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PubMed1982

Reduction in intraocular pressure induced by colchicine and related compounds.

The effects of various microtubule inhibitors on the intraocular pressure (IOP) of albino rabbits were investigated. The compounds produced a marked fall in the IOP which was more prolonged after intravitreal injection than after topical administration. Tolerance to this response developed although no cross tolerance between colchicine and vinblastine was apparent. The drugs produced no effect on the pupil diameters and fluorescein angiography revealed no leakage of dye from the vessels of the iris. Lumicolchicine and trimethylcolchicinic acid were without effect on the IOP. The iris-ciliary processes contained more [3H]colchicine after intravitreal injection than after topical administration, and most was associated with the ciliary processes, the site of formation of aqueous humour. Further colchicine and vinblastine were bound within the tubulin containing fraction of this tissue. We suggest that colchicine and related compounds reduce the IOP via mechanisms of microtubule disruption which may partially inhibit the formation of aqueous humour by the ciliary processes.

Administration, Topical↗
PubMed1984

Effects of colchicine, vinblastine and nocodazole on polarity, motility, chemotaxis and cAMP levels of human polymorphonuclear leukocytes.

We present evidence for intrinsic polymorphonuclear leukocyte (PMN) polarity manifested in presence of microtubule-disrupting drugs. Polarization in response to colchicine correlated with the known dose-dependent effects of this drug on microtubule disassembly. The response to 10(-5) M colchicine, 10(-5) M vinblastine and 10(-6) M nocodazole was associated with stimulated motility and random locomotion. Responses elicited by microtubule-disrupting drugs differed from f-Met-Leu-Phe (fMLP)-induced polarization by functional and morphological criteria. Polarization, motility and orthokinesis responses were much weaker. Furthermore, ruffling was almost absent in PMNs polarized in response to colchicine, vinblastine or nocodazole. The response was inhibited by cytochalasin B, indicating that it is microfilament-dependent. We suggest that microtubule-disrupting drugs induce motility via structural changes in the cytoskeleton which act as signals for the motor apparatus. The intrinsic polarity manifested in the presence of microtubule-disrupting drugs could be reversed by an extracellular chemotactic gradient. Stimulated locomotion and motility in response to microtubule-disrupting drugs was only observed with initially spherical PMNs but not with initially motile cells. The findings provide an explanation for the numerous conflicting statements on the chemokinetic activities of these drugs. The role of cAMP in stimulated polarization and motility has been studied. Colchicine, vinblastine and nocodazole elicited a transient elevation of cAMP levels within 1 min of stimulation. cAMP elevation and stimulated motility were not quantitatively correlated.

Antineoplastic Agents↗
PubMed1987

Colchicine activates cell cycle-dependent genes in growth-arrested rat 3Y1 cells.

When growth-arrested 3Y1 cells (Fischer rat fibroblasts) were exposed to 3 X 10(-5) M colchicine, they entered S phase after a 12-h lag period which is the same as that in serum-stimulated cells. The expression of genes such as c-fos, c-myc, JE, KC, ornithine decarboxylase, and histone H3, analyzed by Northern blotting, increased in a cell-cycle dependent manner after colchicine treatment. The increased level of mRNAs was much smaller in colchicine-stimulated cells than in serum-stimulated cells, corresponding to the lower frequency of the former cells entering S phase. The course of the prereplicative phase seems to be similar in terms of the expression of cell cycle-dependent genes in cells stimulated with colchicine and in those stimulated with serum.

Animals↗
PubMed1987

Properties of B-ring analogues of colchicine.

Absorption spectra of colchicine and its analogues are affected by the presence of the B-ring, although it is not part of the chromophore (C-ring). Thus, 2-methoxy-5-(2',3'4'-trimethoxyphenyl)tropone has absorption maxima at 341 nm, whereas that of desacetamidocolchicine is at 353 nm. A similar red shift in the lambda max of colchicine, desacetamidocolchicine and 2-methoxy-(2',3',4'-trimethoxyphenyl)tropone also occurs when they are immobilized in the binding site to tubulin or in pure glycerol. We also observed that the B-ring of colchicine alone or with substituent does not affect the UV-induced rearrangement of colchicine to lumicolchicine. However, in the absence of the B-ring, as in the case of 2-methoxy-5-(2',3'4'-trimethoxyphenyl)tropone, the rearrangement reaction of the C-ring slows down significantly.

Colchicine↗
PubMed1984

Effects of colchicine on milk yield, composition, and cellular differentiation during caprine lactogenesis.

Intramammary colchicine infusion into goats at parturition reduced milk yield by 20% during the 30 day experimental period. During the first week of lactation, milk composition from colchicine-treated udder halves had elevated somatic cell numbers, serum albumin concentration and pH, while citrate concentration was lower in comparison to uninfused glands. Levels of lactose from both infused and uninfused udder halves were normal during the first week of lactation. No differences were observed in degree of alveolar development in tissue samples collected prior to treatment. Light and electron microscopy suggested that colchicine-treated udder halves consisted predominantly of undifferentiated mammary secretory cells, while uninfused udder halves appeared more cytologically differentiated. Results demonstrated that intramammary colchicine infusion at parturition temporarily altered milk composition and inhibited mammary cellular differentiation.

Animals↗
PubMed1984

Caprine mammary differentiation and initiation of lactation following prepartum colchicine infusion.

Milk from both colchicine-infused and uninfused udder halves had similar levels of somatic cells, serum albumin, pH, citrate, and lactose throughout the experimental period. Milk citrate and lactose concentrations gradually increased in both colchicine-infused and uninfused udder halves during early lactation while levels of somatic cells and serum albumin decreased as lactation progressed. No differences in parenchymal development or cytological differentiation were observed between colchicine-treated and untreated mammary tissue obtained prepartum, at parturition, or 7 days postpartum. Colchicine-infused udder halves produced about 9% less milk than uninfused controls during the first 30 days of lactation.

Animals↗
PubMed1991

Colchicine-induced increases in immunoreactive neuropeptide levels in hypothalamus: use as an index of biosynthesis.

The colchicine-induced accumulation of vasopressin (AVP) and oxytocin (OXT) has recently been applied to estimate the synthesis and turnover rates for these neuropeptides in whole rat hypothalamus. In the present studies, this pharmacologic procedure has been examined as a potential method for estimating hypothalamic somatostatin (SRIF) synthesis rate, and evaluated further for its utility in estimating nonapeptide synthesis in individual hypothalamic nuclei. Adult male rats received a single injection of colchicine (8 micrograms) into the third ventricle under pentobarbital anesthesia. Twenty-four hr later, immunoreactive (IR) levels of AVP and OXT increased considerably, as previously noted. Hypothalamic IR-SRIF levels, however, were unaffected. The absolute increases in IR-AVP and IR-OXT were greatest in the supraoptic nucleus (SON), with smaller increments in the para/periventricular hypothalamus (PVH) and the median eminence (ME). IR-SRIF levels showed no changes in the PVH or the ME. As a test, the method was applied to the detection of changes in AVP synthesis in diabetic rats. The colchicine procedure reported increases in AVP synthesis in both the SON and PVH in diabetic animals, a result compatible with that obtained previously for whole hypothalamus using radiolabeled procedures. Together, the results indicate that the colchicine procedure is useful in detecting changes in the syntheses of some (AVP and OXT) but not all (SRIF) neuropeptides, and that when applicable, the method is sufficiently sensitive to detect changes in small hypothalamic regions. The method may prove useful in estimating changes in peptide synthesis analogous to that used for serotonin and dopamine; e.g., 5-hydroxytryptophan and dopa accumulation following inhibition of aromatic L-amino acid decarboxylase.

Animals↗
PubMed1993

Colchicine alters lactate utilization in isolated hepatocytes of rats treated with CCl4 and ethanol.

Lactic acidosis has been described in patients with liver disease. Hyperlactacidaemia results from an imbalance in lactate production versus lactate utilization. It is estimated that the liver utilizes approximately 30 percent of the total lactate produced in the body under basal conditions, primarily by gluconeogenesis. The gluconeogenesis from lactate 10 mM and lactacidaemia were determined in order to investigate the effects of CCl4+ethanol administration in liver injury and, the possible effect of colchicine in our experimental fibrosis model. The tests were determined after 15, 30 or 45 days of treatment. The results indicate that the gluconeogenesis was significantly inhibited in both CCl4+ethanol groups and CCl4+ethanol+colchicine groups. By contrast, the lactacidaemia levels were much higher in the CCl4+ethanol groups than the colchicine groups. Summarising, we have documented that hyperlactacidaemia is due to the inhibition of lactate utilization by the isolated hepatocytes in experimental cirrhosis, and that the improvement in lactacidaemia caused by colchicine is not primarily due to an increase in hepatic lactate utilization.

Alcoholic Intoxication↗
PubMed1989

Selective working memory impairments following intradentate injection of colchicine: attenuation of the behavioral but not the neuropathological effects by gangliosides GM1 and AGF2.

Bilateral injection of 3.5 micrograms of colchicine into the dentate gyrus produced specific learning and memory impairments together with a selective pattern of neuropathology. Animals injected with colchicine exhibited a significant impairment in their ability to perform the working memory, but not the reference memory, component of a multiple component T-maze task. These deficits were transient and over time all animals were able to reaquire the task to preoperative levels of performance. Histological analyses revealed that intradentate injection of colchicine produced 1) a significant decrease in the width of both the superior and inferior blades of the dentate gyrus reflecting the extensive loss of granule cells, 2) a related decrease in the size of the dentate molecular layer, and 3) a decrease in the number of cholinergic neurons in the medial septum. The second phase of the experiment demonstrated that gangliosides GM1 and AGF2 did not prevent the initial impairments in working memory performance induced by colchicine but rather accelerated the rate at which it recovered. The gangliosides did not decrease the extent of neuronal damage; there was no sparing of granule cells in the dentate gyrus or cholinergic neurons in the medial septum. These data further support a role for the hippocampus in working memory processes and they also indicate that gangliosides GM1 and AGF2 might be useful for treating the behavioral deficits induced by hippocampal damage.

Animals↗
PubMed1995

PTZ-kindling after colchicine lesion in the dentate gyrus of the rat hippocampus.

Pentylenetetrazol (PTZ)-kindling represents a model of a primarily generalized epilepsy. We investigated the role of the dentate gyrus of the hippocampus in this model of epilepsy by destruction of this structure by colchicine, injected in the dorsal and ventral hippocampus of rats. After a period of 7 days PTZ-kindling was started. The kindling development was slightly accelerated in colchicine treated animals compared to control rats. After kindling completion the learning performance of the rats was tested in a shuttle-box experiment. The learning deficit found in fully kindled rats was not influenced by colchicine pretreatment. However, colchicine itself impaired the learning performance of rats in the shuttle-box.

Animals↗
PubMed1984

Influence of the antimicrotubular agents, colchicine and vinblastin, on the uptake of americium by rat liver, kidneys, and skeleton.

The influence of pretreatment with colchicine and vinblastin sulfate, administered ip at dosages of 2.5 mumol/kg on the uptake of im or iv injected 241Am by rat liver, kidneys, and skeleton was investigated. Both agents reduced the nuclide uptake by liver and increased the 241Am contents in kidneys and skeleton. The effect was dependent on the time interval between pretreatment and nuclide injection as well as on the dose of the agents. The minimum effective dose was approximately 0.5 mumol/kg. A thousand times higher po dose of carbon tetrachloride was less effective than the highest colchicine dose. Lumicolchicine (2.5 mumol/kg) did not increase the 241Am skeleton and kidney contents and was less effective in reducing the hepatic content than colchicine or vinblastin. At the light microscopy level, livers of the rats appeared normal after the standard colchicine dose (1 mg/kg), but concentrations of four enzymes, which may indicate damage to the liver, were significantly raised.

Alanine Transaminase↗
PubMed1982

The efficacy of colchicine prophylaxis in articular gout--a reappraisal after 20 years.

Prophylactic colchicine remains an efficacious drug in preventing recurrent attacks of acute gouty arthritis. Its use is indicated especially in those patients with frequent and severe attacks, and in those with coexisting medical complications. In the present study which reviews the experience of 540 patients, 518 males and 22 females over a period of more than 20 yr, excellent results were obtained in approximately 82% of the patients, the response was satisfactory in 12%, and unsatisfactory in 5%. Hyperuricemia per se did not offset the efficacy of the prophylactic regimen. Factors affecting the failure of the regimen were most frequently related to associated uncontrolled medical complications or intemperate habits of food or alcoholic beverages. Few patients were colchicine intolerant. No hematologic or renal toxic effects were observed with extended and regular ingestion of colchicine. At the dosage employed for prophylaxis 0.5 or 1.0 mg, colchicine was most likely involved in the suppression of chemotactic factors involving the synovial lining cells. There is no evidence of chromosomal aberration or infertility. Discontinuance of the prophylactic program may be attempted in any patient who has been free from recurrent attacks for several years, particularly in older patients with no medical complications.

Acute Disease↗
PubMed1989

Use of micelles in studying drug-binding sites: simulation of the tubulin-bound fluorescence of colchicine.

Enhancement of the fluorescence intensity of colchicine occurs in media of low polarity and appreciable viscosity; this is suggested to be the basis of the intensification of its fluorescence when it is bound to and immobilized in tubulin. We show here that the tubulin-bound fluorescence features of colchicine are largely reconstructed upon solubilizing it in chosen micellar aggregates that offer optimal polarities and microviscosities. Triton X-100 and bile salt micelles intensify the colchicine emission but the maximal effects are obtained with tetrameric aggregates of the peptide melittin. Estimates of the polarity, microviscosity and binding-site dimensions of colchicine are obtained using this mimetic approach. Our results suggest that well chosen micellar systems act as good models to reconstruct and analyze the spectral properties of molecules immobilized in their binding sites.

Binding Sites↗
PubMed1992

Colchicine treatment in the preparation of varicella-zoster virus inocula.

Two methods, ultrasonic and colchicine treatment, for preparing varicella-zoster virus (VZV) inocula were compared. Ultrasonic treatment was unsuccessful in achieving the release of detectable, infectious, cell-free VZV from infected human foreskin fibroblast (SF) cells. Sonication of infected SF cells resulted in losses of virus infectivity in direct correlation with losses in cell viability (r = 0.82). In the second method of generating VZV inocula, VZV-infected SF cells were treated for 15 min with 15-20 ng of colchicine per cell. Colchicine treatment maintained short-term survival of virus infectivity, but resulted in a dramatic decrease in long-term cell viability. In addition, colchicine-treated cells could not support the replication of VZV.

Cell Survival↗
PubMed1985

Effects of (dihydro)cytochalasin B, colchicine, monensin and trifluoperazine on uptake and processing of liposomes by Kupffer cells in culture.

We investigated the effects of (dihydro)cytochalasin B, colchicine, monensin and trifluoperazine on uptake and processing of large unilamellar liposomes by rat Kupffer cells in maintenance culture. The phospholipid vesicles were labeled in the lipid moiety with phosphatidyl[14C]choline and contained [3H]inulin or [125I]iodoalbumin as nondegradable and degradable markers of the aqueous vesicle content, respectively. Cytochalasin B and dihydrocytochalasin B, inhibitors of microfilament function, reduced inert inulin label uptake by 75% maximally, but residual uptake was not followed by release of lipid degradation products from the cells. By contrast, colchicine, an inhibitor of microtubule assembly, reduced uptake of liposomal inulin by maximally 55% but could not inhibit release of lipid degradation products from the cells. It is concluded that the cytochalasins partly inhibit uptake but fully prevent the arrival of internalized liposomes in the lysosomal compartment, while the action of colchicine is to slow down the overall process of uptake and subsequent transportation to the lysosomes. Monensin reduced inulin uptake to an extent similar to that found with colchicine, but reversibly blocked degradation of liposomal lipid and encapsulated protein. The kinetics of degradation of liposomal constituents suggests that residual uptake in the presence of monensin represents accumulation in an intracellular compartment. Trifluoperazine did not affect binding, internalization or degradation of encapsulated protein at low concentration (6 microM), but completely inhibited release of liposomal lipid degradation products under these conditions. At intermediate concentration (14 microM), the drug also reduced the internalization, while a high concentration (22 microM) was required to inhibit protein degradation as well. We conclude that trifluoperazine has multiple sites of action in the uptake and processing of liposomal constituents by Kupffer cells.

Animals↗
PubMed1995

Colchicine inhibits lithocholate-3-O-glucuronide-induced cholestasis in rats.

BACKGROUND/AIMS: It has been suggested that vesicular transport of bile acids in hepatocytes occurs, especially at high-dose loads. METHODS: The effect was studied of colchicine, a vesicular transport inhibitor, on lithocholate-3-O-glucuronide-induced cholestasis in rats. Cholestasis was induced by an intravenous infusion of lithocholate-3-O-glucoronide at the rate of 0.1 mumol.min-1.100 g-1 for 40 min. RESULTS: Colchicine treatment almost completely inhibited cholestasis and increased biliary excretion of lithocholate-3-O-glucoronide, whereas lumicolchicine had no effect. Treatment with vinblastine, another vesicular transport inhibitor, also reduced the cholestasis. Colchicine did not affect biliary excretion of taurocholate infused at the rate of 0.3 mumol.min-1.100 g-1 for 40 min, but markedly inhibited its biliary excretion when infused at the rate of 1.5 mumol.min-1.100 g-1 for 40 min. Colchicine had no effect on biliary excretion of tauroursodeoxycholate (1.5 mumol.min-1.100 g-1 for 40 min), lithocholate-3-sulfate (0.3 mumol.min-1.100 g-1 for 40 min), or a trace amount of lithocholate-3-O-glucuronide. CONCLUSIONS: These findings indicate that lithocholate-3-O-glucoronide-induced cholestasis is caused by its increased access to the vesicular transport pathway, possibly beyond the capacity of the transport by the cytosolic binders, and that the transport of lithocholate-3-O-glucoronide via the vesicular pathway induces cholestasis. Furthermore, the contribution of the vesicular pathway to hepatic transport may be different among bile acids, and lithocholate-3-O-glucuronide seems to have higher accessibility to this transport system.

Animals↗
PubMed1991

Colchicine-induced expression of proneurotensin mRNA in rat striatum and hypothalamus.

The effect of colchicine treatment on proneurotensin mRNA expression was examined using a sensitive non-radioactive in situ hybridization histochemistry technique with an enzyme-labelled antisense oligonucleotide probe. Intraventricular injection of colchicine rapidly induced strong neurotensin mRNA expression in a number of neurons in the dorsomedial part of the caudate putamen, and in the paraventricular, and arcuate nuclei while an induction of neurotensin mRNA was not observed in vehicle (saline)-injected animals. Neurotensin mRNA was not induced significantly in other periventricular areas such as the medial preoptic area or the lateral septum. These results indicate that colchicine can itself rapidly induce neurotensin mRNA expression and that this induction is specific to certain cell populations in the vicinity of the ventricles. These results demonstrate that colchicine should be used with caution in immunohistochemical studies demonstrating the normal distribution of peptide immunoreactivity or mRNA.

Animals↗
PubMed1991

Effect of reserpine and colchicine on neuropeptide mRNA levels in the rat hypothalamic paraventricular nucleus.

Using in situ hybridization and immunohistochemistry, we have studied mRNA and peptide levels in the hypothalamic paraventricular nucleus (PVN) 24 h after a single large dose of reserpine (10 mg/kg, i.p.) and 24 h after an intraventricular (i.c.v.) injection of colchicine (120 microliters/20 microliters saline). Sections of the PVN were hybridized using synthetic oligonucleotide probes complementary to mRNA for corticotropin-releasing hormone (CRH), neurotensin (NT), enkephalin (ENK), vasoactive intestinal polypeptide (VIP) and thyrotropin-releasing hormone (TRH). For immunohistochemistry rabbit antisera to CRH, NT, ENK, VIP and TRH were used. In situ hybridization showed a clear increase in CRH mRNA as compared to control rats after both treatments. Also NT and VIP mRNA could be seen in parvocellular neurons in reserpine and in colchicine-treated rats, whereas we so far have not been able to demonstrate these mRNAs in untreated rats. No changes in TRH mRNA could be detected after reserpine of colchicine. These results provide final evidence that subpopulations of parvocellular PVN neurons can synthesize not only CRH and ENK, but also NT and VIP, in agreement with earlier immunohistochemical results. With immunochemistry, after reserpine, many CRH-, but no NT- or VIP- positive neurons could be observed in the parvoecellular part of the PVN. The present results demonstrate that treatment with two drugs, the monoamine depleting drug reserpine and the mitosis inhibitor colchicine, causes increased levels of mRNA for several peptides in neurons of the PVN, located almost exclusively in its parvocellular part and being part of the hypothalamo-pituitary adrenal axis.

Animals↗