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PubMed1999

Cycloheximide rapidly inhibits cortical COX activity and COX-dependent pial arteriolar dilation in piglets.

We have previously shown that cycloheximide (CHX) preserved neuronal function after global cerebral ischemia in piglets, in a manner similar to indomethacin. To elucidate the mechanism of this protection, we tested the hypothesis that CHX would inhibit cyclooxygenase (COX) activity in the piglet cerebral cortex and vasculature. Pial arteriolar responses to hypercapnia, arterial hypotension, and sodium nitroprusside (SNP) were determined before and 20 min after treatment with CHX (0.3-1 mg/kg iv) using a closed cranial window and intravital microscopy. We also determined baseline and arachidonic acid (AA)-stimulated cortical PGF(2alpha) and 6-keto-PGF(1alpha) production before and 20-60 min after CHX (1 mg/kg iv) treatment, using ELISA kits. CHX did not affect baseline diameters (approximately 100 microm) but significantly decreased arteriolar dilation to COX-dependent stimuli, such as hypercapnia and hypotension, but not to COX-independent SNP. In the 1 mg/kg CHX-treated group, increases in vascular diameters were reduced from 22 +/- 2 to 10 +/- 2%, from 49 +/- 5 to 31 +/- 3% (means +/- SE, 5 and 10% CO2, respectively, n = 8), from 12 +/- 3 to 3 +/- 1%, and from 26 +/- 5 to 6 +/- 2% ( approximately 25 and 40% decreases in blood pressure, respectively, n = 6). CHX also inhibited conversion of exogenous AA to both PGF(2alpha) and 6-keto-PGF(1alpha); for example, 20 min after CHX treatment 10 microg/ml AA-stimulated PGF(2alpha) concentrations in the artificial cerebrospinal fluid decreased from 14.28 +/- 3.04 to 5.90 +/- 1.26 ng/ml (n = 9). Thus CHX rapidly decreases COX activity in the piglet cerebral cortex. This result may explain in part the preservation of neuronal function of CHX in cerebral ischemia.

Animals↗
PubMed1990

Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide.

Tumor necrosis factor (TNF), a potent polypeptide mediator released by activated monocytes and macrophages, has a number of proinflammatory effects on endothelial cells. TNF is cytotoxic to tumor cells in vivo and in vitro, but TNF-induced toxicity to endothelial cells is less well established. We now report that cycloheximide (CHX), an inhibitor of protein synthesis, renders endothelial cells highly susceptible to TNF-induced lysis. TNF alone did not change the overall rate of protein synthesis by endothelial cells, whereas the addition of CHX completely abolished protein synthesis. Endothelial cells incubated in TNF alone in high concentrations (up to 1,000 U/ml) showed minimal rounding up and release of 51Cr. Likewise, CHX alone (5 micrograms/ml) had no significant effect on endothelial cell morphology and release of 51Cr. However, incubation of endothelial cells in both CHX and TNF caused injury in a dose-dependent manner. Morphological evidence of cell retraction, rounding, and detachment began within 2 h, but specific 51Cr release did not begin to rise until after 4 h. These changes were not observed when endothelial cells were incubated with TNF/CHX at 4 degrees C. The combination of TNF/CHX was lethal to all endothelial cells tested (bovine pulmonary artery, human umbilical vein, and human aorta), with human aortic cells showing the most pronounced changes. We conclude that healthy endothelial cells are resistant to TNF-induced lysis, but inhibition of their ability to make protein renders them highly susceptible.

Animals↗
PubMed1981

Cycloheximide-induced phase shifting of circadian clock of Neurospora.

Cycloheximide (CHX), an inhibitor of cytosolic (80S) protein synthesis in eucaryotes, causes phase shifts of the circadian clock of Neurospora crassa when administered as 4-h pulses to cultures in liquid medium. Differential effects of the pulses at different phases of the circadian cycle were observed and plotted as a phase-response curve (PRC). Nearly all phase shifts observed were phase advances, with maximum sensitivity in the middle of the subjective day. Inhibition of protein synthesis by CHX was the same at both phases of the cycle. The PRC was the same at 20 and 25 degrees C. Dose-response curves for the effects of CHX on phase shifting and inhibition of protein synthesis were determined and showed a striking parallel in the responses of these two phenomena to CHX. These results support the view that synthesis of one or more proteins at specific phases of the circadian cycle is necessary for the normal operation of the circadian clock of Neurospora.

Biological Transport↗
PubMed2002

Cycloheximide increases glucocorticoid-stimulated alpha -ENaC mRNA in collecting duct cells by p38 MAPK-dependent pathway.

Aldosterone and glucocorticoids (GCs) stimulate Na(+) reabsorption in the collecting ducts by increasing the activity of the epithelial Na(+) channel (ENaC). Our laboratory has used Madin-Darby canine kidney-C7 cells to demonstrate that this effect is associated with an increase in alpha-ENaC gene transcription (Mick VE, Itani OA, Loftus RW, Husted RF, Schmidt TJ, and Thomas CP, Mol Endocrinol 15: 575-588, 2001). Cycloheximide (CHX) superinduced the GC-stimulated alpha-ENaC expression in a dose-dependent manner, but had no effect on basal or aldosterone-stimulated alpha-ENaC expression, whereas anisomycin inhibited basal and corticosteroid-stimulated alpha-ENaC expression. The superinduction of alpha-ENaC expression was also seen with hypotonicity, was blocked by RU-38486, and was independent of protein synthesis. CHX had no effect on alpha-ENaC mRNA half-life, confirming that its effect was via an increase in alpha-ENaC transcription. The effect of CHX and hypotonicity on alpha-ENaC expression was abolished by SB-202190, indicating an effect mediated via p38 MAPK. Consistent with this scheme, CHX increased pp38 and MKK6, an upstream activator of p38, stimulated alpha-ENaC promoter activity. These data confirm a model in which CHX activates p38 in Madin-Darby canine kidney-C7 cells to increase alpha-ENaC gene transcription in a GC-dependent manner.

Aldosterone↗
PubMed1995

Effect of cycloheximide and mRNA synthesis inhibition on death of trophically deprived ciliary ganglion neurons in culture.

1. The relationship between cycloheximide (CHX) and RNA synthesis inhibitors on trophic-deprived neuronal survival was studied with the use of primary cultures of stage (St) 34 chick ciliary ganglion (CG) neurons, to analyze the biological process of neuronal death caused by trophic factor withdrawal. Tissue culture conditions were refined by characterizing the additional medium components required to obtain 100% survival, for at least 1 wk, in the presence of an eye extract [choroid, ciliary body, iris, and pigment epithelium (CIPE)] as a trophic support for the neurons. Highly enriched neuronal cultures almost devoid of nonneuronal cells were used. 2. The time at which trophically deprived neurons cannot be rescued by the addition of trophic support, "commitment point," was established to be between 11 and 17 h after trophic deprivation. 3. CHX, an inhibitor of protein translation, reduced 3H-leucine incorporation by 90-95%, at a concentration of 10-100 micrograms/ml. The effect of the RNA transcription blockers actinomycin D (Act-D), alpha-amanitin, and 5.6 dichlorobenzimidazole riboside (DRB) on 3H-uridine incorporation into macromolecules was evaluated. Total RNA synthesis was inhibited by 10-25% by alpha-amanitin, whereas Act-D and DRB inhibited 80-97.5% of the 3H-uridine incorporation. 4. The effect of short- and long-term incubation with CHX on neuronal survival was analyzed. Continuous application of CHX promoted survival for 2-3 days, but thereafter neurons died regardless of whether CIPE was present or absent. Application of CHX for 6 h from the onset of the culture was enough to delay the commitment point up to 24 h after plating, and the addition of CIPE at this time maintained survival and promoted differentiation of CHX treated neurons. 5. The RNA transcription blockers Act-D, alpha-amanitin, and DRB were applied to both trophically deprived and trophically supported neurons, and the survival of each was evaluated. Neither drug was effective in supporting the survival of trophically deprived neurons in culture, and in most cases neurons even when cultured with CIPE died within 1-2 days in the presence of either drug. 6. Experiments using both CHX and mRNA synthesis blockers were performed to determine the effect of blocking mRNA transcription in trophically deprived neurons rescued by CHX. The addition of mRNA synthesis inhibitors precluded the effect of CHX on neuronal survival. 7. The effect of CHX (20 micrograms/ml) on RNA and protein synthesis was studied by measuring the incorporation of radiolabeled metabolic precursors (3H-leucine or 3H-uridine) into macromolecules. A 95% reduction in the protein synthesis was observed after 1 h of application of the drug, and by 24 h, 3H-leucine incorporation was reduced to 15-20% of the control values. Wash out of CHX after 6 h of incubation produced a recovery of protein synthesis up to 50% of control values 18 h later. CHX did not affect the synthesis of RNA for up to 12 h; however, it impaired the ability of the cell to take up metabolic precursors. 8. In conclusion, the present results support the hypothesis that the CHX effect on neuronal survival is due to its ability to induce the expression of survival or protective genes rather than to block the expression of killer proteins. This view is supported by 1) the 24-h delay of the commitment point following the short-term application of CHX, 2) the impaired ability of CHX to rescue trophic-deprived neurons by the addition of mRNA synthesis blockers, and 3) the fact that neuronal survival caused by trophic factors like CIPE, is blocked by blocking RNA transcription.

Animals↗
PubMed2002

Reassessment of the effects of cycloheximide on mossy fiber sprouting and epileptogenesis in the pilocarpine model of temporal lobe epilepsy.

A feature of animal models of temporal lobe epilepsy and the human disorder is hippocampal sclerosis and Timm stain in the inner molecular layer (IML) of the dentate gyrus, which represents synaptic reorganization and may be important in epileptogenesis. We reassessed the hypothesis that pre-treatment with cycloheximide (CHX) prevents Timm staining in the IML following pilocarpine (PILO)-induced status epilepticus (a multifocal model of temporal lobe epilepsy), but allows epileptogenesis (i.e., chronic spontaneous seizures) after a latent period. Hippocampal slices from PILO-treated rats without Timm stain in the IML after CHX treatment were hypothesized to lack the electrophysiological abnormalities suggestive of recurrent excitation. The primary experimental groups were as follows: 1) CHX (1 mg/kg) 30-45 min prior to administration of PILO (320 mg/kg ip, 2) only PILO, and 3) only saline (0.5 ml, IP). The CHX pre-treatment significantly decreased the number of rats that responded to PILO with status epilepticus compared to rats that received only PILO. Pre-treatment with CHX did not significantly alter the spontaneous motor seizure rate post-treatment compared to treatment with PILO alone in those animals from each group that developed status epilepticus during PILO treatment. Timm stain in the IML was not significantly different between the PILO- and PILO+CHX-treated rats. Using quantitative methods, CHX did not prevent hilar, CA1, or CA3 neuronal loss compared to the PILO-treated rats. Extracellular responses to hilar stimulation in 30 microM bicuculline and 6 mM [K(+)](o) demonstrated all-or-none bursting in both the CHX+PILO- and PILO-treated rats but not in control rats. Whole cell recordings from granule cells, using glutamate flash photolysis to activate other granule cells, showed that both the CHX+PILO- and PILO-treated rats had excitatory synaptic interactions in the granule cell layer, which were not found after saline treatment. Some rats responded to PILO (with or without CHX pre-treatment) with only one or a few seizures at treatment, and some of these animals (n = 4) demonstrated spontaneous motor seizures within 2 mo after treatment. Timm staining and neuron loss in this group were not clearly different from saline-treated rats. These results suggest that in the PILO model, pre-treatment with CHX does not affect mossy fiber sprouting in the IML of epileptic rats and does not prevent the formation of recurrent excitatory circuits. However, the develoment of spontaneous motor seizures, in a small number of rats, could occur without detectable hippocampal neuron loss or mossy fiber sprouting, as assessed by the Timm stain method.

Animals↗
PubMed1979

Hypothalamic injection of cycloheximide in the 4-day cyclic rat. Acute suppression of lordotic behavior and ovulation.

The results of serveral studies imply that estrogen can act upon the central nervous system via a protein synthetic step. Our objective was to determine if the intrahypothalamic (preoptic area, POA) injection of cycloheximide (CHX), an inhibitor of protein synthesis, at 17.00 h on diestrus II of the 4-day cycle altered lordotic behavior and (or) ovulation in the intact rat (sexual receptivity to males normally begins on the evening of proestrus as herein defined; ovulation occurs on estrus of the cycle). CHX-treated females were tested for lordotic behavior at 23.00 h on proestrus, then killed at 17.00 h on the following day. None of the CHX-POA rats were receptive to the males and 90% of these rats did not ovulate. Thus, CHX significantly suppressed sex behavior and ovulation in the cyclic rat.

Animals↗
PubMed1977

Effect of virus infection and cycloheximide treatment on the labeling of cellular phospholipids with 32 P.

The total amount and the relative proportions of labeled phospholipids were studied in chorioallantoic membrane cells (CAM), chick embryo cells (CEC) and L cells which were either infected with Newcastle disease virus (NDV), fowl plague virus (FPV) and mouse encephalomyocarditis (EMC) virus or treated with cycloheximide. In productively infected or nonproductively infected cells, the total amount of labeled phospholipids was not altered, but the relative proportions of individual phospholipids were modified. These modifications were related to the presence of viral proteins. Blocking of protein synthesis for 6 h with 7 microng cycloheximide/ml did not modify the total amount of labeled phospholipids in CAM and CEC. Less label was incorporated into cyclohexidime-treated L cells than in controls. The relative proportions of the labeled individual phospholipids were modified in all three cell types and these modifications were different from those in virus-infected cells.

Animals↗
PubMed1993

Effect of gamma-interferon or cycloheximide treatment on viral and c-myc transcripts in bovine-papillomavirus-type-1-transformed primary mouse fibroblasts.

We have studied the effect of gamma-interferon (IFN-gamma) treatment on the transcription of viral and c-myc oncogenes in bovine papillomavirus type 1 (BPV-1)-transformed mouse fibroblast cell lines. Upon IFN-gamma treatment, viral transcripts always decreased in cell lines containing episomal BPV-1 DNA, while the effect was variable in cell lines containing integrated BPV-1 DNA. Two series of tumour cell lines established by in vivo passage of B6B71 (episomal) and B6B31-J (integrated) cells via nude mice (NuTu A) into immunocompetent C57BL/6 mice (NuTuA B6Tul) also showed a decrease and an increase, respectively, in viral transcripts upon IFN-gamma treatment. IFN-gamma also reduced c-myc transcription in all cell lines derived from tumours, but increased it in the transformed cell cultures. There was selection of c-myc oncogene transcripts in all the tumour-derived cell lines as compared to their transformed cell cultures. Cycloheximide treatment increased both viral and c-myc gene transcripts 3- to 20-fold in all cell lines. These results imply that IFN-gamma produced locally by immunological mechanisms may influence the expression of Papillomavirus oncogenes, and the response to IFN-gamma treatment may change when the viral DNA is integrated into the host genome.

Animals↗
PubMed1981

Nuclear and mitotic abnormalities produced by cycloheximide in the newt egg during cleavage and their relationship to the cell cycle.

In cleaving newt eggs short-lasting treatments with millimolar quantities of cycloheximide (1/2, 1/3, 1/6 cycle) produce, after 6 h recovery, nuclear and mitotic abnormalities which are less drastic, but similar to those produced by treatments lasting 6 h. Special disturbances of the spindle and asters are different from those produced by spindle inhibitors (reduction in size of the asters and of the number of poles by nucleus, usual suppression of the spindle, failure of cytokinesis, separation of asters from nuclei). But the structure of nuclei is different according to the time when the treatment started (telophasic when it begun at anaphase or telophase, prophasic when begun at prophase). The difference in percentage of these two types of nuceli is highly significant and independent of the time passed after the beginning of the treatment. Each nucleus has to complete the whole cycle before the effect can be stopped.

Animals↗
PubMed1980

Effect of cycloheximide on bile flow adaptive response in selective biliary obstruction.

The adaptive increase in bile flow was studied up to 24 h after selective biliary obstruction (SBO) in the rat. Between 6 and 12 h after SBO bile flow increased significantly, such that 12 and 24 h after SBO bile flow did not differ significantly from control. The prior administration of cycloheximide (300 micrograms/100 g) resulted in a significant impairment of the increase in bile flow normally occurring between 6 and 12 h after SBO. These data indicate that the adaptive response in bile flow is dependent on de novo protein synthesis and suggest that the protein composition of the plasma membrane may determine the adaptive increase in bile flow that occurs after SBO in the rat.

Animals↗
PubMed1983

Separation of cholera enterotoxin-induced mucus secretion from electrolyte secretion in rabbit ileum by acetazolamide, colchicine, cycloheximide, cytochalasin B and indomethacin.

In vivo rabbit ileal loops were prepared and inoculated with purified cholera enterotoxin (CT). After a lag period of about 1 h there was persistent stimulation of water and electrolyte secretion and a transient stimulation of mucus secretion into the luminal fluid. Repeated intraluminal inoculation of prostaglandin E1 (PGE1) caused a pattern of water, electrolyte and mucus secretion which was qualitatively the same as that following CT, except that no lag period was observed. Doses of the protein synthesis inhibitor, cycloheximide, the microtubule disrupter, colchicine, and the microfilament disrupter, cytochalasin B, were found that inhibited CT-induced mucus secretion but not water and electrolyte secretion. The carbonic anhydrase inhibitor, acetazolamide, inhibited CT-induced water and electrolyte secretion without inhibiting the mucus secreted over a 5-hour test period. Thus a variety of agents can be used to demonstrate a separation of intestinal water and electrolyte secretion from mucus secretion. The prostaglandin synthesis inhibitor, indomethacin, also inhibited CT-induced water, electrolyte and mucus secretion, but no dose of this agent was found that completely separated the water and electrolyte from the mucus secretion.

Acetazolamide↗
PubMed1982

Effect of cycloheximide on hepatic microsomal lipids as a function of age in rats.

Cycloheximide, at a non-lethal dose of 2 mg/kg body weight, increases the level of total lipids and major lipid fractions in total, rough and smooth liver microsomes obtained from suckling, adult and old rats, but not in the newborns. The rates of increase differ in the different age-groups and fractions. Total lipids and phosphatidyl choline of rough and smooth microsomes in adult rats reach control levels at 6 h after the antibiotic treatment. Phospholipid fractions of old rats tend to approach control levels by 6 h after treatment whereas cholesterol levels remain relatively high. Total lipids, phosphatidyl choline and phosphatidyl ethanolamine of total, rough and smooth microsomes show significant quantitative differences during development.

Aging↗
PubMed1987

Human chorionic gonadotropin and 8-bromo cyclic adenosine monophosphate promote an acute increase in cytochrome P450scc and adrenodoxin messenger RNAs in cultured human granulosa cells by a cycloheximide-insensitive mechanism.

Treatment of human granulosa cells with human chorionic gonadotropin (hCG) or an analogue of its second messenger, cyclic AMP (cAMP), promotes a rapid accumulation of the messenger RNAs (mRNAs) for cytochrome P450 side-chain cleavage (scc) and adrenodoxin. A twofold increase in the cellular content of these mRNAs was observed within 4 h of exposure to 8-bromo-cAMP, and was maintained for up to 48 h. Inhibition of protein synthesis by cycloheximide did not prevent the hCG- or 8-bromo-cAMP-stimulated accumulation of either cytochrome P450scc or adrenodoxin mRNAs. We conclude that human granulosa cells respond rapidly to hCG and cAMP analogues with a coordinate increase in levels of the mRNAs encoding two key proteins of the steroidogenic machinery, and that this stimulation does not require synthesis of a protein intermediate.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Lipopolysaccharide (LPS)-induced cell death of C3H mouse peritoneal macrophages in the presence of cycloheximide: different susceptibilities of C3H/HeN and C3H/HeJ mice macrophages.

Lipopolysaccharide (LPS) induced cytotoxicity toward mouse peritoneal macrophages from C3H/HeN mice but not C3H/HeJ mice in vitro in the presence of cycloheximide (CHX). More than 1 ng/ml LPS induced a significant time-dependent release of a cytoplasmic enzyme, lactate dehydrogenase (LDH), while even 1000 ng/ml LPS failed to induce it in LPS-non-responsive C3H/HeJ mouse macrophages. Although similar LPS-induced cytotoxicity was observed in a murine macrophage-like cell line, J774.1, but not in an LPS-resistant mutant of J774.1, the LPS1916 cell line, these results suggest that the induction of this cytotoxicity is linked to the LPS-sensitivity of mouse macrophages. A recombinant TNF-alpha (rTNF-alpha) at 100 ng/ml augmented LDH release from both C3H/HeN and C3H/HeJ macrophages treated with LPS and CHX, while rTNF-alpha alone or in combination with LPS or CHX failed to induce LDH release. These results suggest that this cytotoxicity might be partially regulated by high concentrations of exogenous TNF-alpha in both C3H/HeN and C3H/HeJ macrophages, implying a possibility of paracrine regulation of TNF-alpha in mice toward LPS-treated macrophages under impaired protein synthesis.

Animals↗
PubMed1977

Ultrastructural localization of acetylcholinesterase in cultured cells. II. Cycloheximide-treated embryo muscle.

The acetylcholinesterase activity (AChE) of cultured chick embryo muscle fibers that remains after the cells have been treated with the protein synthesis inhibitor cycloheximide was examined with cytochemical stains and the electron microscope. AChE activity that decreased rapidly after addition of the inhibitor was associated with enzyme within the cells, and AChE activity that was relatively insensitive to the inhibitor was associated with AChE outside of the cells. The results support the view that there are at least two fractions of AChE in developing muscle fibers, one intracellular and labile, the other extracelullar and stable.

Acetylcholinesterase↗
PubMed2001

Blocking of c-FLIP(L)--independent cycloheximide-induced apoptosis or Fas-mediated apoptosis by the CC chemokine receptor 9/TECK interaction.

Chemokines play a pivotal role in regulating leukocyte migration as well as other biological functions. CC chemokine receptor 9 (CCR9) is a specific receptor for thymus-expressed CC chemokine (TECK). It is shown here that engagement of CCR9 with TECK leads to phosphorylation of Akt (protein kinase B), mitogen-activated protein kinases (MAPKs), glycogen synthase kinase--3 beta (GSK-3 beta), and a forkhead transcription factor, FKHR, in a human T-cell line, MOLT4, that naturally expresses CCR9. By means of chemical inhibitors, it is shown that phosphoinositide-3 kinase (PI-3 kinase), but not MAPK, is required for CCR9-mediated chemotaxis. Akt, GSK-3 beta, FKHR, and MAPK have been previously implicated in cell survival signals in response to an array of death stimuli. When MOLT4 cells, which expressed Fas as well as CXCR4, were stimulated with cycloheximide (CHX), an agonistic anti-Fas antibody, or a combination of these, the cells rapidly underwent apoptosis. However, costimulation of MOLT4 cells with TECK or stromal derived factor--1 significantly blocked CHX-mediated apoptosis, whereas stimulation only with TECK partially blocked Fas-mediated apoptosis. Concomitant with this blocking, cleavage of poly (adenosine 5'-diphosphate--ribose) polymerase and activation of caspase 3 were significantly attenuated, but the expression level of FLICE inhibitory protein c-FLIP(L), which had been shown to be regulated by CHX, was unchanged. This demonstrates that activation of CCR9 leads to phosphorylation of GSK-3 beta and FKHR and provides a cell survival signal to the receptor expressing cells against CHX. It also suggests the existence of a novel pathway leading to CHX-induced apoptosis independently of c-FLIP(L). (Blood. 2001;98:925-933)

Apoptosis↗
PubMed2003

Changes in plasma lipids after a non-lethal dose of cycloheximide in rats.

This paper describes a study of the effect of a single intraperitoneal non-lethal dose of cycloheximide (CHM; 2.0 mg/kg body weight) on the concentration of plasma lipids and lipoproteins in male rats killed one, two, three, four and nine days after receiving the dose. The concentration of triglycerides, total cholesterol, high-density lipoproteins (HDL)-cholesterol and low-density lipoproteins (LDL)-cholesterol was measured in treated and control animals. The effect of CHM on the concentration of triglycerides, total cholesterol, HDL-cholesterol, and LDL-cholesterol was visible in rat plasma throughout the study. Total cholesterol and HDL-cholesterol concentrations showed the same pattern of changes, probably due to the reversible inhibition of apolipoprotein apo A-I synthesis by CHM. The concentration of triglycerides decreased after a lag period of three days when the reserves of apolipoprotein apo B, the main apolipoprotein of very low-density lipoproteins (VLDL)-cholesterols produced in the liver, were consumed.

Animals↗