cells displaced to the inner nuclear layer. These alterations were found to be dose-dependent. Counts of ganglion cell populations at various times after application of colchicine demonstrated optimal concentrations which could be injected at each postnatal age without causing ganglion cell degeneration. Ultrastructural examination of such cells revealed varying degrees of disorganization and dissolution of the endoplasmic reticulum with the formation of occasional small cytoplasmic vacuoles. Higher concentrations of colchicine caused extensive vacuole formation in all classes of retinal neurons, scattered hyperchromic cells and widespread degeneration and autolysis. The diameter of the optic nerve was reduced to 60-95% of normal following intraocular colchicine, depending on the concentration employed, but electron microscopy revealed normal patterns of distribution of axoplasmic microtubules and filaments in control and experimental animals and quantitative analysis revealed no significant loss of axons. While no reactive changes took place in individual elements, the periphery of the nerve was often indented by a highly-folded glia limitans. Maximal doses of intraocular colchicine for each age level were established by this study. These were: 1 day. 10-3 M: 5 days, 5 x 10-3 M; 10 days, 5 X 10-3 M; 15 and 20 days, 10-2 M. The information derived from this morphological analysis provides the foundation for subsequent measurements of axonal transport inhibition in the developing visual system to be reported in the second article of this series.

Animals↗

PubMed1992

Fate of septohippocampal neurons following intracerebroventricular injections of colchicine.

Injection of colchicine into the lateral ventricles (ICV) of rats results in a selective loss of neurons immunoreactive for choline acetyltransferase (ChAT) in the medial septum (MS) and a concomitant loss of acetylcholinesterase (AChE) positive fibers in the hippocampus. To determine if this loss of cholinergic cells is due to neuronal death, septohippocampal neurons were retrogradely labeled with fluoro-gold (FG) 1 week prior to the injection of colchicine. Numbers and sizes of FG-labeled and ChAT-immunoreactive neurons were assessed 3, 6, and 10 weeks after ICV colchicine. In line with previous observations, numbers of ChAT-immunoreactive cells were reduced to fewer than 50% of control in the MS and to fewer than 60% of control in the vertical limb of the diagonal band (vDB). Three weeks after ICV colchicine, numbers of FG-labeled neurons were reduced to 48% in the MS and 24% in the vDB. By 6 weeks, the number in the MS decreased further to 31% of control, whereas the number remained at 24% in the vDB. Ten weeks after colchicine, the numbers of retrogradely labeled cells in both the MS and vDB had decreased to 11% of control. The cells which remained were not reduced in cross-sectional area or in diameter. These data suggest that the selective loss of cholinergic neurons in the MS which occurs following ICV colchicine is due to neuronal death and not just loss of ChAT expression.

Animals↗

PubMed1994

Colchicine injected into the anterior forebrain in rats decreases blood pressure without changing the responses to haemorrhage.

In a previous publication rats were shown to develop a marked positive sodium balance 6 days after injection of 1 microgram colchicine into their anterior forebrains. This was thought to be the normal hydromineral balance response to correct an hypothesised colchicine-induced decrease in blood volume (and/or pressure). To test this hypothesis, fluid and sodium intakes and excretion were measured before and then for 6 days following injection of colchicine (1 microgram in 250 nl) into the anterior forebrain, around the diagonal band of Broca, in male Wistar rats. At the end of the 6 days the animals were anaesthetised with urethane and blood pressure measured continuously before during and after a 3.5 ml haemorrhage. Blood pressure was significantly reduced (86.4 +/- 3.9 n = 11 vs. 67.7 +/- 3.4 mm Hg n = 12, p < 0.01) in the colchicine-treated rats compared to the controls and failed to recover following the haemorrhage. Measured blood parameters were similar in both colchicine-treated and nontreated groups, including plasma levels of vasopressin both before and following the haemorrhage. These results suggest that the colchicine injections may have compromised a central component of the sympathetic nervous system, thereby leading to the significant decrease in blood pressure without compensatory vasopressin release, and the lack of recovery of the decrease in blood pressure following a haemorrhage.

Animals↗

PubMed1989

The endolymphatic sac and inner ear homeostasis. II: Effect of glycerol on the sensory end organs with or without colchicine pretreatment.

The effects of glycerol and colchicine on the sensory end organs of the inner ear were investigated in mice. Glycerol alone induced a widening of the intercellular spaces lining vestibular dark and transitional cells as well as the marginal cells of the stria vascularis. This was noted within 30 min after the injection of glycerol and was normalized again within 4 h after the injection. Colchicine induced some morphological changes in the inner ear sensory cells, such as dissociation of Golgi complexes etc. These isolated glycerol or colchicine injections did not cause any signs of inner ear functional impairment. Treatment with glycerol following pretreatment with colchicine, however, induced marked inner ear dysfunction with impaired sense of balance and audition. The inner ear morphology revealed a combination of changes as compared with what was observed after isolated treatment with glycerol or colchicine i.e. edema of the stria vascularis, and vestibular dark and transitional cells as well as dissociation of Golgi complexes in the sensory cells. The cochlea showed moderate endolymphatic hydrops. These findings indicate that colchicine affects the inner ear fluid regulating mechanisms which may lead to severe functional derangement after additional glycerol treatment. It is conceivable that the present experiment may serve as a useful model for further studies on inner ear changes related to endolymphatic hydrops and Ménière's disease.

Animals↗