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PubMed1996

Cycloheximide-induced activation of mouse eggs: effects on cdc2/cyclin B and MAP kinase activities.

Fertilization of metaphase II-arrested mouse eggs results in resumption of meiosis and a decrease in both cdc2/cyclin B kinase and MAP kinase activities; the decrease in cdc2/cyclin B kinase activity precedes the decrease in MAP kinase activity. Cycloheximide treatment of metaphase II-arrested mouse eggs also results in resumption of meiosis but bypasses the fertilization-induced Ca2+ transient. However, it is not known if cycloheximide treatment results in the same temporal changes in cdc2/cyclin B kinase and MAP kinase activities that are intimately associated with resumption of meiosis. We report that cycloheximide-treated mouse eggs manifest similar temporal changes in the decrease in both cdc2/cyclin B kinase and MAP kinase activities that occur following fertilization, although cortical granule exocytosis is not stimulated. The decrease in cdc2/cyclin B kinase activity, however, does not seem to be required for the decrease in MAP kinase activity, since the decrease in MAP kinase activity still occurs in cycloheximide-treated eggs that are also incubated in the presence of nocodazole, which inhibits cyclin B degradation and hence the decrease in cdc2/cyclin B kinase. Following removal of these drugs, cdc2/cyclin B kinase activity remains high, MAP kinase activity increases to levels similar to that in the metaphase II-arrested eggs, and a spindle(s) forms with the chromosomes aligned on a metaphase plate. Results of these experiments suggest that some other protein with a relatively short half-life, e.g. cmos, a known upstream activator of MAP kinase, may be responsible for events leading to the decrease in MAP kinase activity.

Animals↗

PubMed1976

Flagellar regeneration in Chlamydomonas reinhardtii: evidence that cycloheximide pulses induce a delay in morphogenesis.

The behaviour of a pool of flagellar precursors, assayed by the ability of cells to regenerate flagella in the absence of de novo protein synthesis, has been examined during organelle morphogenesis in the biflagellate alga Chlamydomonas. The results demonstrate that flagellar elongation can continue even when this pool is apparently empty and suggest that 2 sources of precursors are available to the regenerating flagella: those pre-existing in the cellular pool and those synthesized de novo. Further evidence for this was obtained by subjecting regenerating cells to pulses of cycloheximide. Cells exposed to this drug during the first 60 min post deflagellation formed only half-length (5-mum) flagella, whereas a pulse administered after this point allowed the formation of longer flagella and suggested that some de novo protein synthesis was required for the formation of full-length flagella, although it was not a prerequisite for the initiation of regeneration. In addition, it was found that, subsequent to the removal of the cycloheximide, flagellar regeneration did not recommence immediately, but was delayed for a period of approximately 45 min, irrespective of length of flagella formed prior to drug inhibition. The nature of this cycloheximide-induced delay is unclear and certain alternatives, based on the exhaustion of structural/regulatory components are considered. Although it is not possible to distinguish between these alternatives, tubulin is not the limiting component, since a pool of this protein is present when flagellar elongation is prevented by cycloheximide.

Chlamydomonas↗

PubMed2005

Effect of cycloheximide on in vitro development of electrically activated feline oocytes.

This study was conducted to improve parthenogenetic development in vitro of feline oocytes following a combined activation treatment of electrical stimulation and cycloheximide. In vitro matured (IVM) oocytes were stimulated electrically by a DC electrical pulse of 2 kV/cm for 50 micros. The stimulated oocytes were then incubated in MK-1 medium with or without cycloheximide and subsequently cultured in vitro for 6 days. No significant differences were observed between the two groups with respect to the proportions of cleavage, development to the morula stage, and the cell number of blastocysts. However, exposure of electrically stimulated oocytes to cycloheximide significantly increased the rate of development of the stimulated oocytes into the blastocyst stage compared with oocytes stimulated by electrical stimulation alone (31.0% vs 6.7%). The results from the present study suggested that a single electrical stimulation was insufficient to activate the IVM cat oocytes at 24 h of maturation and that exposure to cycloheximide following electrical stimulation improved the efficacy of the parthenogenetic development of domestic cat oocytes.

Animals↗

PubMed1977

Rat adrenal corticosteroidogenesis; effect of ACTH, cycloheximide and sterol carrier protein.

Corticosterone formation was determined in the reconstructed rat adrenal system which consisted of the mitochondria and post-mitochondrial supernatant fraction (PM-fraction) supported by l-malate, and effect of ACTH and cycloheximide in vivo and cycloheximide, Ca++ and sterol carrier protein (SCP) in vitro were examined. Mitochondria isolated from adrenals of rats which received ACTH 15 min before sacrifice showed an elevated corticosterone formation. Cycloheximide administration 15 min prior to ACTH injection completely blocked the effect of ACTH but in vitro addition of this drug to the incubation mixture did not modify the rate of corticosterone production even at higher concentrations. Since the PM-fraction isolated from adrenals of rats received ACTH or cycloheximide or both did not change the mitochondrial capacity for corticosterone formation, factor(s) which influenced by ACTH administration seemed to be localized in mitochondria. The SCP-bound cholesterol was utilized for corticosterone formation more efficiently than the free cholesterol when added to the incubation mixture, and this might be due to, at least in part, higher rate of binding to the mitochondrial inner membrane of the SCP-bound cholesterol.

Adrenal Glands↗

PubMed1986

Blockade by cycloheximide of the prepartum changes in membrane activity and adrenergic response of the circular muscle of rat uterus.

A study was made of the effects of cycloheximide, an inhibitor of protein synthesis, on the transformations of electrical activity and adrenergic response of the circular muscle of rat uterus during pregnancy and postpartum. Electrical activity proceeded from plateau type on Day 18 of gestation to spike type on Day 22. Excitatory reaction of the contraction to noradrenaline (10(-7), 3 X 10(-7) M) on Day 18 altered to an inhibitory one on Day 22. When pregnant rats were injected intraperitoneally with 50 micrograms cycloheximide daily from Day 18, the changes mentioned above were suppressed and parturition delayed. In the preparations obtained on Day 21, the excitatory effect of 10(-7) M noradrenaline on the contraction changed to an inhibitory one by in vitro incubation for 7 h with Krebs solution. This transformation was prevented by the incubation with 2 micrograms/ml cycloheximide for 7 h. Membrane activity and adrenergic response turned to plateau-dominant action potential with long duration and potentiation of the contraction by noradrenaline (10(-7), 3 X 10(-7) M) 48 h after parturition, respectively. Cycloheximide (50 micrograms/day, i.p., immediately after delivery and on the next day) failed to inhibit these postpartum changes. The results suggest that the process of protein synthesis is involved in the alterations in electrical activity and adrenergic response of the circular muscle of rat uterus during late pregnancy stage.

Action Potentials↗

PubMed1983

The immunomodulatory effects of two plant growth regulators, cycloheximide and maleic hydrazide, in white mice.

The immunomodulatory effects of two plant regulators, cycloheximide and maleic hydrazide, were investigated by injecting the compounds twice weekly for 4 weeks in female Swiss Webster white mice. The animals were antigenically challenged with sheep red blood cells on day 24 of the study. Although humoral immunity was the primary system examined, analysis included all of the following parameters: spleen plaque forming cells (PFC's), lymphocyte viability, spleen lymphocyte counts, hemolysin titers, total plasma proteins, total white blood cells counts, hematocrit, total body weight, and liver, thymus and spleen weights. Cyclophosphamide and physiological saline were used as the respective positive and negative control substances. The dosing was as follows: cyclophosphamide at 50 mg/kg/injection, cycloheximide at 12.5, 25 and 50 mg/kg/injection and maleic hydrazide at 125 and 250 mg/kg/injection. Cycloheximide significantly (P less than .05) reduced, in a dose-dependent fashion, the thymus wt/gram of body weight, the number of PFC's/gram of spleen, total lymphocytes/gram of spleen, PFC's per 10(6) viable spleen lymphocytes and the hemolysin antibody titer levels. Maleic hydrazide significantly reduced thymus weights and moderately lowered the ratio of PFC's per 10(6) viable spleen lymphocytes. Maleic hydrazide significantly elevated total lymphocytes per gram of spleen and the hemolysin titer (up to 133% over saline control values). There was an elevation in the number of PFC's per gm of spleen by maleic hydrazide and the overall effects were dose related. Cycloheximide, a known inhibitor of protein synthesis, was distinctly the most suppressive of the two plant growth regulators. Both agents are widely utilized on agricultural products and the results suggest the need for care in their application and residue removal. Used properly, the plant growth regulators may pose little or no human health hazard, but this report documents a new biological activity for these agents.

Animals↗

PubMed1980

Effect of cycloheximide on the LH release induced by a superactive analog of LH-RH.

The effect of cycloheximide on the pituitary response to a superactive analog of LH-RH (D-Ala-6-des-gly-10-LH-RH-ethylamide) was studied in intact male rats. Cycloheximide did not modify the LH release induced by the LH-RH analog within 1 hr after its injection, but produced significant supression between 1 and 4 hr. It is concluded that the early release of LH observed after the administration of the analog occurs from the readily releasable pool of LH in the pituitary gland, which is not affected by cycloheximide. The subsequent LH release that can be suppressed by cycloheximide comes from the second pool of LH.

Animals↗

PubMed1975

Sequential irreversible, actinomycin D-sensitive, and cycloheximide-sensitive steps prior to cortisol inhibition of uridine utilization by P1798 tumor lymphocytes.

Events preceeding the cortisol inhibition of uridine utilization by corticoid-sensitive P1798 lymphocytes have been investigated. When tumor cells were incubated with 1 muM cortisol for 15 min and then washed free of steroid and reincubated in the absence of hormone, the expected decrease of uridine uptake failed to appear 1.5 hr later. In contrast, the removal of cortisol after 30 or 60 min did not prevent subsequent development of the steroid effect. Addition of actinomycin D with cortisol, or 15 min after hormone treatment was started, blocked steroid action. However, when actinomycin D was added 30 or 60 min after the initial exposure to cortisol, hormone-induced depression of uridine uptake was no longer prevented. To study the role of protein synthesis, cycloheximide was added to the tumor cell suspensions at various times after cortisol treatment was started. Cortisol suppression of uridine utilization was blocked when cycloheximide was added with the hormone or 30 min after the start of hormone treatment. Cycloheximide added together with cortisol and washed out with the steroid after 30 min did not prevent subsequent appearance of decreased nucleoside uptake. Hydroxyurea, an inhibitor of DNA synthesis, did not prevent cortisol action, even when present throughout a 2 hr exposure to the steroid. Hormone removal or actinomycin D addition after 1.5 to 2 hr (when uridine uptake was already inhibited about 25%) did not prevent intensification of the steroid effect during a subsequent 1.5- to 2-hr incubation period, while addition of cycloheximide at this time completely prevented its progression. These results suggest aht: (a) cortisol inhibition of uridine uptake by P1798 lymphocytes involves an early irreversible step and appears to require continuing RNA but not protein synthesis during the first 15 to 30 min of hormone action; (b) protein synthesis but not RNA synthesis is required between 30 and 60 min; and (c) continuing protein synthesis but not RNA synthesis or hormone presence is necessary for the preestablished cortisol effect to progress.

Animals↗

PubMedDate not supplied

[Effect of pentoxyphylline on certain indicators of the proteinase-proteinase inhibitor system in rats upon administration of cycloheximide].

The pentoxifylline influence on neutral proteinase, alpha-2-macroglobulin, trypsin-alpha-1-proteinase inhibitor and elastaseinhibitory activity under cycloheximide injection has been investigated. Two hours after cycloheximide injection the activity of neutral proteinases increases in rats serum, lungs, heart, liver and kidneys. The preliminary injection of pentoxifylline prevents increase of neutral proteinases activity. Cycloheximide also decreases alpha-2-macroglobulin activity in serum and liver and trypsin-, elastaseinhibitory activity of alpha-1-proteinase inhibitor in all investigated organs. At using pentoxifylline the alpha-2-macroglobulin activity doesn't change in liver and increases in serum in comparison with only cycloheximide and there are no observed any alpha-1 inhibitor proteinase activity changes in rats serum and organs.

Animals↗

PubMed1982

Phenobarbital-induced alterations in the sexual differentiation of the female rat: reversal by hydroxyurea and cycloheximide.

The possible mechanism of action of phenobarbital in prenatal female rats has been studied using different inhibitors of protein/DNA/RNA synthesis. Administration of phenobarbital (40 mg/kg/day) subcutaneously from day 17 to day 20 of pregnancy resulted in a delay of the onset of puberty, disorders of estrous cycle, infertility, and high estrogen levels in the female offspring. Cycloheximide (60 microg/kg/day)--a protein synthesis inhibitor and hydroxyurea (160 mg/kg/day)--a DNA synthesis inhibitor when combined with phenobarbital, significantly reduced the incidence of reproductive dysfunctions listed above. Alpha-amanitin (15 microg/kg/day), an inhibitor of m-RNA synthesis, produced reproductive disorders in the female offspring when administered alone to pregnant rats and also failed to reverse the PB-induced reproductive alterations. Cycloheximide and hydroxyurea produced no effect upon reproductive function when administered alone. Cycloheximide administration resulted in low body weight at birth and delayed eye opening. These results suggest that prenatal administration of phenobarbital produces its effect via new protein synthesis and that cycloheximide and hydroxyurea protect the offspring from phenobarbital-induced toxic effects by inhibiting its biochemical action.

Animals↗

PubMed2004

Cycloheximide prevents production of arresting, a fraction of 30-50 kDa obtained from seminiferous tubule conditioned medium.

AIM: To evaluate the effect of a protein synthesis inhibitor cycloheximide on arresting activity in spermatogenesis and sperm count in male rats. METHODS: The study used seminiferous tubule (ST) segments from adult rats cultured in vitro with or without cycloheximide to condition culture media, which have been concentrated, size fractioned (30-50 kDa) and administered 7 days to adult rats by intraperitoneal injections. The effects on testicular and epididymal weights, spermatogenesis and epididymal sperm count were determined. RESULTS: The fraction (30-50 kDa), named arresting, obtained from the culture without cycloheximide decreased testicular and epididymal weights (P<0.01) and reduced the epididymal sperm count significantly. Study of the spermatogenic cycle by transillumination showed spermatogenic arrest at stage VII in rats treated with arresting compared to that observed in controls. The length of stage VII in the group receiving the seminiferous tubules culture media with cycloheximide (30-50 KDa CHX-STCM fraction) was similar to control. CONCLUSION: The difference in the effect may be the result of the presence or absence of arresting, a protein secreted by the tubules.

Animals↗

PubMed1991

Translational inhibitors cycloheximide, emetine, and puromycin inhibit cellular autophagy in mouse liver parenchymal and pancreatic acinar cells in vivo.

The protein synthesis inhibitor cycloheximide is widely used (in vitro or in vivo) to inhibit the autophagic degradation of endogenous cellular proteins. Circumstantial evidence has been obtained largely from in vitro experiments for a similar effect of other translational inhibitors. In the present study, the in vivo effects of cycloheximide, emetine and puromycin on autophagy in murine exocrine pancreatic and liver cells were tested using electron microscopic morphometry. The experiments were based on the assumption that the autophagic compartment will regress if the formation of the vacuoles is blocked while degradation in the pre-existing vacuoles goes on. To make the measurements easier, autophagic compartment of the cells was greatly enlarged in both cell types by administering vinblastine (10 mg/kg b. wt.) for 2 h when the inhibitors were set on for an additional 30 min. During this half-an-hour, cycloheximide (0.2 mg/g b. wt.), emetine (0.12 mg/g b. wt.) and puromycin (0.2 mg/g b. wt.), respectively caused 58.5, 35.6, and 69.5% regression of the pancreatic and 46.7, 64.2, and 54.2% of the hepatocytic autophagic vacuole compartment. Thus, similarly to cycloheximide, both emetine and puromycin have proved to be inhibitors of autophagy in vivo. The results argue for a possible relationship between the synthesis and degradation of endogenous cellular proteins.

Animals↗

PubMed1990

[Alcohol motivation in rats under blockade of protein synthesis by cycloheximide].

The influence of protein blocker cycloheximide on the ethanol intake in alcohol-dependent rats was studied. It was found that intracerebroventricular as well as perifornical area hypothalamus injection of cycloheximide caused inhibition of ethanol consumption in alcohol-dependent rats, persisting for 5-9 weeks. The blockade action of cycloheximide was more strong after its injection in phase of decreased ethanol intake. At the same time it was shown an increase in water and food intake. The blockade action of cycloheximide on ethanol intake was not found in alcohol-dependent rats. These data indicate that some protein substances take part in mechanisms of organization of alcohol motivation and dependence.

Alcohol Drinking↗

PubMed1990

Cycloheximide enhances factor binding to the native 40S ribosomal subunit of Microsporum canis.

Native and derived ribosomal particles from the mycelial cells of Microsporum canis grown in the presence and absence of cycloheximide were compared by CsCl equilibrium density gradient centrifugation. Since the buoyant densities of ribonucleoprotein complexes are dependent on the protein-RNA ratio, they reflect the composition of these particles. The native monosomes from cells grown in the presence and absence of cycloheximide had a buoyant density of 1.585 g/cc. The native 60S subunits showed a density of 1.540 g/cc from cells grown in both presence and absence of cycloheximide, while the derived subunits showed a density of 1.610 g/cc. The derived 40S subunits had a density of 1.550 g/cc while the native 40S showed a major species of density 1.535 g/cc with three other minor species ranging in densities from 1.450-1.390 g/cc. The mycelia grown in the presence of cycloheximide showed an increased proportion of native 40S subunits in the density range of 1.450-1.390 g/cc, indicating that the drug enhances factor binding to native ribosomal subunits in M. canis.

Centrifugation, Density Gradient↗

PubMed1986

Regression of rat liver autophagic vacuoles by locally applied cycloheximide.

Defined areas of the intact liver surface of male Sprague-Dawley rats were exposed by means of small plastic rings to cycloheximide (1.8 X 10(-6) M to 1.8 X 10(-2) M). The incorporation of systemically applied [3H]leucine in a subcapsular tissue layer of 40 in micron thickness, was completely abolished at 1.8 X 10(-2) M and was reduced to 20 to 30% by concentrations between 1.8 X 10(-4) M and 1.8 X 10(-6) M cycloheximide as assessed by autoradiography. After fixation in situ with OsO4 this tissue layer was used for electron microscopy. Early autophagic vacuoles (AVs) whose contents could clearly be identified as being derived from cytoplasm were evaluated morphometrically. Their volume fraction in hepatocyte cytoplasm was reduced by cycloheximide within 10 minutes to about 50% of control tissue exposed to Ringer solution only. Maximal reduction was already observed with concentrations as low as 1.8 X 10(-5) M. When exposing the test areas to 1.8 X 10(-4) M cycloheximide for time intervals of 10, 20, 30, and 60 minutes, an exponential decrease in the AV volume fraction was seen in each individual animal over 20 minutes without further decrease between 30 and 60 minutes. The half-life of AV contents which could be calculated from this exponential decrease, was different for the different AV types, as distinguished according to their contents. Glycogen sequestered within AVs showed the largest morphological half-life of about 45 minutes, whereas, the half-life of the remaining components of AV contents, i.e., mitochondria, microbodies and endoplasmic reticulum together with cytoplasmic ground substance, was 10.1, 5.7, and 5.2 minutes, respectively. The average half-life of total AVs excluding those containing glycogen was 7.9 minutes. (first order rate constant: 0.088 min-1). The coefficient of variation (s/x), as calculated from single animal values, was lower for AV half-life (0.21) than for control AV volume fraction (0.67).

Animals↗

PubMed1982

[Turnover of potential-dependent ion channels in the membrane of neuroblastoma cells studied using the protein synthesis inhibitor cycloheximide].

The influence of cycloheximide on currents through sodium and potassium channels in dialysed neuroblastoma cells of clone N18A-1 has been studied under voltage clamp conditions. When cells are incubated with cycloheximide, the conductance of sodium decreases, whereas that of potassium changes only slightly, if at all. The cycloheximide concentration, at which sodium conductance is reduced by 50% during 24 hours incubation, was about 0.5 microgram/ml. The half-time of inhibition at the concentration of 15 microgram/ml was about 9 hours, with the time of 50% inhibition of sodium being more complex than single exponential. The density of sodium channels in control and after the maximal inhibition was estimated to be about 25 and 2.2 micron-2, respectively. The sodium-potassium selectivity and the gating mechanism parameters were shown to be unchanged following cycloheximide treatment.

Animals↗

PubMed1983

Effects of cycloheximide on the temperature profile of Sacharomyces cerevisiae.

Tmax, the maximum temperature for growth of Saccharomyces cerevisiae, decreased linearly with increasing concentrations of cycloheximide added to the medium, to about 20 degrees C at 2.5 microgram ml-1. In this concentration range thermal death was not enhanced. The Arrhenius plot of growth was shifted to lower temperatures as a function of the cycloheximide concentration and became dissociated from the Arrhenius plot of thermal death. It was concluded that the target site of cycloheximide, the cytoplasmic ribosome, is not identical with the physiological Tmax site of S. cerevisiae and that the binding of cycloheximide to its target sites is strongly enhanced by the temperature.

Cycloheximide↗

PubMed1983

[Interaction with cholinergic drugs in reversal of cycloheximide-induced amnesia by thyrotropin-releasing hormone and its analog DN-1417 in mice].

The reversal effect of drugs on experimental amnesia was studied using one-trial passive avoidance task in mice. Cycloheximide (120 mg/kg) given sc 30 min before the acquisition of avoidance response caused amnesia by showing short latency to enter from the safety compartment into the shocked compartment in the retention test conducted 24 hours later. In these cycloheximide-treated animals, physostigmine (0.1 mg/kg), thyrotropin-releasing hormone (TRH: 10-20 mg/kg) and DN-1417 (5-20 mg/kg) given sc 15-60 min before the retention test markedly prolonged response latency, indicating reversal of amnesia. The effects of all these drugs were almost completely antagonized by anticholinergic drug, scopolamine (0.4-10 mg/kg). Although physostigmine when administered in conjunction with TRH potentiated the reversal effect, there was no potentiation with DN-1417. Since these drugs did not affect test performance in the cycloheximide-treated mice which had experienced no foot-shock, it is unlikely that the amnesia-reversing effect of the drugs was a result of non-specific suppression on motor activity. These results suggest that cholinergic activation reverses cycloheximide-induced amnesia, and TRH and DN-1417, while they showed a difference in the action of potentiation with physostigmine, may also activate a retrieval process of memory by mediation of cholinergic mechanism.

Amnesia↗