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At least 631 records · Page 35Linked to original sources
PubMed1986

Denervation-like postsynaptic supersensitivity to dopamine agonists induced by microinjection of colchicine into the substantia nigra pars compacta.

Circling behavior induced by dopamine (DA) agonists following microinjection of colchicine or 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNC) or electrolytic lesions of the SNC was investigated. Methamphetamine produced a contralateral circling behavior 3, 7 and 14 days following injection of colchicine into the SNC. Apomorphine produced an ipsilateral circling behavior followed by a contralateral rotation 3 and 7 days after the infusion of colchicine, whereas only an ipsilateral circling behavior was produced by apomorphine on day 14. 6-OHDA lesions of the SNC produced a contralateral circling behavior to apomorphine and an ipsilateral circling to methamphetamine, whereas both apomorphine and methamphetamine induced ipsilateral circling behaviors in rats with electrolytic lesions of the SNC. The possible mechanisms of action of colchicine are discussed in relation to the known effects of colchicine on axoplasmic transport.

Animals↗
PubMed1987

Colchicine lesions in the rat hippocampus mimic the alterations of several markers in Alzheimer's disease.

An infusion of colchicine into the hippocampi of rats resulted in destruction of hippocampal cells. Twelve days after infusion, preoperative trained colchicine-treated rats showed a significant decrease in choice accuracy in a T-maze learning task. There was also local reduction in choline acetyltransferase (ChAT) activity and significant losses of 55-kDa protein in the soluble fraction and of 50-kDa protein in myelin and synaptosomal fractions in the hippocampi of colchicine-lesioned rats. There was a marked increase in [3H]glutamate binding in the hippocampus and cortex. In contrast, [3H]quinuclidinyl benzilate binding in the hippocampus was slightly reduced, whereas [3H]dihydroalprenolol binding was not affected by the colchicine treatment. Scatchard analysis revealed that the increase in glutamate binding is due to an increase in the number of glutamate receptors without significant change in their affinity. Some of the changes caused by hippocampal infusion of colchicine resemble those seen in Alzheimer's disease suggesting the use of such rats as one model for the disease.

Alzheimer Disease↗
PubMed1987

Time-dependent neurobiological effects of colchicine administered directly into the hippocampus of rats.

Rats were given bilateral injections of colchicine into the dorsal and ventral hippocampus. Behavioral, neurochemical and histopathological measurements were taken, up to 12 weeks after surgery. Colchicine produced a consistent increase in spontaneous motor activity, enhanced acoustic startle reactivity, and accelerated acquisition of two-way shuttle box avoidance, but did not affect reactivity to a noxious thermal stimulus. Measurement of dynorphin in the hippocampus indicated that colchicine rapidly depleted this neuropeptide, which is thought to be contained preferentially in the mossy fibers of granule cells of the hippocampus. Colchicine also decreased Met-enkephalin in the hippocampus, but the magnitude of the change (22%) was less than that (89% depletion) observed for hippocampal dynorphin. Examination of hippocampal morphology using light microscopic techniques indicated that colchicine caused approximately 60% degeneration of granule cells in the hippocampus. Although the length of the pyramidal cells was decreased (12-16%), the width of the CA1 and CA3 region of the hippocampus was not affected. These data underscore the importance of the granule cells in the mediation of behavioral processes such as motor activity, startle reactivity and performance of shuttle box avoidance.

Acoustic Stimulation↗
PubMed1987

Atrophy of the striatum and motor disturbance induced by colchicine.

To determine the functional role of the striatonigral system in the circling behavior of rats and the mode of action of colchicine, we investigated the circling behavior induced by dopamine agonists after microinjection of colchicine into the unilateral striatum. Both apomorphine and methamphetamine produced ipsilateral circling behaviors in rats injected with colchicine, indicating that ipsilateral striatonigral pathways were damaged by the drug. Histological and biochemical examinations showed that intracaudate injection of colchicine damaged not only the dopaminergic neurons but also caused atrophy of the striatum with loss of neuronal perikarya. These results suggest that treatment with colchicine may be used as a model of senile atrophy or degenerative atrophy in these animals.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Neurotoxic lesions of the nucleus basalis induced by colchicine: effects on spatial navigation in the water maze.

Neuronal loss in the nucleus basalis magnocellularis (NBM) has been consistently associated with learning and memory impairments. Previous studies have used excitotoxicants such as kainic acid or ibotenic acid to examine the behavioral consequences of NBM lesions. In the present study, rats were given bilateral injections of the neurotoxicant colchicine (1.0 micrograms/site) into the NBM and examined for changes in learning and memory. Unlike excitotoxicants, which can produce extensive subcortical damage, colchicine produced a lesion limited to the site of injection. Histological studies demonstrated that colchicine decreased the number of choline acetyltransferase (ChAT)-positive cells in the NBM, and resulted in a marked loss of cortical acetylcholinesterase staining. Separate neurochemical analysis showed that colchicine lesions decreased ChAT activity in the neocortex but not the hippocampus or caudate nucleus. Similar to previous studies, rats with NBM lesions showed a large deficit in a passive avoidance task. Lesions of the NBM impaired acquisition of a reference memory task in the Morris water maze. However, the deficit was transient and with continued training lesioned rats performed as well as controls. In a reversal test in the water maze the learning deficit reappeared. These data suggest that colchicine may be useful in producing lesions of the NBM, which primarily affects the rate of acquisition of a spatial reference memory task.

Animals↗
PubMed1990

Redistribution of neuronal lysosomes induced by colchicine: an electron microscopic quantitative study.

We have previously demonstrated that a single injection of the microtubule poison colchicine, into the lateral cerebral ventricle of the rat, induced a rapid redistribution of the lysosomal marker enzymes, dipeptidylaminopeptidase II (Dpp II) and acid phosphatase, from their normal location in neuronal cell bodies out into the dendrites. In the present study, we have quantitatively analyzed this phenomenon at the electron microscopic level by identifying and counting the number of lysosomes and mitochondria in neuronal cell bodies and dendrites of control and colchicine-treated rats. Areas examined included the anterior dorsal (AD) thalamus, pontine nucleus, and facial nucleus. The results show that the cytoplasm of these neurons contains significantly fewer large lysosomes after treatment with colchicine while the dendrites become abnormally enriched with large and small lysosomes after treatment. Lysosomes were rarely seen in the axons of either control or colchicine-treated animals. A significant increase in the density and the shape of mitochondria was also observed in the dendrites following colchicine treatment. The data presented support the hypothesis that neurons contain a transport system which selectively translocates lysosomes, and possibly other organelles, into dendrites. The size, shape, and number of these organelles may change as a result of this transport.

Acid Phosphatase↗
PubMed1991

Effects of colchicine on retrogradely-transported WGA-HRP.

The effects of colchicine treatment on retrogradely-transported WGA-HRP were examined in the cat. The ventroposterolateral nucleus of the thalamus was bilaterally injected with WGA-HRP followed 2 days later by a unilateral injection of colchicine into the dorsal column nuclei (DCN). The cats were sacrificed by perfusion 24 h later. Retrogradely-transported WGA-HRP within DCN neurons was visualized in coronal, vibratome-cut sections of the medulla using the procedure of Rye and collaborators (J. Histochem. Cytochem., 32 (1984) 1145-1153). On the uninjected side, as expected, the reaction product filled numerous neuronal perikarya and their dendrites. In contrast, on the colchicine-treated side, the reaction product was restricted to dendrites; little labeling was observed within perikarya. These findings appear to reflect colchicine's effects on the translocation of lysosomes from neuronal perikarya to their dendrites are important for the interpretation of data from experiments using colchicine to enhance perikaryal immunohistochemical staining.

Animals↗
PubMed1995

Fate of lysosomes transported to the dendrites by a colchicine-induced mechanism.

Lysosomes in hypoglossal motoneurons were retrogradely labeled with fluorescent latex microspheres and their distribution as well as that of acid phosphatase was examined after a single 50 microgram intracerebroventricular (i.c.v.) injection of colchicine. In saline injected controls the fluorescent label was distributed mainly in cell bodies. Twenty-four hours after the colchicine injection we observed a re-distribution of fluorescent label from the cell body of neurons to the dendrites. Seventy-two hours after the colchicine injection the fluorescent label had returned from the dendrites to the cell body. A similar pattern was obtained by following the effect of colchicine on the distribution of acid phosphatase reaction product. We conclude that the reappearance of fluorescent label in cell bodies following colchicine treatment is the result of the retrograde transport of dendritic lysosomes.

Animals↗
PubMed1994

Comparison of intracranial infusions of colchicine and ibotenic acid as models of neurodegeneration in the basal forebrain.

Colchicine and ibotenic acid were compared for their ability to produce neurodegeneration and cognitive deficit after bilateral infusions into the nucleus basalis magnocellularis of male Long-Evans rats. Four weeks post-lesion, there was no difference in locomotor activity following infusion of either neurotoxicant or vehicle. In a passive avoidance task, both treated groups had significantly shorter step-through latencies compared with vehicle. Five weeks post-lesion, rats were killed for neurochemistry or histochemistry. Choline acetyltransferase (ChAT) activity in both the frontal and parietal cortex was significantly decreased (25-35%) in the colchicine- and ibotenic acid-infused rats when compared to control. There was no effect of either neurotoxicant on ChAT activity in the hippocampus or striatum. Both neurotoxicants produced damage in the general area of the ventromedial pallidum, although ibotenic acid infusion consistently produced a larger area of damage as assessed in Nissl-stained sections. Analysis of the number of ChAT-immunoreactive cells in the nucleus basalis magnocellularis (NBM) showed an average 60% cell loss following colchicine infusion and a 75% cell loss after ibotenic acid infusion. Area of glutamic acid decarboxylase (GAD) staining was significantly decreased in several regions surrounding the NBM for ibotenic acid (51% average decrease), and showed non-significant decreases (28%) following colchicine infusion. Colchicine infusion decreased dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum; ibotenic acid had no effect on brain catechol of indoleamine levels. The results indicate that although similar cholinergic hypofunction and behavioral deficits were achieved, several non-cholinergic differences between the neurotoxicants were detected.

Animals↗
PubMed1983

Metabolic and morphologic effects of colchicine on human T-lymphocyte expression of Fc mu and Fc gamma receptors.

The influence of colchicine on human T-cell Fc mu- and Fc gamma-receptor expression during culture was studied utilizing a rosette technique with bovine erythrocytes coated with IgM (EOx-IgM) or IgG (EOx-IgG). Treatment of T cells with greater than or equal to 10(-6) M concentrations of colchicine induced in these cells progressive loss of microtubules and surface microvilli, inhibited their Fc mu-, but not Fc gamma-receptor expression during culture, and increased their cyclic AMP levels. However, similar treatment of cells with lumicolchicine, a photoinactivated isomer, identically inhibited the T-cell Fc mu-receptor expression as well, without inducing loss of microtubules or microvilli or raising cyclic AMP levels in them. A direct influence on T-cell protein synthesis by either colchicine or lumicolchicine is likely, as greater than or equal to 10(-6) M concentrations of alkaloid identically inhibited [3H]leucine incorporation and Fc mu-receptor expression by T cells without inhibiting their alpha-methyl isobutyric acid transport. No impairment of optimal EOx-IgM rosette formation occurred in control T lymphocytes cultured for 24 hr and then treated with colchicine, which suggests that its effects did not directly influence the receptor-ligand interaction itself. These findings suggest colchicine has several sites of action on T cells, dependent and independent of microtubular depolymerization, which may be responsible for alterations of T-lymphocyte cellular metabolism and function.

Colchicine↗
PubMed1996

Formylcolchicine bound to lactosaminated serum albumin is a more active antifibrotic agent than free colchicine.

Liver fibrosis was induced by chronically (7 weeks) administering CCl4 to rats. Animals were divided into four groups: (a) controls, (b) treated with CCl4 alone, (c) treated with CCl4 and colchicine and (d) treated with CCl4 and formyl-colchicine bound to lactosaminated serum albumin (FC-LASA). Liver dysfunction was monitored by biochemical tests (alkaline phosphatase [ALP], gamma-glutamyltransferase [gamma GT], aspartate and alanine transaminases [AST and ALT], albumin and total bilirubin). Fibrosis was evaluated by determining hydroxyproline and by microscopic examination. The exposure to CCl4 produced major alterations of liver structure and collagen deposition. These effects were partially counteracted by colchicine and to a greater extent by FC-LASA. Morphological findings paralleled biochemical data. The information reported here indicates that colchicine has an antifibrotic activity on the liver of intoxicated rats and that FC-LASA is more active than colchicine itself as an antifibrotic agent.

Amino Sugars↗
PubMed1983

The relationship between the disassembly of microtubules during G1 and the enhancement of DNA synthesis by colchicine in mouse fibroblasts stimulated with peptide growth hormones.

By immunofluorescent staining to visualize the cytoplasmic microtubular cytoskeleton in mouse fibroblasts we have ascertained that after a relatively short exposure of cells to colchicine, microtubules remain disassembled for a prolonged period of time after cells are transferred to a colchicine-free medium. In contrast to the persisting effects of colchicine, a brief exposure of cells to nocodazole first induces the expected disruption of microtubules followed by regeneration of the cytoskeleton within a few hours after removal of extracellular drug. These results shed light on our previous finding that quiescent mouse fibroblasts first treated with colchicine and then transferred to colchicine-free medium exhibit an enhanced proliferative response to EGF and insulin, whereas cells treated in a similar manner with nocodazole show no enhancement of DNA synthesis stimulated by peptide growth hormones. We conclude that cytoplasmic microtubules must remain disaggregated during the prereplicative G1 period in order for cells to exhibit the enhancing effects of the microtubule-disrupting drugs on DNA synthesis.

Animals↗
PubMed1986

B-ring of colchicine and its role in taxol-induced tubulin polymerization.

Taxol-induced assembly of purified tubulin is not inhibited by the colchicine analogue 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone. Colchicine analogues having intact A, C and B-rings (without NH-CO-CH3) such as desacetamidocolchicine have also been found to be inactive. It has been observed that these two colchicine analogues are incorporated into polymers when incubated in the presence of taxol. Furthermore, preformed taxol-induced polymers of tubulin have been found to bind these two colchicine analogues. These results suggest that colchicine-binding domains on the tubulin molecule are mostly (if not completely) exposed in the taxol-induced polymers.

Alkaloids↗
PubMed1995

Colchicine treatment of primary sclerosing cholangitis.

BACKGROUND/AIMS: There is no medical treatment of documented benefit in primary sclerosing cholangitis (PSC). Colchicine has been observed to reduce mortality in primary biliary cirrhosis in one study. The aim of this study was to examine the effect of colchicine in PSC. METHODS: Eighty-four patients with PSC were randomized to receive 1 mg of colchicine daily (n = 44) or placebo (n = 40) in a double-blind 3-year study. The effect of treatment was evaluated through blind scoring of 10 variables in prestudy and poststudy liver biopsy specimens, daily recording of symptoms, and biochemical tests (serum bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, albumin, immunoglobulins, ceruloplasmin, alpha 1-antitrypsin, and plasma prothrombin levels) at 6-month intervals. RESULTS: There was no evidence of a favorable effect of colchicine on survival, symptoms, serum biochemistry, or liver histology in patients with PSC. CONCLUSIONS: One milligram of colchicine daily is ineffective in PSC.

Adult↗
PubMed1987

Separation of tubulin-binding and anti-inflammatory activity in colchicine analogs and congeners.

The effects of colchicine and its analogs on the carrageenin-induced footpad edema in rats were investigated. The anti-inflammatory effects of colchicine analogs were measured at 3 and 5 hr after the carrageenin injection. Colchicine, 1-demethylcolchicine and 3-demethylcolchicine markedly inhibited the carrageenin edema whereas 2-demethylcolchicine was much less active. Thiocolchicinoids, having a thiomethyl group at C-10 instead of a methoxy group, were considerably less potent. These results suggest that the presence of methoxy groups at C-2 and C-10 in colchicine is necessary to maintain anti-inflammatory activity. Inactivity of deacetylcolchicine indicates that substitution of the amino group at C-7 with electron withdrawing groups is also important. Significant inhibition of carrageenin edema and strong binding to tubulin in vitro were manifested by colchicine, 3-demethylcolchicine, N-butyryldeacetylcolchicine and colchifoline. On the other hand, N-carbethoxydeacetylcolchicine which did bind well to tubulin, did not show much effect on the carrageenin edema. These results suggest that the anti-inflammatory action of colchicinoids may not be regulated through the microtubule system.

Animals↗
PubMed1988

Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by colchicine: implications for glucagon and corticosteroid secretion.

In the study reported, colchicine, often regarded as a specific inhibitor of microtubular function, was shown to exert a concentration-dependent inhibition of the low Km cyclic AMP phosphodiesterases of the pancreatic islet, adrenal cortex and various other tissues of the rat. The results indicated that colchicine is only slightly less active as an inhibitor of the enzyme than theophylline on a molar basis and kinetic analysis revealed that both inhibitors acted competitively in the case of the liver enzyme. Our results show that the inhibitory effect of colchicine upon cyclic AMP phosphodiesterase is a general property of the alkaloid at concentrations of 5 x 10(-5)M and above in both endocrine and non-endocrine tissues. Thus, results obtained employing colchicine at concentrations significantly greater than those which are known to lead to microtubular disaggregation must be viewed with great caution if incorrect implication of microtubular participation in biological processes is to be avoided. For example, we propose that the previously reported paradoxical stimulatory effects of colchicine on the secretion of glucagon from the rat pancreatic islet and on steroidogenesis in the rat adrenal may be due to cyclic AMP accumulation consequent upon phosphodiesterase inhibition in these endocrine tissues and not to microtubular disaggregation as has hitherto been assumed.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Phorbol ester-induced loss of colchicine ultrasensitivity in chronic lymphocytic leukaemia lymphocytes.

On exposure to the phorbol ester 12-O-tetradecanoyl-13-acetate (TPA) the pathological (non-dividing) lymphocytes of B-cell chronic lymphocytic leukaemia (CLL) lose their characteristic ultrasensitivity to the cytocidal action of colchicine in vitro. They are no longer killed in 1 day by the drug at 10(-6)M-concentration. The effect was the same whether the cells were incubated in the continuous presence of TPA, or subjected instead to pulse-treatment with it (for as little as 5 min.). Colchicine at one thousand times greater concentration was now needed to kill the cells. CLL lymphocytes already primed to undergo interphase death by pretreatment with colchicine could be prevented from doing so by early addition of TPA. A marked proportion of those CLL lymphocytes destined to undergo early spontaneous death in vitro in the absence of colchicine could be prevented from doing so by TPA. The loss of colchicine ultrasensitivity applied to cells which had not yet undergone TPA-induced morphological transformation to blast-like cells or differentiation to cells containing abundant cytoplasmic immunoglobulins (CIg). These transformed cells materialised in greatest incidence (70-80%) after 3 days of culture, an observation in agreement with others workers.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

The effects of colchicine in mammalian brain from rodents to rhesus monkeys.

The injection of colchicine into rats and monkeys produced two different types of brain damage. At selected doses, intradentate colchicine preferentially destroyed DGC in rats, whereas damage was less selective and more severe in monkeys. Experiments were performed with different tubulin-binding drugs to investigate the structure-function relationship of tubulin binding and DGC death. The tubulin-binding characteristics of these and other drugs reported in the literature did not correlate with their ability to damage DGC. The role of seizure-induced cell death was investigated by recording the EEG in monkeys and in rats treated with phenobarbital. The data suggest that seizures are an infrequent epiphenomenon of colchicine's action. We proposed that colchicine is not a selective neurotoxin and that it causes brain damage by inducing a non-specific inflammatory response. This response is both dose- and species-dependent. We concluded by discussing the medical implications of the present and proposed uses of colchicine.

Animals↗