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PubMed1996

Intraventricular cycloheximide attenuates the restraint-induced long-lasting effect on plus maze exploration.

Rats submitted to 2 h of restraint stress show reduced open arm exploration in the elevated plus maze 24 h later. To determine if this effect is dependent on protein synthesis during or after the restraint period, cycloheximide, a protein synthesis inhibitor, was injected into the right cerebral ventricle of male Wistar rats (200-250 g), immediately before (N = 19 animals per group), immediately after (N = 7 animals per group) or 2 h (N = 10 animals per group) following a 2-h period of forced restraint. Twenty-four hours later the animals were tested in the elevated plus maze. Non-stressed control groups received saline (SAL, N = 8-9 per group) or cycloheximide (CHX, N = 8-9 per group) and were tested 1 h or 24 h later in the maze. Pre- but not post-stress microinjections of cycloheximide (20 micrograms in 2 microliters) increased exploration in the elevated plus maze (% of time spent in open arms, pre-stress injection: SAL = 4.6 +/- 1.2, CHX = 10.7 +/- 2.3; number of enclosed arms entries: SAL = 3.6 +/- 0.5, CHX = 5.6 +/- 0.4). No drug effect was observed in non-stressed animals. These results suggest that blockade of protein synthesis during the restraint period may attenuate the behavioral consequences of stress.

Animals↗
PubMed1984

Induction of polyploid nuclei in Physarum polycephalum by cycloheximide treatment in prophase.

Macroplasmodia of the acellular slime mold Physarum polycephalum were treated with pulses of cycloheximide (10 micrograms/ml medium, for 3 h), initiated 10-20 min before metaphase in the synchronous nuclear division cycle. This treatment interfered with normal division of the nuclei, but permitted DNA synthesis in the next S phase. This interpretation is supported by measurements of the DNA content per nucleus in cycloheximide-treated cultures as compared to control cultures, which show that some nuclei after cycloheximide treatment are polyploid. By this method we can produce polyploid strains of Physarum, but the elevated nuclear DNA content is not stable, and after several months the strains have reverted to the normal diploid DNA content.

Cell Cycle↗
PubMed2003

Mutants of the nematode Caenorhabditis elegans that are defective specifically in their attraction to cycloheximide.

The nematode Caenorhabditis elegans exhibits chemotaxis toward a wide variety of chemicals including water-soluble molecules and volatile organic compounds. We have previously discovered that C. elegans wild-type strain N2 is strongly attracted by cycloheximide which has long been known as a bitter tastant for humans and other mammals. We describe here the isolation and initial characterization of the first mutants which were defective specifically in their attraction to cycloheximide. In our screenings, we selected two mutants that were defective in chemotaxis to cycloheximide but normal in their attraction to NH4Cl and histidine. These mutants also avoided quinine hydrochloride, CuSO4 and high concentrations of NaCl similar to the wild-type strain N2. Furthermore, no observable defect was detected in their attraction to volatile odorants such as isoamyl alcohol and diacetyl. Dye-filling experiments suggested that they have no morphological defect in the sensory endings of the amphid neurons.

Journal Article↗
PubMed1970

Effect of cycloheximide, gamma irradiation, and phosphorus deficiency on root pressure exudation in tobacco.

Cycloheximide drastically reduced the rate of root pressure exudation in detopped tobacco (Nicotiana tabacum L.), and the effect was more pronounced for nitrate salts in the external solution than for some other salts or when the roots were in water. Diurnal periodicity was greatly decreased, and its phase was changed. Effects began within an hour. Cation uptake was reduced by relatively low levels of cycloheximide. The effects of cycloheximide seemed to be reversible. Mild phosphorus deficiency resulted in decreased exudation rates from detopped tobacco and in no response to nitrate. Periodicity of exudation was not greatly affected by phosphorus deficiency, however. Gamma ray irradiation with a (60)Co source at levels (up to 40-50 kiloroentgens) which are considered disruptive of moderately large molecules had relatively little effect on the exudation rate. Higher levels of irradiation, which disrupt most protein molecules, decreased exudation and obscured periodicity. The results indicate either that new protein (or peptide) synthesis is needed for the rapid nitrate transport or that the deficiency and inhibitor disrupt cellular membranes. Phosphorus deficiency increased the sensitivity of the plants to inhibition by irradiation of the exudation process.

Journal Article↗
PubMed1971

Influence of cycloheximide on the synthesis and utilization of amino acids in suspension cultures.

Cells from 4-days old suspension cultures of Paul's Scarlet rose were incubated with acetate-U-(14)C for 10 minutes. After washing, cells were incubated for 2 hours in growth medium in the presence and absence of cycloheximide. The (14)C content of individual amino acids in the soluble form and in protein were determined at the end of the 10 minute pulse and at intervals thereafter in control cells and those treated with cycloheximide. During the period following the pulse there was a 3-fold increase in the (14)C content of protein in control cells; no such increase occurred in the presence of cycloheximide.In the control cells there was a net increase in the (14)C content of eight individual amino acids during this period. For six of these, the corresponding increases in the presence of cycloheximide were curtailed by the following amounts: arginine 98%, lysine 94%, isoleucine 93%, threonine 82%, valine 49%, and proline 36%. This is interpreted to mean that the synthesis of each of these amino acids was slowed down when their incorporation into protein was prevented.

Journal Article↗
PubMed1974

Effects of Cycloheximide upon Formation of Ribonucleic Acid Cytidylic and Uridylic Acids.

Concentrations of cycloheximide as low as 3 mug/ml inhibited incorporation of labeled orotic acid or uridine into RNA cytidylic acid of soybean (Glycine max) hypocotyl sections. Even lower concentrations of this well known protein synthesis inhibitor interfered with conversion of labeled cytidine into RNA uridylic acid. Both cycloheximide and puromycin inhibited absorption of (3)H-phenylalanine and its incorporation into protein, but puromycin did not significantly affect the labeling patterns of RNA cytidylic and uridylic acids when orotic acid-6-(14)C was fed. Results give further support to the hypothesis that cycloheximide inhibits the interconversion of uridine and cytidine nucleotides, presumably by acting as a glutamine antagonist in the glutamine-dependent reaction catalyzed by cytidine triphosphate synthetase.

Journal Article↗
PubMed1975

Cycloheximide is not a specific inhibitor of protein synthesis in vivo.

Cycloheximide is frequently presumed to inhibit specifically the cytoplasmic protein synthesis of eukaryotes. Although previous investigators have shown that it had other effects on the cells of a variety of organisms, these results were frequently presumed to be secondary effects of the inhibition of protein synthesis. This paper shows that a wide range of deleterious effects are produced by cycloheximide on a single organism, Chlamydomonas reinhardi Dangeard. If, protein synthesis is inhibited by nonpermissive conditions in temperature-sensitive mutants or with other treatments these "secondary" effects are not produced. Instead, cycloheximide appears to have two or three independent inhibitory effects on the cell. Moreover, in contrast to a number of previous investigations, these results show that protein synthesis is not required for RNA synthesis. Instead the rate of RNA synthesis is actually increased by interference with protein synthesis.

Journal Article↗
PubMed1978

Corn Leaf Isoperoxidase Reaction to Mechanical Injury and Infection with Helminthosporium maydis: Effects of Cycloheximide.

Mechanical injury or infection with Helminthosporium maydis race T or O enhanced peroxidase activity in leaves of two corn inbreds which differ in their susceptibility to the fungal race T. Increases in activity were found in the soluble fraction extracted from tissues with 20 mm phosphate buffer (pH 6), and in the ionically bound fraction extracted from wall debris with 0.6 to 1 m NaCl; the covalently bound wall peroxidase fraction was unaffected. Mechanical injury and infection with either race enhanced the same distinctive cathodic isoforms present in the soluble fraction or in both the soluble and ionically bound fractions.During the first 20 to 22 hours after inoculation no differences were found in the enzyme enhancement in relation either to the corn line or fungal race. During the second day, the weaker the infection symptoms, the greater was the peroxidase enhancement. The race T-infected susceptible inbred showed no increase or a decrease in the enzyme activity, whereas in most cases both inbreds infected with race O exhibited a further peroxidase enhancement.Pretreatment of healthy leaves or leaf discs with cycloheximide at concentrations which did not cause a loss of turgor had no effect on peroxidase enhancement. However, in tissues inoculated with either the race T or O, cycloheximide, at concentrations which did not affect the mechanical injury-induced increase in peroxidase activity, did inhibit the enzyme enhancement and did cause a loss of turgor.The observed changes in isoperoxidase activities (a) confirm the assumption that the infection-induced enhancement of this enzyme results from a nonspecific response to injury; (b) support the postulation that the often observed small or no increases in peroxidase activity to compatible hosts are a consequence of metabolic disorders rather than the cause of a lower resistance; and (c) indicate that cycloheximide as a protein synthesis inhibitor may increase the compatibility between the host and pathogen, enhance metabolic disorders in inoculated tissues, and in consequence interfere with the nonspecific cell response to injury.Actinomycin D did not affect the mechanical injury- or infection-induced peroxidase enhancement. Neither did ethylene at 5 to 80 mul/l have a significant effect on the enzyme activity in healthy, injured, or infected tissues.

Journal Article↗
PubMed1987

Inadequacy of the eucaryote inhibitor cycloheximide in studies of protozoan grazing on bacteria at the freshwater-sediment interface.

Four guilds from a lake sediment-water interface microbial community were isolated and tested for sensitivity to cycloheximide (0.1 to 200 mg liter). Field experiments were conducted to compare the inhibition, dilution, and filtration methods for determining grazing rates. Cycloheximide inhibited anaerobic bacteria at 50 mg liter, and inhibition of bacterial growth was observed in the grazing experiments. The results show that the assumption of selective inhibition of heterotrophic eucaryotes was violated and preclude the use of cycloheximide in grazing experiments.

Journal Article↗
PubMed1970

Accelerated Cytopathology in HeLa Cells Induced by Reovirus and Cycloheximide.

The addition of the protein inhibitor cycloheximide, at concentrations which suppress virus replication, to HeLa cell monolayers infected with reovirus type 2 results in the appearance of accelerated cytopathic effects (CPE). At high multiplicity of infection, CPE appeared after a lag period of 2 to 3 hr and increased progressively, until by 12 hr the entire monolayer had rounded and sloughed off. During this same period, both the uninfected cycloheximide-treated and untreated virus-infected controls exhibited no CPE. The phenomenon is affected by the kind of cell species employed and can be reversed if the antibiotic is removed within 1 hr after exposure. The evidence obtained through studies in which specific metabolic inhibitors and direct biochemical analyses were used suggests that the accelerated CPE observed in cycloheximide-treated reovirus-infected cells is the consequence of the combined inhibition of the synthesis of both cellular protein and ribonucleic acid. The accelerated CPE is also induced in the antibiotic-treated cells by reovirus serotypes 1 and 3.

Journal Article↗
PubMed1987

Ultrastructure of the choroid plexus epithelium of pigeons treated with drugs: I. Effect of Thyradin, 2,4-dinitrophenol, and cycloheximide.

Possible changes in the epithelial cells of the pigeon choroid plexus induced by administration of thyroid powder (Thyradin), 2,4-dinitrophenol, and cycloheximide were studied by scanning and transmission electron microscopy. A marked increase in the number of large bulbous and bleblike protrusions on the apical end of the epithelial cells was observed after oral administration of Thyradin for a month. The endoplasmic content of the protrusions consisted mainly of electron-lucent material. These results provide morphological evidence for the stimulatory effect of Thyradin. Intramuscular injections of 2,4-dinitrophenol for 15 days caused the collapse or deformation of the mitochondria and bleblike or bulbous protrusions. This indicates that changes in the surface configuration of the choroid plexus are controlled by an energy-dependent mechanism. The decrease of protrusions and polyribosomes and increase of the tubular saccules of varying electron density, size, and shape were noted in cells after 15 days of intramuscular cycloheximide injection. The electron density of the protrusions is lower than that of the control pigeons. The results of this study suggest that a curious pleomorphic structure on the apical surface of the choroid epithelial cell of pigeon is closely related to the functional state of choroidal cells. The study also demonstrates that a secondary ultrastructural response due to diverse physiologic effects is reflected in the architecture of the choroid plexus cells.

2,4-Dinitrophenol↗
PubMed2004

5-fluorouracil-induced oligodendrocyte death and inhibitory effect of cycloheximide, Trolox, and Z-VAD-FMK in murine cortical culture.

BACKGROUND: 5-fluorouracil (5-FU) is a widely used anticancer drug. One of the adverse effects of this drug is selective cerebral white matter injury, but to the authors' knowledge its mechanism has not been well documented. The current study was performed to investigate the mechanism of cerebral white matter injury caused by 5-FU and to develop the intervention to attenuate its injury in vitro. METHODS: Mixed oligodendrocyte/astrocyte cells were dissociated from specimens taken from approximately 2-day-old postnatal mouse cortex and cultured for 3-4 weeks. The culture cells were exposed to 5-FU, cycloheximide, emetine, Z-VAD-fmk, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX), Trolox, and epigallocatechin gallate. Oligodendrocyte cell death was assessed by counting the number of viable galactocerebroside-positive cells per x 100 field. RESULTS: Mixed oligodendrocyte/astrocyte culture cells that were exposed to 5-FU (at doses of 10 microM, 30 microM, and 100 microM) for 24 hours ensued concentration-dependent oligodendrocyte death. The majority of oligodendrocytes, but few astrocytes, were injured by 100 microM 5-FU. Trolox, a vitamin E analog antioxidant, as well as cycloheximide (a protein synthesis inhibitor) and Z-VAD-fmk (a caspase inhibitor), significantly attenuated the 5-FU-induced oligodendrocyte death. However, NBQX, an alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropionic acid (AMPA) receptor antagonist, did not appear to effect the 5-FU-induced oligodendrocyte death. CONCLUSIONS: The findings of the current study suggested that 5-FU led to oligodendrocyte death rather than astrocyte death by way of the apoptotic process, whereas antioxidants may prevent the 5-FU-induced oligodendrocyte cell death in vitro.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Induction of cMrp/cMoat gene expression by cisplatin, 2-acetylaminofluorene, or cycloheximide in rat hepatocytes.

The human multidrug-resistance-associated protein (MRP), a member of the adenosine triphosphate (ATP)-binding cassette transporter superfamily, is frequently overexpressed in tumor cells resistant to antineoplastic drugs. In the rat, two Mrp isoforms have been identified, Mrp and cMrp. cMrp, also called Mrp2 or cMoat (canalicular multispecific organic anion transporter), is expressed in the canalicular membrane of rat hepatocytes and mediates the excretion of glucuronate, sulfate, and glutathione conjugates into bile. We investigated the expression of cMrp and Mrp in rat hepatocytes in primary culture. Treatment with the chemical carcinogen 2-acetylaminofluorene (2-AAF), the antineoplastic drug cisplatin, and the protein-synthesis inhibitor cycloheximide led to a dose-dependent and time-dependent increase in cmrp gene expression. A 347-base pair cmrp complementary DNA (cDNA) probe served to demonstrate the induction of cmrp messenger RNA (mRNA) with 40 micromol/L 2-AAF, 5 micromol/L cisplatin, or 5 micromol/L cycloheximide. An analogous response was obtained for the increase in cMrp protein. Mrp mRNA was below the detection limit in Northern blots of RNA from liver and hepatocyte cultures, in contrast to rat testis mRNA which served as a positive control. Immunofluorescence microscopy of cultured hepatocytes was used to visualize cMrp in the plasma membrane. Treatment with 2-AAF led to a marked increase in the immunofluorescence signal confirming the cMrp-inducing potency of 2-AAF. In conclusion, the inducing effect of the compounds studied may reflect a general inducibility of hepatic cMrp by a variety of cytotoxic, carcinogenic, and chemotherapeutic agents which is likely to be of relevance for the acquisition of multidrug resistance during chemotherapy and in the process of chemical carcinogenesis in the liver.

2-Acetylaminofluorene↗
PubMed1978

Inhibition of basal protein degradation in rat embryo fibroblasts by cycloheximide: correlation with activities of lysosomal proteases.

Rat embryo fibroblasts were grown in medium containing 14C-leucine and 3H-thymidine. After a 24-hour chase in nonlabeled medium, cultures were placed in either fresh growth medium or medium containing 10-20 microgram/ml cycloheximide. Cell monolayers were processed at daily intervals for three days. Four hours prior to processing, cultures were placed in fresh medium and the accumulation rate of trichloroacetic acid soluble 14C in the media assayed. Cycloheximide effects a progressive decrease in the fractional degradation rate of the labeled cell protein, primarily during the first 24 hours. The specific activities of cathepsin D, cathepsin B, and neutral protease correlate closely with the fractional degradation rate. Other lysosomal hydrolases show little change during this period. The activities of the lysosomal proteases approach a new steady state which is correlated with the new steady state level of protein synthesis. A model is proposed which relates the rate of protein breakdown in the cell to the level of protein synthesis. The data also suggests the possibility that subpopulations of high turnover and low turnover cells exist in these cultures.

Animals↗
PubMed1981

Effect of cycloheximide and dexamethasone phosphate on hyaluronic acid synthesis and secretion in cultured human skin fibroblasts.

We have studied some aspects of the regulation of hyaluronic acid synthesis in cultured human skin fibroblasts derived from normal individuals. In these cells 85% of radiolabeled glucosamine is incorporated into two types of macromolecules, hyaluronic acid and glycoproteins, characterized by district partitions between the cell and medium compartments. Treatment of cells with cycloheximide under conditions in which protein and glycoprotein synthesis is inhibited by at least 90% has no effect on hyaluronic acid synthesis. This result is consistent with the hypothesis that protein synthesis is not necessary for the synthesis of hyaluronic acid. Conversely, 5 X 10(-6) M dexamethasone phosphate inhibits hyaluronic acid by 60% but has no effect on protein or glycoprotein or glycoprotein synthesis. Concomitant treatment with dexamethasone phosphate and cycloheximide restores the synthesis of hyaluronic acid to normal values. The dexamethasone phosphate effect on hyaluronic acid synthesis is therefore not a primary induction response since it requires protein synthesis. The secretion of hyaluronic acid and glycoproteins from the cells into the medium is not affected by either of the two drugs. This experimental approach will be useful in the study of the regulation of glycosaminoglycan metabolism in human cells especially with respect to disorders of connective tissue.

Cells, Cultured↗
PubMed1982

Effects of cycloheximide and actinomycin D on the amino acid transport system of Tetrahymena.

Tetrahymena pyriformis were grown in axenic culture to late logarithmic and stationary phases, resuspended in an inorganic medium, and the rates of transport of alpha-aminoisobutyric acid (AIB) and of the decarboxylation of L-[1-14C]leucine and L-[1-14C]tyrosine were measured. There was a rapid loss of each of these measures of amino acid transport in both late log phase and stationary phase cells, Addition of actinomycin D to the washed cells caused a small increase in the rate of loss of capacity to decarboxylate tyrosine and leucine. Addition of cycloheximide to the washed cells caused a reduction in the rates of loss of capacity to transport AIB and to decarboxylate leucine and tyrosine except that in late log phase cells cycloheximide markedly increased the rate of loss of capacity to decarboxylate leucine. When cells that had been pretreated with chlorpromazine to reduce their amino acid transport capacity were washed and resuspended in proteose peptone the capacity to decarboxylate tyrosine and leucine increased to control values within 1.5 hours. Addition of actinomycin D reduced the rate of recovery of transport systems in this cell. The finding that AIB and N-methylaminoisobutyrate are both taken up by Tetrahymena, the latter at one-eighth the rate of the former, but that neither one alters the rate of uptake of the other provides preliminary support for this possibility. The present results further suggest that the transport system(s) has a short lifetime and that the balance between rate of synthesis and rate of loss of the transport system is controlled in part by the presence of exogenous amino acids.

Amino Acids↗
PubMed1992

Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis.

The glucose regulated proteins (GRPs) are major structural components of the endoplasmic reticulum (ER) and are involved in the import, folding, and processing of ER proteins. Expression of the glucose regulated proteins (GRP78 and GRP94) is greatly increased after cells are exposed to stress agents (including A23187 and tunicamycin) which inhibit ER function. Here, we demonstrate that three novel inhibitors of ER function, thapsigargin (which inhibits the ER Ca(2+)-ATPase), brefeldin A (an inhibitor of vesicle transport between the ER and Golgi) and AIF4-, (which inhibits trimeric G-proteins), can increase the expression of both GRP78 and 94. The common characteristic shared by activators of GRP expression is that they disrupt some function of the ER. The increased levels of GRPs may be a response to the accumulation of aberrant proteins in the ER or they may be increased in response to structural/functional damage to the ER. The increased accumulation of GRP78 mRNA after exposure of cells to either thapsigargin, brefeldin A, AIF4-, A23187, or tunicamycin can be blocked by pre-incubation in cycloheximide. In contrast, accumulation of GRPs after exposure to hypoxia was independent of cycloheximide. In addition, the protein kinase inhibitor genistein blocked the thapsigargin induced accumulation of GRP78 mRNA, whereas the protein phosphatase inhibitor okadaic acid caused increased accumulation of GRP78 mRNA. The data indicates that there are at least 2 mechanisms for induced expression of GRPs, one of which involves a phosphorylation step and requires new protein synthesis (e.g., thapsigargin, A23187) and one which is independent of both these steps (hypoxia).

3T3 Cells↗
PubMed1993

Different patterns of apoptosis of HL-60 cells induced by cycloheximide and camptothecin.

Cells of the human promyelocytic HL-60 line, when treated with a variety of antitumor agents in the presence of the protein synthesis inhibitor cycloheximide (CHX), or with CHX alone, rapidly undergo apoptosis ("active cell death"). It is presumed, therefore, that such cells are "primed" to apoptosis in that no new protein synthesis is required for induction of their death. We have studied apoptosis of HL-60 cells triggered by the DNA topoisomerase I inhibitor camptothecin (CAM) in the absence and presence of CHX and apoptosis induced by CHX alone. Two different flow cytometric methods were used, each allowing us to relate the apoptosis-associated DNA degradation to the cell cycle position. Apoptosis induced by CAM was limited to S phase cells, e.g., at a CAM concentration of 0.15 microM, nearly 90% of the S phase cells underwent apoptosis after 4 h. In contrast, apoptosis triggered by CHX was indiscriminate, affecting all phases of the cycle: approximately 40% of the cells from each phase the cycle underwent apoptosis at 5 microM CHX concentration. When CAM and CHX were added together, the pattern of apoptosis resembled that of cycloheximide alone, namely, cells in all phases of the cycle in similar proportion were affected. Thus, CHX, while itself inducing apoptosis of a fraction of cells, protected the S phase cells against apoptosis triggered by CAM. Because CHX (5 microM) did not significantly affect the rate of cell progression through S phase, the observed protective effect was most likely directly related to inhibition of protein synthesis, rather than to its possible indirect effect on DNA replication. Furthermore, whereas apoptosis (DNA degradation) triggered by CAM was prevented by the serine protease inhibitor N-tosyl-L-lysylchloromethyl ketone (TLCK), this process was actually potentiated by this inhibitor when induced by CHX. The present data indicate differences in mechanism of apoptosis triggered by CAM (and perhaps other antitumor drugs) as compared with CHX. Apoptosis caused by CHX may be unique in that it may not involve new protein synthesis. These data are compatible with the assumption that the loss of a hypothetical, rapidly turning over suppressor of apoptosis may be the trigger of apoptosis of HL-60 cells treated with CHX, whereas de novo protein synthesis is required when apoptosis is triggered by other agents.

Apoptosis↗