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PubMed1991

Central effects of cycloheximide alone and of its combination with T-2 toxin.

The antibiotic cycloheximide inhibits protein synthesis in eukaryotic cells. This overall effect is similar to that of T-2 toxin, but the mechanism of intoxication by these two inhibitors are different. This is shown here by intracerebral injections of mixtures of T-2 toxin and cycloheximide, leading to potentiation of their toxic effects. The histopathology of cerebral intoxication by the two compounds is similar, but after cycloheximide the lesions appear earlier, and repair is faster.

Animals↗
PubMed2005

Behavioral changes resulting from the administration of cycloheximide in the pilocarpine model of epilepsy.

Cycloheximide influences synaptic reorganization resulting from pilocarpine-induced status epilepticus (SE). To investigate the possible behavioral consequences of this effect, we subjected animals to pilocarpine-induced SE either in the absence (Pilo group) or presence of cycloheximide (Chx group). Animals were further divided regarding the occurrence of spontaneous recurrent seizures (SRS). Two months after SE induction animals were exposed to different behavioral tests. Age-matched naïve animals were used as controls. All epileptic groups showed a significantly diminished freezing time in contextual and tone fear conditioning, performed poorly in the Morris water maze and present less seconds in immobility position as compared to controls. Only Pilo animals explored more extensively the open arms of the elevated plus maze and showed increased in horizontal exploratory activity in the open field as compared to controls. With the exception of Pilo animals without recorded SRS, all other groups had extensive tissue shrinkage in central nucleus of the amygdala as compared to controls. Cycloheximide-treated animals differed from Pilo animals in the extent of hilar loss and supragranular mossy fiber sprouting as well as tissue shrinkage in the dorsal hippocampus. Despite the histological differences seen in the dorsal hippocampus between experimental groups, no differences were encountered in the cognitive tests used to evaluate dorsal hippocampal function. The encountered histological differences between Chx and Pilo animals, however, might underlie the different emotional responses between the two groups.

Acoustic Stimulation↗
PubMed1999

Prevention of cycloheximide-induced apoptosis in hepatocytes by adenosine and by caspase inhibitors.

The mechanism by which cycloheximide induces apoptosis in isolated rat hepatocytes was studied. Cycloheximide (1-300 microM) induced apoptosis within 3-4 hr in the hepatocytes. Specific apoptotic characteristics such as blebbing, phosphatidyl serine (PS) exposure, chromatin condensation, and nuclear fragmentation were induced. Cycloheximide (CHX) dose dependently activated the caspase-3-like proteases, but not the caspase-1-like proteases. Pretreatment of the hepatocytes with 100 microM of the caspase inhibitors z-Val-Ala-DL-Asp-fluoromethylketone or Ac-Asp-Glu-Val-Asp-aldehyde completely abrogated the caspase activation and the apoptosis. Addition of adenosine (100 microM) reduced phosphatidyl serine exposure and other morphological characteristics of apoptosis by 50%; however, it did not prevent the activation of the caspases, suggesting that adenosine inhibited downstream of caspase activation. The adenosine receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl]methyl]oxy]phenyl]-1,3-dipropylxa nthine abolished the capacity of adenosine to prevent apoptosis, indicating that prevention was receptor-mediated. During apoptosis, the mitochondrial membrane potential in apoptotic cells (cells with PS exposition) was decreased to 50-60% of the control value; in the population viable cells, however, the mitochondrial membrane potential remained stable. Prevention of apoptosis by the caspase inhibitor z-Val-Ala-DL-Asp-fluoromethylketone or adenosine prevented the decrease in mitochondrial membrane potential. In conclusion, CHX rapidly induces apoptosis in isolated rat hepatocytes, which is inhibited by adenosine at a relatively late step.

Adenosine↗
PubMed2001

Cycloheximide reduces infarct volume when administered up to 6 h after mild focal ischemia in rats.

We have previously described a rodent model of brief (30 min) middle cerebral artery occlusion followed by reperfusion, in which infarction develops gradually, reaching completion more than 3 days after ischemia, accompanied by morphological, biochemical, and pharmacological evidence of apoptosis. In the present study, we tested the hypotheses that delayed administration of a protein synthesis inhibitor would be effective in reducing tissue injury in this slowly evolving ischemic infarction, and that efficacy of this treatment would wane with more prolonged ischemia. Focal cerebral ischemia was induced in Long-Evans rats by occlusion of the right middle cerebral artery. Infarction volume was analyzed using triphenyl tetrazolium chloride staining, and morphology was studied using hematoxylin and eosin stained sections. Following 30 min middle cerebral artery occlusion and reperfusion, the core ischemic region exhibited vacuolization in the neuropil by 36 h after ischemia, and infarction reached full size by 7 days after ischemia. Cycloheximide reduced infarct volume when given up to 6 h after ischemia. If the duration of ischemic insult was increased to 90 min, the therapeutic window for delayed cycloheximide was only 30 min. In permanent middle cerebral artery occlusion, cycloheximide was ineffective even when given prior to ischemia onset. After mild, but not severe, ischemic insults, cerebral infarction develops slowly and may be treatable with protein synthesis inhibitors, even when treatment is delayed for up to 6 h after the onset of ischemia.

Animals↗
PubMed1997

Superinduction of COX-2 mRNA by cycloheximide and interleukin-1beta involves increased transcription and correlates with increased NF-kappaB and JNK activation.

Many primary response genes, including cyclooxygenase-2 (COX-2), exhibit mRNA superinduction following agonist stimulation in the presence of translational blockers such as cycloheximide. This is widely assumed to result from mRNA stabilisation. However, superinduction of IL-1beta-induced COX-2 mRNA levels by cycloheximide in pulmonary type II A549 cells occurred by increased transcription and not by mRNA stabilisation. Furthermore, equivalent effects were observed on NF-kappaB binding to COX-2 promoter kappaB sites and activation of the Jun N-terminal kinases (JNK), p54 and p46. These signalling pathways play important roles in COX-2 induction and may therefore account for the observed increases in COX-2 transcription. These data are consistent with negative feed-back involving down-regulation of NF-kappaB by de novo IkappaB alpha synthesis and suggest that JNK activation may also be down-regulated by a cycloheximide sensitive process.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2002

A cycloheximide-sensitive factor regulates TCDD-induced degradation of the aryl hydrocarbon receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototype of environmental halogenated aromatic hydrocarbons, induces a rapid reduction in steady state aryl hydrocarbon receptor (AhR). Here, we analyzed the biochemical pathway and function of the downregulation. Our results reveal that TCDD downregulates the AhR protein by shortening the halflife of AhR. The TCDD-induced degradation of AhR is inhibited by MG132, a potent inhibitor of the 26S proteasome, indicating the ubiquitin-26S proteasome mediated proteolysis as a mechanism for the degradation of AhR. Furthermore, inhibition of protein synthesis by cycloheximide blocks the degradation of AhR by TCDD, suggesting a labile factor in controlling the stability of ligand-activated AhR (hence, designated as AhR degradation promoting factor, or ADPF). Analyses of nuclear AhR demonstrated that cycloheximide increases nuclear AhR protein and functional AhR/Arnt DNA-binding complex, resulting in superinduction of CYP1A1. Lastly, genetic analyses by using AhR- or Arnt-defective variant cells demonstrate that superinduction by cycloheximide requires the transcription activation (TA) domain of AhR, implicating the TA domain in the control of AhR turnover by ADPF. These findings provide new insights into the mechanism by which TCDD-activated AhR is regulated in nucleus through the 26S proteasome protein degradation pathway.

Animals↗
PubMed2003

Effect of cycloheximide, 6-DMAP, roscovitine and butyrolactone I on resumption of meiosis in porcine oocytes.

Improvement of the ability to maintain germinal vesicle stage oocytes in vitro is important for the acquisition of developmental competence. Maintaining oocytes at this stage without damaging their quality would allow synchronization of maturation and homogenization of the oocytes population. More investigations are needed to better understand how the oocyte cell cycle is blocked without consequences to future developmental competence. This study tested the efficacy of pharmacological inhibitors of the G2/M cell cycle transition in keeping porcine oocytes at the germinal vesicle (GV) stage and the reversibility of this inhibition. Porcine cumulus-oocyte complexes (COCs) were thus incubated without any hormones for 24 h in the presence or absence of tested inhibitors: 6-DMAP (protein kinase inhibitor, 2 mM), cycloheximide (protein synthesis inhibitor, 2 microg/ml), roscovitine (cyclin-dependent kinase inhibitor, 50 microM) and butyrolactone I (cyclin-dependent kinase inhibitor, 50 microM). Cumulus-oocyte complexes cultured with any of the inhibitors were significantly blocked at the GV stage. The inhibitory effect varied according to the products, with cycloheximide being the most efficient. Reversibility of the pharmacological inhibitors was assessed by culturing COCs an additional 24 h in inhibitor-free culture medium. Examination of oocytes revealed that the inhibitory effect was fully reversible. This study suggests that 6-DMAP, cycloheximide, roscovitine and butyrolactone I can be use to block meiotic resumption in porcine oocytes in NCSU culture medium.

4-Butyrolactone↗
PubMed1998

Intra-hippocampal administration of cycloheximide attenuates the restraint-induced exploratory deficit of an elevated plus maze.

Rats submitted to 2 h of restraint stress show a reduced open arm exploration in the elevated plus maze 24 h later. The stress-induced exploratory deficit is prevented by i.c.v. pre-stress administration of cycloheximide (CHX), a protein synthesis inhibitor. The objective of the present work was to determine if the hippocampus could be involved in this effect. CHX (4 or 8 microg) was injected into the dorsal hippocampus of male Wistar rats (200-250 g), immediately before (n = 9-20 animals/group) a 2 h period of forced restraint. After 24 h the animals were tested in the elevated plus maze. Non-stressed, control groups, received saline (SAL) or cycloheximide (CHX, n = 6-12/group) and were tested 1 or 24 h later in the maze. Pre-stress microinjections of cycloheximide increased exploration of open arms in the elevated plus maze (percentage of entries, SAL = 10.3 +/- 2.7, CHX 4 microg = 24.5 +/- 4.6, CHX 8 microg = 28.2 +/- 4.8, percentage of time spent, SAL = 2.0 +/- 0.6, CHX 4 microg = 8.4 +/- 2.3, CHX 8 microg = 9.6 +/- 2.6, Duncan test, P < 0.05). No drug effect was observed in non stressed animals. These results suggest that blockade of protein synthesis in the dorsal hippocampus during the restraint period may attenuate the behavioural consequences of stress.

Animals↗
PubMed1999

Cycloheximide and 4-OH-TEMPO suppress chloramphenicol-induced apoptosis in RL-34 cells via the suppression of the formation of megamitochondria.

Toxic effects of chloramphenicol, an antibiotic inhibitor of mitochondrial protein synthesis, on rat liver derived RL-34 cell line were completely blocked by a combined treatment with substances endowed with direct or indirect antioxidant properties. A stable, nitroxide free radical scavenger, 4-hydroxy-2,2,6, 6-tetramethylpiperidine-1-oxyl, and a protein synthesis inhibitor, cycloheximide, suppressed in a similar manner the following manifestations of the chloramphenicol cytotoxicity: (1) Oxidative stress state as evidenced by FACS analysis of cells loaded with carboxy-dichlorodihydrofluorescein diacetate and Mito Tracker CMTH2MRos; (2) megamitochondria formation detected by staining of mitochondria with MitoTracker CMXRos under a laser confocal microscopy and electron microscopy; (3) apoptotic changes of the cell detected by the phase contrast microscopy, DNA laddering analysis and cell cycle analysis. Since increases of ROS generation in chloramphenicol-treated cells were the first sign of the chloramphenicol toxicity, we assume that oxidative stress state is a mediator of above described alternations of RL-34 cells including MG formation. Pretreatment of cells with cycloheximide or 4-hydroxy-2,2, 6,6-tetramethylpiperidine-1-oxyl, which is known to be localized into mitochondria, inhibited the megamitochondria formation and succeeding apoptotic changes of the cell. Protective effects of cycloheximide, which enhances the expression of Bcl-2 protein, may further confirm our hypothesis that the megamitochondria formation is a cellular response to an increased ROS generation and raise a possibility that antiapoptotic action of the drug is exerted via the protection of the mitochondria functions.

Animals↗
PubMed2000

Cycloheximide-induced cPLA(2) activation is via the MKP-1 down-regulation and ERK activation.

Extracellular signal-regulated kinase (ERK)-dependent phosphorylation is an important regulator for cytosolic phospholipase A(2) (cPLA(2)). In this study, we found that the protein synthesis inhibitor cycloheximide can potentiate thapsigargin-induced arachidonic acid (AA) release concomitant with ERK phosphorylation from murine RAW 264.7 macrophages. The cycloheximide effect is not due to the activation of p38 mitogen-activated protein kinase (MAPK) nor c-Jun NH(2)-terminal kinase (JNK), because the activator of both MAPKs anisomycin does not elicit AA release. Cycloheximide effect is additive to the tyrosine phosphatase inhibitor orthovanadate since these two stimuli induced sustained ERK activation respectively through inhibition of the translation and activity of MAPK phosphatase-1 (MKP-1).

Animals↗
PubMed1986

Cycloheximide sensitivity in regulation of acyl coenzyme A:cholesterol acyltransferase activity in Chinese hamster ovary cells. 2. Effect of sterol endogenously synthesized.

We reported in another paper [Chang, C. C. Y., Doolittle, G. M., & Chang, T. Y. (1986) Biochemistry (preceding paper in this issue)] that in Chinese hamster ovary (CHO) cells activation of acyl coenzyme A:cholesterol acyltransferase (ACAT) activity by treating cells with cycloheximide was abolished by providing exogenous sterol in the medium. We now report that providing 20 mM DL-mevalonate to cells grown in sterol-free medium increases the ACAT activity by approximately 6-fold and diminishes the cycloheximide activation effect. The mevalonate supplement has no significant effect on the rate of triglyceride or polar lipid synthesis, [3H]cholesterol efflux, or bulk protein degradation in cells. The activation of ACAT by mevalonate is prevented by adding a specific squalene oxide cyclase inhibitor to cells, indicating the requirement for endogenous sterol synthesis to mediate the mevalonate effect. In sterol-free medium, if sterol synthesis is blocked by specific enzyme inhibitors or through mutation, the ACAT activation by cycloheximide is again abolished. These results support the hypothesis that there may exist a short-lived factor(s) serving directly or indirectly as an endogenous ACAT inhibitor(s), the inhibitory action of this (these) factor(s) is (are) abolished, and its (their) turnover rate(s) is (are) increased by either exogenous sterol or by sterol endogenously synthesized. Conversely, removing exogenous sterol coupled with blocking endogenous sterol synthesis decreases the turnover rate(s) of the inhibitor(s), rendering its (their) action insensitive to intracellular degradation over the time period studied.

Animals↗
PubMed1976

A cycloheximide sensitivity factor from yeast required for N-acetylphenylalanylpuromycin formation.

A protein (factor P) has been isolated from yeast, which was required for sensitivity to cycloheximide of a partially purified polyphenylalanine synthesis system. In the absence of factor P, 10(-3) M cycloheximide was required for 50% inhibition of polyphenylalanine synthesis, while in its presence, 10(-6) M gave 50% inhibition. Coincident with cycloheximide sensitivity was an activity required for EF-2 dependent N-acetylphenylalanylpuromycin (N-AcPhePuro) formation. Transfer of N-AcPhe to puromycin from the tRNA bound in the presence of 26 mM MgCl2 required factor P, as well as EF-2. Studies with antibody against EF-2 demonstrated that P factor was not required during the EF-2 translocation step but for some subsequent step.

Cycloheximide↗
PubMed1986

Cycloheximide analogues as potential anticonvulsants.

A series of 22 cycloheximide analogues in which the substituents on the cycloheximide ring and imide nitrogen were varied, the glutarimide ring was changed to a succinimide ring, and the ring and/or side-chain oxygens were present as ketone and/or alcohol groups were prepared and sent to the Anticonvulsant Drug Development program of the National Institute of Neurological and Communicative Disorders and Strokes for evaluation as anticonvulsants. Three compounds, namely cycloheximide (1a), 2-methyl dione 2c, and dihydrocycloheximide (4a), were further evaluated in Phase II testing for quantification of maximum activity with the latter eventually progressing to Phase IV and Phase VI screens.

Animals↗
PubMed2000

Cycloheximide-induced inhibition of chitin synthesis, and decay of apical vesicles and chitosomes in Phycomyces blakesleeanus.

Addition of cycloheximide rapidly inhibited protein synthesis in Phycomyces blakesleeanus. In contrast, chitin biosynthesis decreased with biphasic kinetics displaying a slow and a rapid decay phases. Electron microscopic studies revealed a decrease in the number of apical vesicles and chitosomes after cycloheximide addition; and no change in wall thickness. It is proposed that the slow phase of decay in chitin biosynthesis represents the exhaustion of the pool of chitosomes which transport the chitin synthase necessary to maintain apical wall growth; whereas the second one corresponds to inactivation of the enzyme, which is short lived in vivo. Data also rule out a change in the polarization of wall synthesis induced by cycloheximide, as suggested in other systems.

Antifungal Agents↗
PubMed1966

Effect of cycloheximide on protein and ribonucleic acid synthesis in cultured human lymphocytes.

1. Phytohaemagglutinin stimulates the transformation into blast cells of human lymphocytes incubated in vitro. This transformation is accompanied by an increase in the incorporation of [(14)C]leucine into protein and [(3)H]uridine into RNA. 2. The incorporation of [(14)C]leucine by cultures grown in the presence or absence of phytohaemagglutinin is inhibited to the same extent by cycloheximide, a known inhibitor of protein synthesis. 3. Lymphocytes grown without phytohaemagglutin synthesize mainly non-ribosomal RNA. [(3)H]Uridine incorporation by these cells was increased by cycloheximide. 4. Lymphocytes incubated with phytohaemagglutinin begin to synthesize substantial quantities of ribosomal RNA. Under these conditions [(3)H]uridine incorporation was partially inhibited by cycloheximide. This inhibition is shown to be largely a result of inhibition of the synthesis of ribosomal RNA.

Amino Acids↗
PubMed1977

Specific protein synthesis in isolated rat testis leydig cells. Influence of luteinizing hormone and cycloheximide.

The effect of luteinizing hormone (luteotropin) and cycloheximide on specific protein synthesis in rat testis Leydig cells has been investigated. Proteins were labelled with either I114C]leucine, [3H]leucine or [35S]methionine during incubation with Leydig-cell suspensions in vitro. Total protein was extracted from the cells and separated by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. No detectable increase in the synthesis of specific proteins could be observed after incubation of Leydig cells with luteinizing hormone for up to 1 h. However, after a 2h incubation period, an increase in [35S]methionine incorporation was observed in a protein with an apparent mol.wt. of 21000 (referred to as 'protein 21"). When, after labelling of this protein with [35S]-methionine, Leydig cells were incubated for another 30min with cycloheximide, no decrease in radioactivity of this protein band was observed, indicating that it does not have a short half-life. However, another protein band was detected, which after incubation with cycloheximide disappeared rapidly, the reaction following first-order kinetics, with a half-life of about 11 min. This protein, with an apparent mol.wt. of 33000 (referred to as "protein 33"), was found to be located in the particulate fraction of the Leydig cell, and could not be demonstrated in other rat testis-cell types or blood cells. No effect of luteinizing hormone on molecular weight, subcellular localization or half-life of protein 33 was observed. A possible role for protein 33 and protein 21 in the mechanism of action of luteinizing hormone on testosterone production of Leydig cells is discussed.

Animals↗
PubMed1977

Effects of anti-microtubular agents and cycloheximide on the metabolism of chylomicron cholesteryl esters by hepatocyte suspensions.

1. Post-heparin plasma that promoted rapid hydrolysis of about 90% of the triacylglycerol markedly stimulated the uptake or binding of chylomicron cholesteryl ester by suspended hepatocytes. The net hydrolysis of chyle cholesteryl ester after the uptake by the cells was, however, slower than in vivo. 2. The cholesteryl ester uptake in the presence of post-heparin plasma was larger if the cells had been preincubated for 2h. It was inhibited by the presence of colchicine, vinblastine or cycloheximide during the preincubation, and by mild trypsin treatment of the preincubated cells. 3. The results suggested that the anti-microtubular agents, but not cycloheximide, also inhibited the hydrolysis of chyle cholesteryl ester after uptake or binding to the cells. 4. The uptake of isolated chylomicron remnant particles was more efficient than that of native chyle lipoproteins. It was, however, still stimulated by heparin alone and by post-heparin plasma. The heparin-stimulated uptake was markedly decreased if cycloheximide was present during the preincubation period.

Animals↗
PubMed1979

Cycloheximide as a probe of fibrinogen synthesis.

Fibrinogen synthesis in the intact rat was perturbed by treatment with cycloheximide. Specific radioactivities of fibrinogen in plasma and liver both decreased at 2 h after treatment and increased over 2-fold by 18 h. Labelled-antibody--polyribosome binding experiments showed that more polyribosomes were engaged in fibrinogen synthesis at 18 h after treatment. Radioactivity of plasma fibrinogen chains from untreated control rats showed a constant ratio of A alpha--B beta/gamma = 1.03. At 2 h after cycloheximide treatment the A alpha- and B beta-chains showed the greatest decrease in labelling (A alpha--B beta/gamma = 0.66) and at 18 h all chains were much more labelled (the A alpha--B beta/gamma ratio chainged to 1.39). The observed imbalance in fibrinogen-chain synthesis suggests that cycloheximide has a selective effect on gene expression.

Animals↗