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PubMed1991

Colchicine-induced cholinergic denervation of the hippocampus elicits sympathetic ingrowth.

Sympathetic neurons from the peripheral nervous system invade the hippocampus following destruction of its septal inputs. It is thought that sympathetic ingrowth is due to the loss of cholinergic innervation since damage to the medial septum-diagonal band complex (MSDB) or its major efferent bundle, the fimbria-fornix, is required to induce ingrowth. The MSDB provides the major source of cholinergic fibers projecting to the hippocampus; however, non-cholinergic (e.g. GABAergic) neurons are also present in the MSDB and project to the hippocampus. Thus, the role of cholinergic denervation in sympatho-hippocampal sprouting cannot be directly tested by non-specific lesion techniques. In the present study, colchicine, which has been demonstrated to be specifically toxic to cholinergic neurons in the medial septum, was injected into each lateral ventricle of female Sprague-Dawley rats. Following colchicine-induced degeneration of cholinergic septohippocampal neurons, coarse, branched fibers immunoreactive for dopamine-beta-hydroxylase were observed predominantly in the dentate gyrus, on both sides of the granule cell layer, with increasing density as survival time increased. These results support the hypothesis that the invasion of the hippocampal formation by sympathetic fibers results from cholinergic denervation.

Acetylcholinesterase↗

PubMed1995

The neurotoxins colchicine and kainic acid block odor-induced fast waves and olfactory-evoked potentials in the dentate gyrus of the behaving rat.

It has previously been shown that the hilus of the dentate gyrus responds to odors (e.g. toluene) with a burst of fast waves and to electrical stimulation of the olfactory bulb with an evoked potential consisting of an early component immediately after the stimulus artifact, a second component with a 16-18-ms latency and additional late components. Spectral analysis revealed that odor-induced fast-wave bursts in the olfactory bulb and dentate gyrus both had a peak frequency of 15-20 Hz and were highly coherent. Unilateral intrahippocampal injections of colchicine or kainic acid were used in an attempt to destroy granule and pyramidal cells, respectively, while saline was injected on the opposite side as a control. Recordings from chronically implanted electrodes in the olfactory bulb and dentate gyrus demonstrated that saline had no effect while either neurotoxin abolished the odor-induced fast waves. In addition, the late 16-18-ms component of the dentate-evoked potentials after single-pulse stimulation of the olfactory bulb was abolished by either kainic acid or colchicine; the early dentate response, probably a volume-conducted olfactory response, was not abolished. Histological analysis indicated that kainic acid produced widespread non-specific damage in the hippocampal formation. Kainic acid-treated tissue exhibits a thinning of granule cell and molecular layers of the dentate gyrus as well as cell loss in CA3 and part of CA1.

Animals↗

PubMed1977

Inhibition of colchicine binding to rat liver tubulin by aldehydes and by linoleic acid hydroperoxide.

The onset of fat accumulation within CCl4 poisoned hepatocytes, occurring as early as 1 h after treatment, is known to be provoked by a block in lipoprotein secretion. Lipoprotein secretion involves the function of the microtubular system. Several data indicate that this early block in lipoprotein secretion is not primarily the consequence of impaired protein synthesis. Therefore effects of some derivatives of lipid peroxidation, i.e. aldehydes and linoleic acid hydroperoxide were investigated. The results described in this paper shown that the above mentioned lipid peroxidation derivatives inhibit, with different activities, [3H] colchicine binding to liver high-speed supernates. Percentage binding inhibition is directly related to concentrations of aldehydes of LAHPO. LAHPO is more effective than aldehydes. Among the aldehydes tested, 4-hydroxypentenal, produced during lipid peroxidation of biological materials, was the most active. The presence of thiols, added to the incubation medium, partially protects against the inhibition of [3H] colchicine binding by aldehydes. This suggests that aldehydes act by reacting with -SH groups of tubulin. The possibility that interaction between lipoperoxidation derivatives and tubulin in vivo may contribute to the onset of fat infiltration in CCl4 poisoning is discussed.

Aldehydes↗

PubMed1987

Enzyme markers of collagen synthesis in carbon tetrachloride-induced fibrosis and during colchicine modification of CCl4-induced liver injury.

Serum galactosylhydroxylysyl glucosyltransferase (S-Glu-Gal-Hyl-Tase), liver galactosylhydroxylysyl glucosyltransferase (L-Glu-Gal-Hyl-Tase), liver hydroxylysyl galactosyltransferase (L-Gal-Hyl-Tase), and liver prolyl hydroxylase (L-PH) activities were measured in rats during the development of CCl4-induced cirrhosis (0.2 ml of 33% CCl4 in light mineral oil two times weekly for 10 weeks followed by 6 weeks of no treatment). Serum and liver markers of collagen synthesis increased in a time-dependent manner reaching maximum activity at 6 weeks (S-Glu-Gal-Hyl-Tase, two times; L-PH, two times). These enzyme levels returned to normal during the 4-week recovery period. In a separate 4-week experiment, colchicine (10 micrograms/rat/day) was administered with CCl4. Colchicine prevented the increase in S-Glu-Gal-Hyl-Tase, L-Glu-Gal-Hyl-Tase, and L-Gal-Hyl-Tase induced by CCl4 and resulted in a smaller increase in L-PH. These results demonstrate that S-Glu-Gal-Hyl-Tase elevation occurs following CCl4 because of increased liver collagen synthetic activity and the hepatocellular injury produced by CCl4.

Animals↗

PubMed1988

Effect on the rat hypoglossal nucleus of vinblastine and colchicine applied to the intact or transected hypoglossal nerve.

The possibility that interruption of axonal transport in otherwise intact axons induces retrograde neuronal and nonneuronal reactions was examined. In addition, the proposal that blockade of axonal transport proximal to nerve injury might inhibit or delay the axon reaction was examined. Cuffs containing various doses of vinblastine were applied to the intact hypoglossal nerve. Colchicine was applied in a similar way to the intact hypoglossal nerve, injected directly into the intact nerve, or administered proximal to the site of hypoglossal nerve transection. The effect on retrograde axonal transport in the nerve was evaluated in the vinblastine experiments by the retrograde horseradish peroxidase (HRP) technique following injection of HRP or wheat germ agglutinin-conjugated HRP into the tongue. A dose of 0.01% caused an almost complete, but transient, blockade of the retrograde transport of the tracer, and induced a clearcut chromatolytic reaction in hypoglossal neurons. The chromatolytic changes were accompanied by a significant increase in the number of glial cells, many of which were identified as microglia. Similar results were obtained with colchicine alone or in combination with nerve transection. Signs of Wallerian degeneration after vinblastine treatment (0.01%) were observed only in a small number of myelinated fibers. The findings are compatible with the view that depletion of retrogradely transported factors from the peripheral innervation territory (including the distal nerve stump) to the perikaryon and/or a premature return of anterogradely transported substances at the site of drug exposure are factors inducing retrograde neuronal and nonneuronal changes.

Animals↗

PubMed1983

Involvement of colchicine binding site of tubulin in the polymerisation process.

Role of lysine residues in the colchicine binding site and in the assembly-disassembly process was examined. It was observed that at 4 degrees C (pH 7.5-8, 8 +/- 1) lysine residues and the N-terminal methionine residue of tubulin were all buried within the molecule. Evidence indicates that epsilon-amino groups of lysine residues of tubulin are shared by both the colchicine binding site and the polymerisation process.

Acetylation↗

PubMed1988

Colchicine therapy of the renal amyloidosis of ulcerative colitis.

Two patients with severe proteinuria, due to renal amyloidosis complicating chronic ulcerative colitis, improved remarkably with colchicine therapy. One patient with an initial daily urine protein excretion of 13.70 g had a reduction within 2 mo to 6.50 g and to 0.37 g after 9 yr. The other patient's daily urine protein excretion was 9.00 g. This was reduced to 5.10 g/day within 3 mo and was 0.53 g/day by 8 mo. Renal function remained stable or improved during the period of therapy. Colchicine resulted in rapid and prolonged benefit for these patients, despite their amyloid-induced nephrotic syndrome.

Adult↗

PubMed1985

Inhibition of experimental porphyria with colchicine.

Colchicine at the concentrations of 5 X 10(-7) - 5 X 10(-6) M decreased significantly both delta-aminolevulinic acid synthase activity and accumulation of porphyrins in monolayers of chick embryo liver cells induced by allyl-isopropylacetamide, by 3,5-diethoxycarbonyl-1,4-dihydrocollidine or by phenobarbitone. No effect was noted in non-induced cells. In rats, colchicine 0.3 mg/kg, reduced significantly the allyl-isopropylacetamide induced increase in the activity of delta-aminolevulinic acid synthase in the liver and the concentration of urinary porphyrins while it did not affect these parameters in non-induced rats.

5-Aminolevulinate Synthetase↗

PubMedDate not supplied

Effects of methyl prednisolone and colchicine on the development of aortic atherosclerosis in swine.

The effect of methyl prednisolone and colchicine on the development of both the early proliferative and advanced atherosclerotic lesion in swine aorta was studied. In order to accelerate the development of atherosclerosis, the abdominal aortic endothelium was partially denuded by a balloon before the animals were placed on either a moderate or severe hypercholesterolemic diet. Neither drug in either dietary group inhibited the development of atherosclerosis. Swine receiving methyl prednisolone and severe hypercholesterolemic diet actually had a significantly greater number of the advanced necrotic lesions and more arterial calcification than the group receiving the atherogenic diet alone. In addition, the thoracic aorta of swine receiving the moderate hypercholesterolemic diet and methyl prednisolone showed larger amounts of lipid than did the non-drug fed control group. In swine receiving the moderate hypercholesterolemic diet, methyl prednisolone significantly raised serum cholesterol levels. Colchicine only slightly worsened the atherosclerosis in swine aorta and had no effect on serum cholesterol levels.

Animals↗

PubMed1992

RM values of some colchicines and colchiceinamides determined by reversed-phase thin-layer chromatography.

The RM values of twelve colchicines and eight colchiceinamides were measured using reversed-phase thin-layer chromatography. The RM values were calculated by extrapolation from the linear range of a plot of RM values versus the composition of the mobile phase. The results showed that in the colchicine series substitution at the nitrogen in position C7 decreases the lipophilicity, whereas in the colchiceinamide series substitution at the nitrogen in position C10 increases lipophilicity. The influence of other substituent groups on the RM values are considered.

Chromatography, Thin Layer↗

PubMed1993

Cytokinesis-block micronucleus assay with kinetochore detection in colchicine-treated human fibroblasts.

A modified micronucleus assay using antikinetochore antibody has been developed in cytokinesis-blocked human fibroblasts as a simple method to identify aneuploidy-inducing agents. Different protocols for inducing binucleated cells by cytochalasin B in colchicine-treated human fibroblasts were investigated. A dose-related increase in kinetochore-positive micronuclei was obtained when cytochalasin B was given subsequent to colchicine treatment. No induction of micronuclei was observed in combined treatments of the two substances. These results indicate that the detection of kinetochores in micronucleated cytokinesis-blocked human fibroblasts can be effectively applied to the identification of environmental agents with aneuploidy-inducing potential. However, in testing such compounds particular attention should be paid to the protocol used for inducing cytokinesis-blocked cells.

Cell Division↗

PubMed1996

Comparative analysis of colchicine induced micronuclei in different cell types in vitro.

In the present study we analyzed the induction of micronuclei (MN) by colchicine, at different treatment times, in four histogenetically different cell cultures: human skin fibroblasts (HSF), bovine skin fibroblasts (BSF), bovine bladder fibroblasts (BBF) and human skin epithelial cells (HK), developed and characterized in our laboratory. The frequencies of dead cells, nuclear budding and mitotic index were also evaluated. The HSF and BSF cell lines showed similar frequencies of micronucleated cells (4.7% and 4.9%, respectively) at 96 h of treatment time. The BBF cell line showed the lowest frequency of micronucleated cells (2.6%) and HK did not show any MN. The studied cell lines differed in their responses to colchicine. The data revealed the relevance of utilization of other end-points as growth curves, dead cells, mitotic index and other nuclear alterations for accurate analysis of the effect of agents that disturb cell cycle or are cytotoxic.

Animals↗

PubMed1987

Colchicine-induced lesion of rat hippocampal granular cells prevents conditioned active avoidance with perforant path stimulation as conditioned stimulus, but not conditioned emotion.

Successful acquisition of active avoidance by rats with low frequency (15 cps) stimulation of the perforant path as a conditioning stimulus is correlated with a slowly developing long-term enhancement of perforant path-granular cell synapses. After selective destruction of granular cells of the stimulated side by unilateral microinjection of 1.6 micrograms/0.2 microliter colchicine into the dentate area, field potentials could no longer be evoked by test stimuli and animals subsequently failed to acquire the conditioned active avoidance with perforant path stimulation as a CS. However, colchicine-treated animals showed the same development of conditioned emotional responses as saline controls and they could also successfully be conditioned with light and tone as the CS. These results suggest that the granular cells are necessarily involved in the conditioning pathway for the active avoidance with perforant path stimulation as the CS. Other targets of the perforant path, e.g., ipsi- and contralateral CA1 pyramidal cells and contralateral granular cells, or antidromic activation of the entorhinal cortex seem an insufficient substitute for granular cells in the pathway for this conditioned active avoidance, but would probably participate in the conditioned emotional responses. The results additionally support our hypothesis, that post-conditioning LTP in granular cell synapses contribute to the acquisition and/or the storage of a memory trace.

Animals↗

PubMed1984

Systemic colchicine inhibits goldfish optic nerve regeneration.

Experiments were carried out to further investigate the regenerating goldfish optic nerve as a preparation for screening drugs or environmental toxins for adverse effects on neuronal circuit development. Regeneration was induced by unilateral retrobulbar optic nerve crush, and the opposite eye was kept intact. The time to recovery of vision was measured, as an index of regeneration and neurotoxicity, by an improved behavioral technique. The visual stimulus was changed to eliminate extraretinal photoresponding and to permit testing for vision with the right or left eye independently in a trial. Visual recovery occurred within 14 to 25 days. Colchicine, a potent inhibitor of microtubules and axonal transport, was administered semiweekly by ip injection, as in earlier experiments, to study the efficacy of the protocol. The drug resulted in an inhibition of regeneration at doses up to 0.2 micrograms/g body wt which did not impair responding with the control eye. Administration of beta-lumicolchicine, a photoisomer of colchicine that is a weak inhibitor of microtubules or axonal transport, up to 2.0 micrograms/g body wt, had no effect on regeneration or maintenance of visual responding. The results support the thesis that regenerating circuits are more sensitive indicators of neurotoxicity than are established circuits and confirm that the regenerating optic nerve can be used to screen molecules that may impair neuronal circuit development in vivo and to measure their relative potency.

Animals↗

PubMed1991

Colchicine prophylaxis in familial Mediterranean fever: reappraisal after 15 years.

As determined in this study of 45 patients, the prolonged use of colchicine therapy in familial Mediterranean fever (FMF) is safe and effective in preventing flares of FMF and amyloidosis. It has acceptable adverse effect profile and can be used in children and pregnant women. Its discontinuation predisposes patients to acute FMF attacks and the development of amyloidosis. Articular involvement is less responsive to colchicine and may require therapy with nonsteroidal antiinflammatory drugs.

Adolescent↗

PubMed1975

Prostaglandin synthesis by rheumatoid synovium and its stimulation by colchicine.

The synthesis of prostaglandins by rheumatoid synovial tissue in organ culture was studied utilizing radioimmunoassay, with antisera to PGB1, PGF1alpha and PGF2alpha. It was established that PGE2 and PGF2alpha were the major prostaglandins formed by analyses of culture media with the two antisera to PGF, before and after alkali treatment. Indomethacin at 5 mug/ml suppressed prostaglandin synthesis, usually to less than 1% of control cultures. Colchicine, 0.1 mug/ml resulted in marked stimulation of prostaglandin synthesis, in some cases over 10 fold. It is suggested, because of the colchicine effect, that the state of the microtubules may regulate the rate of prostaglandin biosynthesis. It is possible that prostaglandin E2 produced by rheumatoid synovia may contribute to the pathogenesis of the inflammatory reaction and lead to destruction of juxta-articular bone in rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed1989

Colchicine lesions of ventromedial hypothalamus: effects on regulatory thermogenesis in the rat.

Experiments were carried out to test whether the ventromedial hypothalamus (VMH) is the site of a pathway that stimulates thermoregulatory heat production in brown adipose tissue (BAT). Adult Sprague-Dawley rats received bilateral 50 nl microinjections of colchicine solution into the VMH (0.1, 0.32, 1.0 or 3.2 micrograms per side). Beginning a day later, hyperphagia developed consistently with 0.32 microgram colchicine; and with higher doses there appeared the additional effect that for several days rats developed hypothermia when placed temporarily at 6 degrees C. The degree of hypothermia was limited by activation of nonshivering thermogenesis (NST) in BAT, as evidenced by increased shivering after propranolol injection to block NST, and by increased GDP binding measured in IBAT mitochondria after cold exposure. The findings suggest that chemical lesioning to induce the VMH hyperphagia syndrome does not produce an obligatory impairment of thermoregulation against cold unless the dose of neurotoxin and lesion area extends beyond that which underlies the overeating response. Furthermore, when tolerance to cold is thus compromised, the effect is not readily explained in terms of simply disconnecting a proposed stimulatory pathway from the VMH to BAT.

Animals↗

PubMed1990

Hyperactivity following intradentate injection of colchicine: a role for dopamine systems in the nucleus accumbens.

The role of dopamine systems in the nucleus accumbens (NA) in mediating the hyperactivity following colchicine-induced granule cell damage was investigated. In the first experiment adult Sprague-Dawley rats were bilaterally injected with 6-hydroxydopamine (6-OHDA; 8 micrograms/2 microliters) or 0.5% ascorbate into the NA. Eight days later, rats received intradentate COLCH or CSF and were tested for locomotor activity 2, 4, 6, 8, and 10 days later. Intradentate COLCH produced a significant hyperactivity which was prevented by prior injection of 6-OHDA into the NA. Neurochemical analysis revealed that 6-OHDA decreased dopamine (80%) but not norepinephrine in the NA without altering either catecholamine in the striatum. In the second experiment animals were injected with COLCH or CSF in the dentate gyrus and immediately implanted with bilateral cannulae in the NA. Animals received intraaccumbens injections of CSF or d-amphetamine (20 micrograms/l microliters) and were tested for locomotor activity. Amphetamine produced a significant increase in locomotor activity in both CSF- and COLCH-treated animals. However, COLCH produced an exaggerated response to the motor stimulating effects of amphetamine. These results suggest that the destruction of dentate granule cells following colchicine results in a "functional" hyperactivity of the mesolimbic dopamine input to the NA which might disinhibit locomotor activity.

Animals↗