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PubMed2006

Colchicine delays the development of hepatocellular carcinoma in patients with hepatitis virus-related liver cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant neoplasm associated with liver cirrhosis, with an annual incidence of 3% to 9%, which is one of the main causes of death in patients with cirrhosis. Viral hepatitis is associated with an increased risk of HCC, probably due to an inflammatory reaction. Colchicine is an antiinflammatory agent that inhibits the formation of intracellular microtubules, affecting mitosis and fibrogenesis. Diverse clinical studies have failed to demonstrate the benefit of colchicine over the progression of fibrosis in patients with liver cirrhosis; nevertheless, to the authors' knowledge there are no studies that evaluate its effect in the development of HCC. METHODS: The effect of the administration of colchicine on the development of HCC was evaluated in 186 patients with hepatitis virus-related liver cirrhosis in a retrospective cohort study. The minimum follow-up time was 3 years (median, 84 months +/- 2.8 months). One hundred sixteen patients received treatment with colchicine. The characteristics of both groups were similar. RESULTS: The percentage of patients who developed HCC was significantly smaller in the colchicine group when compared with the noncolchicine group (9% vs. 29%; P = .001). On multivariate analysis, an alpha-fetoprotein level > or = 5 ng/dL (P = .03), a platelet count < 100,000 at diagnosis (P = .05), alanine aminotransferase > or = 52 IU (P = .006), and a lack of treatment with colchicine (P = .0001) were found to be associated with an earlier development of HCC. The average time for the development of HCC was 222 months +/- 15 months and 150 months +/- 12 months in the patients who received and who did not receive colchicine, respectively. CONCLUSIONS: The results suggest that treatment with colchicine prevents and delays the development of HCC in patients with hepatitis virus-related cirrhosis. The protective mechanisms of colchicine over the development of HCC could be related to antiinflammatory properties and inhibition of mitosis. Prospective studies to confirm this observation with a greater number of patients and long-term follow-up may be indicated.

Adult↗

PubMed2003

Extended delivery of the antimitotic agent colchicine from thermoresponsive N-isopropylacrylamide-based copolymer films to human vascular smooth muscle cells.

The aim of this study was to establish the capacity of thermoresponsive poly(N-isopropylacrylamide) copolymer films to deliver bioactive concentrations of an antimitotic agent to human vascular smooth muscle cells (HASMC) over an extended period of time. Copolymer films were prepared using a 50:50 (w/w) ratio of N-isopropylacrylamide (NiPAAm) monomer to the more hydrophobic N-tert-butylacrylamide (NtBAAm) and loaded with the antimitotic agent colchicine (0.1 micromol per film) at room temperature. Colchicine release from films was sustained over a 14-day period. At 24 h postloading, the concentration of colchicine in the medium overlying films was 2.12 +/- 0.16 microM; this fell to 0.20 +/- 0.01 microM at 7 days and decreased further to 0.12 +/- 0.01 microM after 14 days. Colchicine released from copolymer films inhibited proliferation when subsequently placed on HASMC: at 0.1 microM, released colchicine reduced proliferation to 18.5 +/- 0.8% of control cells (p < 0.001, n = 9). The antiproliferative effect of released colchicine was comparable to that of native colchicine, as observed in separate experiments. Furthermore, colchicine released from 50:50 polymer films inhibited the proliferation of cells grown in the same environment as the copolymer. Inhibition of cell proliferation was not due to the release of cytotoxic particles from the copolymer because medium incubated with copolymer for 5 days and then applied to HASMC did not alter cell viability. In conclusion, this study demonstrates that 50:50 NiPAAm:NtBAAm copolymers can deliver bioactive concentrations of the antimitotic agent colchicine to human vascular cells over an extended period of time.

Acrylamides↗

PubMed1990

Differential effects of intracerebroventricular colchicine administration on the expression of mRNAs for neuropeptides and neurotransmitter enzymes, with special emphasis on galanin: an in situ hybridization study.

The axonal transport blocker colchicine has been extensively used in immunohistochemical studies to induce accumulation of neuroactive compounds, especially neuropeptides, in neuronal somata and thus improve their visualization. To assess whether colchicine might, in addition, influence the synthesis of such compounds, we have now used in situ hybridization to examine the levels of mRNAs encoding for several neuropeptides (galanin [GAL], cholecystokinin [CCK], somatostatin [SOM], neuropeptide Y [NPY]) and neurotransmitter-synthesizing enzymes (choline acetyltransferase [ChAT], tyrosine hydroxylase [TH], amino acid decarboxylase [AADC], and glutamic acid decarboxylase [GAD]) after intraventricular administration of the drug. The results show that colchicine differentially modifies the levels of several mRNA species in different brain areas. Thus GAL mRNA levels increase in virtually all regions examined, including the basal forebrain, hypothalamus, dorsal raphe nucleus, locus coeruleus, and nucleus tractus solitarii. In addition, after colchicine treatment, GAL mRNA appears to be induced in the ipsilateral hemisphere in regions such as the cortex, hippocampus, striatum, lateral septum, and some nuclei of the thalamus as well as within white matter, where it cannot be detected in control animals. Although GAL mRNA in the vast majority of cases is neuronal, some findings indicate a possible glial localization. In parallel, colchicine depletes ChAT mRNA and increases GAD mRNA in the basal forebrain and striatum and decreases AADC mRNA in the dorsal raphe nucleus and locus coeruleus. In the latter nucleus, NPY and TH mRNA levels are increased by colchicine. In contrast, TH mRNA and also CCK mRNA levels decrease in the substantia nigra. In the cortex, hippocampus, and thalamus ipsilateral to colchicine injection CCK mRNA levels are markedly decreased, whereas SOM mRNA is decreased and NPY mRNA increased in the hippocampus but unchanged in the cortex. The results are discussed with reference to the possible artifacts that the use of colchicine might induce in immunohistochemical mapping studies and in relation to possible neurotoxic actions of colchicine, in some cases perhaps related to impaired retrograde transport of growth factor(s).

Animals↗

PubMed1992

Identification of kinetochores and DNA synthesis in micronuclei induced by mitomycin C and colchicine in Chinese hamster ovary cells.

The presence of kinetochore and DNA synthesis in micronuclei (MN) induced in Chinese hamster ovary (CHO) cells by clastogenic and aneuploidogenic substances such as mitomycin C (MMC) and colchicine was determined by immunofluorescence technique using CREST antikinetochore antibodies and anti-bromodeoxyuridine (BrdUrd) antibodies. A cytofluorimetric analysis was also performed. Colchicine significantly increased micronucleated cells at least up to 96 h from the end of treatment. As expected, among colchicine-induced micronucleated cells the majority contained at least one CREST + MN. MMC induced a significant increase in micronucleated cells up to 120 h from the end of treatment and the great majority of MN lacked kinetochore fluorescence, indicating that MMC-induced MN were derived from acentric fragments. However, colchicine and MMC at 48 and 72 h from the end of treatment, induced a significant increase of CREST- and CREST + MN, respectively, suggesting an induction of clastogenicity by colchicine and aneuploidy by MMC. The clastogenic effect of colchicine after 48 h was also confirmed by the presence of chromatid fragments in metaphase cells. A cytofluorimetric analysis indicated that, as expected, colchicine and MMC interfere with the G2/M and S phases, respectively; however, a slight interference of colchicine with the S phase was also observed. DNA synthesis was present in MN and it was in most cases synchronous with synthesis in the main nucleus. The frequency of cells with MN in S phase observed in untreated or MMC-treated cells is in agreement with the proportion of cells without MN showing DNA synthesis. On the contrary, the frequency of cells with MN in S phase observed in colchicine-treated cells was significantly lower than that observed in control and MMC-treated cells.

Animals↗

PubMed1987

Regulatory aspects of the colchicine interactions with tubulin.

Limited proteolysis of tubulin with subtilisin results in the cleavage of both tubulin subunits yielding S-tubulin heterodimer and 4 kDa peptide fragments containing the carboxyl-terminal domains of alpha- and beta-polypeptide chains. S-tubulin binds colchicine and the characterization of the binding of colchicine to S-tubulin molecules showed a decreased rate of decay of colchicine binding activity as compared to that of undigested tubulin. However, S-tubulin exhibited a lower colchicine binding constant than tubulin. Peptide fragments resulting from the controlled tryptic proteolysis of both pure tubulin and S-tubulin were purified by filtration chromatography and presented a strong colchicine binding activity with association constants of 4.5 X 10(6) and 2.7 X 10(6) M-1, respectively. Furthermore, these studies support our initial findings on the localization of the tubulin site for colchicine (Serrano L, Avila J, Maccioni RB: J Biol Chem 259:6607-6611, 1984) and define the colchicine binding domain in a domain of alpha-subunit from the point of limited tryptic cleavage to the site of subtilisin controlled proteolysis of that tubulin subunit. On the basis of these alterations in the interaction of colchicine upon removal of the C-terminal moiety of tubulin and since no change in the number of binding sites was found after subtilisin digestion, we suggest that the carboxyl-terminal region of tubulin subunits modulates the binding of colchicine.

Animals↗

PubMed1992

Alterations of choline acetyltransferase, phosphoinositide hydrolysis, and cytoskeletal proteins in rat brain in response to colchicine administration.

Colchicine, a microtubule disrupting toxin, was administered intracerebroventricularly to rats, followed by measurements of (i) the activity of choline acetyltransferase, a biochemical marker of cholinergic neurons, (ii) cytoskeletal protein concentrations, including tau, MAP-2, spectrin, and tubulin, and (iii) the activity of the second messenger-generating system, receptor-coupled phosphoinositide hydrolysis. One week after colchicine treatment there was a 60% decrease in choline acetyltransferase activity in the hippocampus, which was followed by a gradual increase in only a 29% deficit after 12 weeks. In the striatum and cerebral cortex, choline acetyltransferase activity was slightly reduced (by 13% and 19%, respectively) 1 week after colchicine treatment followed by increases to control values. The concentrations of tau and tubulin in the hippocampus were unaltered by colchicine treatment, and MAP-2 and spectrin were only slightly reduced 4 weeks after colchicine. Hippocampal phosphoinositide hydrolysis induced by norepinephrine was elevated approximately 28% 1 and 2 weeks after colchicine treatment and that induced by ibotenate was increased by 53% 2 weeks after colchicine. These results demonstrate that colchicine causes a severe depletion of choline acetyltransferase 1 week after administration. There was not a significant reduction of the concentration of any of the cytoskeletal proteins after 1 week, possibly due to the cell-selectivity of the toxic effect of colchicine, but there was a delayed, and temporary, decline of MAP-2 and spectrin concentrations. Associated with the decreased choline acetyltransferase activity after 1 week was an enhanced phosphoinositide hydrolysis in response to norepinephrine, and after 2 weeks there were enhanced responses to norepinephrine and to ibotenate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Cardiotoxicity of colchicine in the rat.

OBJECTIVES: Colchicine poisoning may be lethal and a decrease in cardiac function has been reported in several case reports, but the precise cardiotoxicity of colchicine remains unknown. DESIGN: The experimental in vitro study assessed the intrinsic contractility of left ventricular papillary muscle in rats, 24 h after administration of intraperitoneal colchicine or saline. RESULTS: The administration of colchicine (2 or 4 mg.kg-1) in adult Wistar rats markedly impaired intrinsic myocardial contractility, as shown by a decrease in maximum shortening velocity (-32 and -61%, respectively), active isometric force (-47 and -65%, respectively), and peak power output (-57 and -69%, respectively) of left ventricular papillary muscle. Colchicine impaired isotonic relaxation and load dependence of relaxation, suggesting a decrease in sarcoplasmic reticulum function. Conversely, colchicine significantly accelerated isometric relaxation, suggesting a decrease in calcium myofilament sensitivity. Myothermal economy was markedly impaired only in some rats (3/10 in each group), in which the negative inotropic effect of colchicine appeared to be more particularly pronounced. CONCLUSION: The results indicate that the administration of high doses of colchicine induced intrinsic cardiotoxic effects. Due to its amplitude, such cardiotoxic action may participate in the fatal outcome of acute colchicine poisoning.

Acute Disease↗

PubMed1997

Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis.

The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-alpha) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of alpha 1 (III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the alpha 1 (III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-alpha, IL-1, platelet-derived growth factor, and transforming growth factor-beta). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.

Cells, Cultured↗

PubMed1999

Localization and expression of Jun-like immunoreactivity in apoptotic neurons induced by colchicine administration in vivo and in vitro depends on the antisera used.

The expression of members of the Jun family of transcription factors was examined by immunohistochemistry, Western blotting, in situ hybridization and Northern blotting in the developing and adult rat brain following colchicine administration. Apoptotic cells, as revealed by their typical morphology and positive staining with the method of in situ end-labeling of nuclear DNA fragmentation, were restricted to granule cells of the dentate gyrus and olfactory bulb, and a few cells in the upper layers of the entorhinal cortex in adult rats, whereas widespread apoptosis occurred in developing rats after colchicine administration. No modifications in the expression of Jun D and Jun B, except for a generalized and moderate Jun B expression in glial cells, were observed in colchicine-treated rats. Generalized and strong c-jun mRNA induction and c-Jun/AP-1 (Ab-1) protein expression was observed in the cerebral neocortex, entorhinal and piriform cortices, CAI and CA3 areas of the hippocampus and granule cell layer of the dentate gyrus in adult treated rats, thus indicating a generalized c-Jun response to colchicine administration. In contrast, c-Jun/AP-1 (N) and c-Jun/AP-1 (Ab-2) immunoreactivity was restricted to apoptotic cells in colchicine-treated adult and developing brains. Western blots of hippocampal homogenates and total brain homogenates in adult and developing rats, respectively, demonstrated a band of 39 kDa for the c-Jun/AP-1 (Ab-1) antibody in control animals, the intensity of which increased in colchicine-treated rats. However, a band of 37 kDa, the intensity of which also increased following colchicine administration, was observed for the c-Jun/AP- (N) and c-Jun/AP- (Ab-2) antibodies. Selective c-Jun/AP-1 (N) and c-Jun/AP-1 (Ab-2) expression was also observed in apoptotic cells of the SH-SY5Y neuroblastoma line after the addition of colchicine to the culture medium. Taken together, the present in vivo and in vitro results indicate a generalized c-Jun response to colchicine in sensitive cells, whereas the antibodies c-Jun/AP- (N) and c-Jun/AP-1 (Ab-2) recognize vulnerable cells dying via apoptosis.

Aging↗

PubMed2003

Colchicine treatment in children with familial Mediterranean fever.

Prophylactic colchicine therapy has been shown to be a safe and effective method of eliminating the attacks and preventing the development of amyloidosis in patients with familial Mediterranean fever (FMF). However, information about effective dosages that control FMF attacks and prevent amyloidosis in childhood is not available. The aim of this study is to determine the 'effective colchicine dose' for children in terms of body weight and surface area. Sixty-two (34 male, 28 female) children with FMF were selected and colchicine treatment was initiated by giving 0.5-1 mg/day to each patient. The dose was gradually increased up to a maximum 2 mg/day in unresponsive patients; mean duration of therapy was 45.6 +/- 35.5 months. When the 'optimal effective dosage' (i.e. the one that reduced the frequency of attacks and ESR, CRP and fibrinogen levels during the attack-free period) was achieved, the optimal effective dose was calculated according to the body weight and body surface area for each patient. Based on these values 'mean colchicine dose' was computed for the study group and values for different age groups were evaluated. Mean colchicine doses according to the body weight and surface area of the whole group were found to be 0.03 +/- 0.02 mg/kg/day and 1.16 +/- 0.45 mg/m(2)/day, respectively. It was shown that children less than 5 years of age might need colchicine doses as high as 0.07 mg/kg/day or 1.9 mg/m(2)/day. These dosages are approximately 2.5-3 times more than the 'mean colchicine dose' for children aged 16-20 years. These results clearly show that small children need higher doses of colchicine in order to control their attacks. Thus, we conclude that colchicine, when given according to body weight or body surface area, would be more effective in childhood.

Adolescent↗

PubMed1990

Cholinergic cell loss and cognitive impairments following intraventricular or intradentate injection of colchicine.

Bilateral injections of colchicine (3.5 or 7.0 micrograms/0.5 microliters/site) into either the dentate gyrus or the lateral cerebroventricles (i.c.v.) of Sprague-Dawley rats produced specific behavioral, histopathological and neurochemical alterations. Colchicine, administered via either route, produced impairments in the performance of a radial-arm maze task which did not subside during 8 weeks of testing. Intradentate colchicine decreased (1) the thickness of both blades of the dentate granule cell layer, (2) the size of the overlying molecular layer, (3) hippocampal volume, and (4) the number of cholinergic neurons in the medial septum/vertical limb of the diagonal band (MS/VLDB). I.c.v. administration of colchicine did not alter any index of hippocampal morphology but did significantly decrease the number of cholinergic neurons in the MS/VLDB. An analysis of the time course of cholinotoxicity revealed that both intradentate and i.c.v. colchicine decreased choline acetyltransferase (ChAT) activity and high affinity choline uptake (HAChU) in the hippocampus at 1 and 3, but not 9, weeks following surgery. Furthermore, i.c.v. colchicine decreased ChAT activity in the septum at both 3 and 9 weeks following surgery. Neither route of administration altered ChAT or HAChU in the frontal cortex, olfactory bulb or striatum. The decreases in presynaptic cholinergic parameters were paralleled by a reduction in acetylcholinesterase staining in the hippocampus which appeared to recover within 9 weeks. These data suggest that intradentate colchicine produces either (i) transsynaptic degeneration of cholinergic neurons due to a loss of their target sites (granule cells in the dentate gyrus), (ii) a direct cholinotoxic effect, or (iii) a combination of these mechanisms. The i.c.v. injection of colchicine appears to exert a direct toxic effect on cholinergic neurons and/or nerve terminals that results in the death of these neurons. Colchicine may be a useful tool for investigating the behavioral and neurobiological properties of the septohippocampal cholinergic pathway and its response to injury.

Animals↗

PubMed1992

Studies related to the use of colchicine as a neurotoxin in the septohippocampal cholinergic system.

Colchicine has been shown to be neurotoxic to cholinergic neurons in the medial septum 1 week following intracerebroventricular injections. The experiments described here were designed to examine the selectivity of this effect over a longer time course, and to examine the role of axoplasmic transport in the neurotoxic effect. As previously reported, 1 week after intracerebroventricular injections of colchicine, the numbers of choline acetyltransferase (ChAT)-immunoreactive neurons in the medial septum-diagonal band complex (MSDB) were reduced to 38% of control; this reduction was stable 2 and 3 weeks post injection. Injections of colchicine placed into the body of the fornix produced similar results. GAD-immunoreactive somata, the other major population of neurons in the MSDB, were unaffected 3 weeks following colchicine, as previously reported 1 week following similar injections. The normal AChE staining pattern in the hippocampus, particularly the dentate gyrus, was depleted following either ICV or intrafornical injections of colchicine. This depletion was more severe with longer survival times. Injections of lumicolchicine, an isomer of colchicine which does not bind tubulin, had no effect on ChAT-immunoreactive neurons in the MSDB or on AChE staining in the hippocampus. Injections of colchicine, but not of lumicolchicine, partially blocked the retrograde transport of the fluorescent dye Fluoro-Gold from the hippocampus to the MSDB. In addition, the content of NGF in the hippocampus rose 84% above control values 2 weeks following colchicine and remained elevated at three weeks. Together these results indicate that colchicine is selectively toxic for cholinergic neurons in the septohippocampal system, and suggest that the alkaloid's neurotoxic effects work via the blockade of axoplasmic transport.

Acetylcholine↗

PubMed1995

A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid.

BACKGROUND/AIMS: Ursodeoxycholic acid (UDCA) and colchicine have beneficial effects in primary biliary cirrhosis (PBC). The efficacy of colchicine and UDCA in PBC was compared in a 2-year placebo-controlled study (n = 90). METHODS: Clinical events, laboratory test results, and liver histology were recorded at the beginning and end of the trial. RESULTS: There were significantly fewer dropouts for hepatic reasons with UDCA than with placebo. Pruritus was reduced by both active drugs. Colchicine improved liver function test results only modestly, whereas UDCA significantly decreased the serum activities of aminotransferases, alkaline phosphatase, and gamma-glutamyltransferase compared with colchicine and placebo. Serum total bilirubin levels were decreased only by UDCA. Both colchicine and UDCA reduced serum cholesterol levels, and UDCA also reduced high-density lipoprotein cholesterol levels. Furthermore, UDCA reduced the serum levels of immunoglobulin (Ig) M and IgG, and colchicine reduced IgG levels compared with placebo. The elevated serum level of aminoterminal propeptide of type III procollagen remained unchanged by colchicine or UDCA, whereas the serum level of carboxyterminal propeptide of type I procollagen was significantly decreased by UDCA. UDCA significantly decreased ductular proliferation compared with colchicine or placebo. CONCLUSIONS: These data suggest that UDCA frequently is superior to colchicine and especially to placebo in the treatment of PBC.

Alanine Transaminase↗

PubMed1995

Inhibition of colchicine absorption by the fat substitutes, sucrose polyester and tricarballylate triester, in the rat.

The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on the enterohepatic circulation of colchicine was studied in the rat. In a first experiment, emulsions of either sunflower oil (SFO), SPE, or TCTE, were introduced into the ligated small intestine and compared to a control group receiving physiological saline. All the groups received colchicine as an intravenous bolus. The plasma levels of colchicine in all groups was not affected, and luminal samples indicated that SPE and TCTE have no influence on the biliary excretion of colchicine (a previous experiment in bile duct-cannulated rats showed that SPE and TCTE, introduced by intragastric tube, have no effect on bile flow rate). In a second experiment, colchicine diluted in bile was mixed with saline or emulsions of either SFO, SPE or TCTE, and introduced into the ligated small intestine. The area under the curve and the maximal plasma concentration of colchicine were reduced when the drug was mixed with SPE or TCTE rather than saline (p < 0.0005). After 150 min, luminal samples were taken and showed significantly higher (p < 0.034) concentrations of colchicine in both SPE and TCTE groups compared to the saline group, indicating a significant inhibition of reabsorption of biliary colchicine. In conclusion, the non-absorbable fat substitutes, SPE and TCTE, did not influence biliary excretion of colchicine but reduced its reabsorption, thus altering its enterohepatic circulation.

Animals↗

PubMed1987

Colchicine as an investigative tool in neurobiology.

Neurotoxicants are being used with increasing frequency in neurobiology as investigative tools to study the structure and function of the nervous system. Colchicine administered directly into the hippocampus produces preferential destruction of dentate gyrus granule cells and mossy fibers and affects conditioned behavior. Studies from our laboratory have demonstrated the dose- and time-dependent loss of dentate gyrus granule cells and stimulation of motor activity following intradentate administration of colchicine. Preferential degeneration of pyramidal cells and other morphological changes observable at the light microscopic level were not seen in colchicine-treated rats. Other studies showed that intradentate colchicine produces specific damage to granule cells in both the dorsal and ventral hippocampus and that this damage is associated with depletion of dynorphin, a neuropeptide preferentially localized in the granule cells and mossy fibers of the hippocampus. Finally, it was noted that there are compensatory changes in the nervous system following treatment with colchicine and that the behavioral effects of colchicine can be modified by factors such as handling. One potentially important compensatory change occurring after intradentate colchicine is an alteration in cholinergic function. Pharmacological studies suggest that colchicine-treated rats may be less sensitive to the behavioral effects of scopolamine. These experiments support the conclusion that given at the appropriate dose into the hippocampus, colchicine may be a useful investigative tool to study the function of the dentate gyrus granule cells and mossy fibers, as well as the compensatory changes in the nervous system that follow chemical-induced neurodegeneration.

Animals↗

PubMed1996

Dose-dependent delivery of colchicine to the rat hippocampus by microdialysis.

The time courses of the colchicine delivery and diffusion rate in the brain were studied by microdialysis in the rat. Microdialysis allowed the exposure of the brain tissue to colchicine to be regulated, unlike a bolus injection. Colchicine was infused directly into the dorsal hippocampus at 40 ng/ml and 40 micrograms/ml, for 8 h. The amount of colchicine delivered to the brain and the diffusion rate from the probe were dose-dependent: colchicine diffusion into the brain was linear at 40 ng/ml but tended to plateau after 4 h at 40 micrograms/ml. The drug actually delivered with the higher dosage was only about 50% of that predicted from a constant diffusion. The total amount delivered at 40 ng/ml was 3.73 +/- 0.14 ng and at 40 micrograms/ml, it was 2.06 +/- 0.20 micrograms. Thus tissues surrounding the infusion site were saturated at high concentration and no more colchicine was diffused. Postmortem measurements of colchicine concentration in the forebrain confirmed these findings. Hence, the way in which colchicine is delivered to the brain is a critical factor for induction of its neurotoxic effects. These data open the way to a research on the correlation between local brain concentrations of colchicine and neurodegenerescence.

Animals↗

PubMed2004

Effects of colchicine on liver functions of cirrhotic rats: beneficial effects result from stellate cell inactivation and inhibition of TGF beta1 expression.

Liver cirrhosis (LC) is a chronic disease with high mortality rate and its pathophysiology includes hepatic parenchymal cell destruction, connective tissue formation, and nodular regeneration. Colchicine has been used in liver diseases as an anti-inflammatory and anti-fibrotic drug. However, there is controversy over the beneficial effects of colchicine in LC treatment. In the present study, we injected rats with multiple doses of dimethylnitrosamine for 4 weeks and used rats with severe LC to determine whether colchicine treatment improved liver functions and resolved cirrhotic nodules. Colchicine (30-150microg/kg per day, i.p., for 4 weeks) failed to significantly increase the survival rate of LC rats. Animals were subjected to blood biochemical, liver histopathological and immunochemical analyses. The plasma albumin level, decreased in cirrhotic rats, was restored by colchicine treatment along with reduction of ascites. Colchicine decreased the accumulated extracellular matrix and the multiple fibrotic nodules formed in cirrhotic liver, and eliminated alpha-smooth muscle actin (alpha-SMA)-positive cells. In activated stellate cells, colchicine inhibited alpha-SMA and transforming growth factor-beta1 (TGFbeta1) expression. The results of the present study showed that colchicine resolves cirrhotic nodules and accumulated fibers in the liver of LC rats, but failed to significantly improve the survival rate of LC animals, and that the beneficial effects of colchicine in cirrhotic animals result from stellate cell inactivation and inhibition of TGFbeta1 expression.

Animals↗

PubMed2004

In vitro investigation on the impact of Solutol HS 15 on the uptake of colchicine into rat hepatocytes.

In the current investigation, the impact of the surface-active formulation ingredient Solutol HS 15 on the uptake of colchicine into freshly isolated rat hepatocytes was investigated using a centrifugal filtration technique through a silicone oil layer. Colchicine is taken up into the cells by an active transport mechanism. When conducting the experiment at 37 degrees C, it was found that at concentrations below its critical micellar concentration (CMC) of 0.021% (0.0003 and 0.003%, w/v), Solutol HS 15 did not impact the uptake of colchicine. By contrast, at a Solutol HS 15 concentration above its CMC (0.03%, w/v), the amount of colchicine taken up into the cells as well as its uptake velocity were significantly decreased. However, in control experiments performed at 4 degrees C, a temperature at which active transport processes should be significantly slowed down, Solutol HS 15 at 0.03% did not affect colchicine uptake and/or its association with the cells. The described findings might be rationalized by inhibition of colchicine transport either due to direct interaction at the transport site or due to alterations of membrane properties in the presence of Solutol HS 15 at concentrations above its CMC. Moreover, a strong molecular interaction between Solutol HS 15 and colchicine as well as an incorporation of colchicine into micelles formed by Solutol HS 15, this way resulting in a limited contact of colchicine with the cells, cannot be excluded as contributors to the observed effect.

Animals↗