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PubMed1982

Diminished toxicity of methotrexate in CD2F1 mice pretreated with cycloheximide.

Cycloheximide at 100 mg/kg administered intraperitoneally to P388 tumor-bearing CD2F1 mice diminished protein synthesis in the liver, spleen, kidneys, lungs, small intestine and P388 tumor 75 min after administration. Six hours after administration all the above tissues except the tumor no longer demonstrated suppression of protein synthesis. The lethal toxicity of single intraperitoneal doses of methotrexate administered at 1, 3 or 6 h after the cycloheximide was diminished. However, no increase in therapeutic index was achieved with this dose schedule in P388 tumor bearing CD2F1 mice.

Animals↗

PubMed1993

Cycloheximide downsynthesizes inhibitory molecules for neurite outgrowth in neural transplantation.

Rat fetal substantia nigra treated with cycloheximide, a protein synthesis inhibitor, were implanted to adult rat striatum. After 4 weeks, tyrosine hydroxylase (TH)-like immunoreactive (-LI) fibers of host striatum penetrated grafts, and TH-LI neurites in the grafts elongated and mingled with the host striatal neurites. Astrocytes proliferated in the grafts without glial scar between the graft-host border. A few chondroitin sulfate- or tenascin-LI glial cells were found in the grafts, while in transplants without cycloheximide, glial scar expressed strong immunoreactivity for these molecules. Downsynthesis of these inhibitory molecules may alter the glial character and permit neurites traversing the border.

Animals↗

PubMed1994

Cycloheximide abolishes pertussis toxin-induced increase in glutamate release from cerebellar granule neurones.

Release of glutamate from cerebellar granule neurones was stimulated either by adding 50 mM K+ to normal Krebs medium, or by adding 5 mM Ca2+ to neurones continuously depolarised with 50 mM K+ in the absence of Ca2+. Pre-incubation of neurones for 16 h with pertussis toxin (PTX) increased the stimulated glutamate release in both K(+)-stimulated and continuously depolarised neurones. Under both conditions, the PTX-induced increase in release was abolished by cycloheximide. In contrast, in the presence of cycloheximide, PTX still prevented the GABAB agonist (-)-baclofen from inhibiting glutamate release. These results suggest that G-protein ADP-ribosylation by PTX in cerebellar granule neurones may increase synthesis of a protein associated with the L-type calcium channel.

Animals↗

PubMed1976

Interaction between glucocorticoids and cyclic AMP in the regulation of phosphoenolpyruvate carboxykinase (GTP) in the isolated perfused rat liver. Effects of cordycepin and cycloheximide.

The mechanism of the interaction between glucocorticoids and cyclic AMP in the regulation of phosphoenolpyruvate carboxykinase (GTP: oxalocetate carboxylase, transphosphorylating, EC 4.1.1.32) was investigated in the isolated perfused rat liver using inhibitors of transcription or translation. Dibutyryl cyclic AMP produced a rapid increase in P-enolpyruvate carboxykinase activity. The response of the enzyme to the cyclic nucleotide ceased however, at 4 h, but was restored by dexamethasone. The dibutyryl cyclic AMP-induced increase in P-enolpyruvate carboxykinase activity was completely blocked by cycloheximide, but not not by cordycepin. However, cordycepin totalaly suppressed the "permissive" effect of dexamethasone on the response of the enzyme to dibutyryl cyclic AMP. Preperfusion of the livers with dexamethasone and cycloheximide, following by perfusion without the steroid hormone and the inhibitor, resulted in a rapid rise in P-enolpyruvate carbosykinase activity, which was not affect by cordycepin. If livers were preperfused with cordycepin for different time-periods, followed by dibutyryl cyclic AMP stimulation of P-enolpyruvate carboxykinase synthesis, the response of the enzyme to the cyclic nucleotide was progressively reduced, achieving 50% inhibition after 1.5 h of preperfusion. These results suggest that the induction of hepatic P-enolpyruvate carboxykinase to maximum values, brought about by cyclic AMP at the level of translation, depends on the supply of newly synthetized mRNA provided by the transcriptional action of glucocorticoids.

Animals↗

PubMed1976

Reduction by cycloheximide of lysosomal proteolytic enzyme activity and rate of protein degradation in organ-cultured hearts.

Cycloheximide, an agent whose primary action is inhibition of protein synthesis, also causes a decrease in the rate of protein degradation in cultured fetal mouse hearts. This is associated with marked decreases in the activities of cathespin D and other lysosomal hydrolases. It is suggested that reduced lysosomal proteolytic capacity may contribute to cycloheximide-induced inhibition of protein degradation.

Acetylglucosaminidase↗

PubMed1990

S-phase accumulation of human salivary adenocarcinoma cells by cycloheximide.

Cycloheximide (1.0 ug/ml) reversibly induced a 1.7-fold increase in the distribution of cells in S phase and a 0.9-fold decrease in G1 phase in DNA histograms of human salivary adenocarcinoma cells (HSG). At this time, cycloheximide inhibited the synthesis of proteins by HSG cells and secretion of proteins in the media to 28.1% and 9% of the control values, respectively, which resulted in the almost complete arrest of cell reproduction. This indicates that HSG cells can pass through G1 to S phase even under the conditions of the arrest of protein synthesis.

Adenocarcinoma↗

PubMed1982

Effect of cycloheximide on different stages of Drosophila melanogaster.

Cycloheximide, an antibiotic inhibiting protein synthesis, exerted a toxic effect on different developmental stages egg, larva and adult of Drosophila melanogaster. At the egg stage the early embryos were most sensitive. With larvae, a strong decrease in viability was found, with no sex difference. In adults, there was a dose-effect relationship, mortality increasing with concentration. At 10 and 15 mM, males were more sensitive than females. There were consistent differences between the control and cycloheximide-fed females in respect of the average number of eggs deposited and offspring produced.

Animals↗

PubMed1996

Ergocalciferol and cycloheximide in vivo stimulate protein kinase C of intestinal crypt cells.

Previous reports have suggested that 1,25-dihydroxychole-calciferol regulated cellular differentiation via its effects on protein kinase C activity. This study examined the in vivo effects of ergocalciferol on the activity of protein kinase C, and whether the differentiation of crypt intestinal cells is dependent on the activation of this enzyme. Ergocalciferol in saline was injected intramuscularly into rats and the animals sacrificed 24 hr after fasting. Protein kinase C specific activity was determined from the rate of incorporation of 32p-ATP into protamine. Injections of 60 micrograms ergocalciferol/200 g of body wt, raised protein kinase C specific activity to 59818 +/- 4010 (SEM, n = 5) cpm 32p-protamine/min/mg cell protein, compared with a control of 46173 +/- 4612 (P < 0.0005). Optimal specific activities were seen within 72 hr of injection. Administration of 120 micrograms ergocalciferol/200 g of body wt, raised the concentrations of serum calcium to 9.8 and 10.4 mg/dl following the intramuscular injection by 24 and 72 hr, respectively, compared with a control of 7.7 mg/dl. Actinomycin D (intramuscular, 100 micrograms/200 g of body wt) together with ergocalciferol (120 micrograms/200 g of body wt) reduced protein kinase C activity by 51% 24 hr after injection. Cycloheximide blocked the activation, but when injected alone stimulated endogenous protein kinase C activity by 34% 24 hr injection. The study shows activation of crypt protein kinase C by ergocalciferol. The inhibition of activation by actinomycin D and cycloheximide suggests the involvement of both transcriptional and translational processes in this activation.

Animals↗

PubMed1984

Rapid inactivation of Ca2+, Mg2+-dependent endonuclease of rat liver nuclei after cycloheximide treatment.

Ca2+, Mg2+ dependent endonuclease activity of isolated nuclei from rat liver disappeared completely within one to two hours after intraperitoneal administration of inhibitors of eukaryotic protein synthesis such as cycloheximide or puromycin. Actinomycin D, on the other hand, revealed no inhibition of the endonuclease activity, but even reversed the effect of cycloheximide by simultaneous addition.

Animals↗

PubMed1988

Protection from heat-induced protein migration and DNA repair inhibition by cycloheximide.

The mechanism by which Cycloheximide (CHM) protects cells from heat induced killing has been investigated. Cycloheximide (10 micrograms/ml) added for 2 hr before and during a 3 hour heating at 43 degrees C prevented a 40% increase of heat-induced protein accumulation in the nucleus and protected cells (0.0001 vs. 0.15 surviving fraction) from heat-induced killing. Heat-induced DNA repair inhibition was also suppressed when cells were treated with CHM in the above manner. This combination of results suggests that protein accumulation in the nucleus and inhibition of DNA repair are related and these events are associated with CHM protection from heat induced cell killing.

Animals↗

PubMed1997

Mechanisms of cycloheximide-induced apoptosis in liver cells.

Cycloheximide in sublethal doses caused apoptosis in liver cells in vivo, inducing c-myc, c-fos, c-jun and p53 genes and accumulation of sphingosine, a toxic product of the sphingomyelin cycle. These data support the hypothesis that continuous synthesis of labile protective proteins is required to restrain apoptosis in liver; sphingosine might be important in mediating cycloheximide-induced apoptosis as an endogenous modulator of protein kinase C activity.

Animals↗

PubMed1991

The effect of heparin on glomerular coagulation induced in mice by cycloheximide and bacterial lipopolysaccharide.

The glomerular capillary coagulation in mice which follows challenge with cycloheximide and a submicrogram dose of endotoxin was shown to become fully established between 4 h and 6 h after challenge. Complete protection against the renal lesion was achieved by heparin treatment 4 h after challenge. The antifibrinolytic agent, tranexamic acid, given 4 h and 6 h after challenge, abolished this heparin-induced protection, but had no effect when given 6 h and 8 h after challenge. These findings suggest that heparin in some way delayed the onset of cycloheximide and endotoxin-induced irreversible coagulation in glomerular capillaries, and by so doing, allowed the development of local, protective, fibrinolytic activity. A relatively brief period of such fibrinolytic activity appeared to confer lasting protection against coagulation in glomerular capillaries. Appropriately timed treatment with hydrocortisone also abolished the heparin-initiated protection, and the evidence suggests that the steroid acts by inhibiting the development of local fibrinolytic activity.

Animals↗

PubMed1993

Cycloheximide or nordihydroguaiaretic acid protects mice against the lethal and hepatocytolytic effects of a combined challenge with D-galactosamine and bacterial endotoxin.

Both cycloheximide and nordihydroguaiaretic acid protect mice against the fatalities and associated panlobular hepatocyte necrosis that follow a challenge with D-galactosamine and bacterial endotoxin. It is proposed that cycloheximide acts as an inhibitor of the endotoxin-induced activation of phospholipase A2, thereby inhibiting the synthesis of leukotrienes which is now known to be a prerequisite for tumour necrosis factor-alpha (TNF) biosynthesis, the latter cytokine being regarded as the terminal mediator of the fatal D-galactosamine and endotoxin-induced syndrome. Nordihydroguaiaretic acid protection is explained by its inhibition of lipoxygenase enzymes, and thus ultimately of TNF production in response to endotoxin.

Animals↗

PubMed1997

Comparison of susceptibility to apoptosis induced by rhTNF-alpha and cycloheximide between human circulating and exudated neutrophils.

To determine whether exudated neutrophils differ from circulating ones in their apoptosis, rhTNF-alpha plus cycloheximide-induced apoptosis in human salivary neutrophils was compared to that in human neutrophils in peripheral blood. Concomitant treatment of peripheral blood neutrophils with rhTNF-alpha and cycloheximide-induced apoptosis in blood neutrophils within 3 hr, as evaluated both by light microscopic changes characteristic to apoptosis and by DNA fragmentation, whereas the same treatment failed to induce any apoptosis in salivary neutrophils. These results indicate that the exudation of neutrophils from blood into tissue is associated with marked changes in their functions such as alteration in their sensitivity to apoptosis-inducing stimuli.

Apoptosis↗

PubMed1983

Substance p reversal of electroconvulsive shock and cycloheximide-induced retrograde amnesia.

Subcutaneous post-trial administration of the neuropeptide substance P was found to reverse the amnestic effects of both electroconvulsive shock and cycloheximide. Substance P was observed to reverse the amnestic effects of cycloheximide in both C57B1/6J and heterogeneous strain (HS) mice. Substance P was found to reverse the amnestic effects of electroconvulsive seizures in C57B1/6J animals. Peripheral injections of substance P were also found to facilitate the retention of a single-trial passive avoidance habit in animals of both genotypes, provided a weak footshock was used during training.

Animals↗

PubMed1982

Problems associated with the use of cycloheximide to distinguish between animal drug residues bound to protein and those incorporated into protein.

The user of cycloheximide to distinguish between covalently-bound drug residues in animals and residues due to the incorporation of drug fragments into endogenous molecules was explored. The results indicated that cycloheximide prevented the absorption of both glycine and ronidazole from the gastro-intestinal tract, an effect that complicates its use in the characterization of drug residues in animals.

Animals↗

PubMed1997

Protein synthesis inhibitor cycloheximide dose-dependently decreases formalin-induced c-Fos protein and behavioral hyperalgesia in rats.

We had previously demonstrated that c-fos antisense oligodeoxynucleotides dose-dependently suppressed formalin-induced c-Fos protein and behavioral hyperalgesia. To test whether de novo protein synthesis is required for the development of persistent pain after peripheral inflammation, we observed formalin-induced spinal c-Fos protein and nociceptive behaviors following pretreatment with cycloheximide, a protein synthesis inhibitor. Cycloheximide dose-dependently inhibited formalin-induced spinal c-Fos protein and tonic nociceptive responses. The possible non-specific effects other than protein synthesis inhibition on nociceptive behavior were carefully discussed and excluded. These results provide further support to the hypothesis that de novo protein synthesis is essential for the development of behavioral hyperalgesia.

Animals↗

PubMedDate not supplied

Cyclooxygenase inhibitors decrease apoptosis initiated by actinomycin D, cycloheximide, and staurosporine in amnion-derived WISH cells.

Apoptosis is a process by which external or developmental factors induce a specific series of events leading to cell death. Recently, apoptotic cells have been described in rat amnion membrane at late gestation, suggesting apoptosis may be involved in membrane rupture. Mechanisms controlling amnion cell apoptosis are unknown. The objective of this study was to investigate whether cyclooxygenase and prostaglandins are integral to apoptosis in amnion, as reported in intestinal epithelial cells and renal mesangial cells. Amnion-derived WISH cells underwent apoptosis in a dose- and time-dependent manner after incubation with actinomycin D, cycloheximide, or staurosporine, as determined by cell viability, DNA fragmentation analysis, and fluorescent in situ fragmentation analysis. Cells cultured with increasing doses of these agents also demonstrated concomitant increases in prostaglandin E2 output. WISH cell coincubation with these agents and the cyclooxygenase inhibitors indomethacin or piroxicam resulted in dose-dependent decreases in both prostaglandin E2 and apoptosis. Cultures incubated with 0.5 microgram/mL actinomycin D showed 80.7% cell apoptosis after 12 hours compared with 1.1% in untreated cultures. After 24 hours incubation with actinomycin D, 0.8% of the original cell number remained attached to the plate. In cultures coincubated with 0.5 microgram/mL actinomycin D and 100 mumol/L indomethacin, only 19.2%, 24.7%, and 39.3% of the cells were found to be apoptotic after 12, 24, and 48 hours in culture, respectively. Similar trends were observed after the use of cycloheximide or staurosporine in combination with indomethacin or prioxicam. These data suggest that cyclooxygenase and/or prostaglandins play a role in programmed cell death of amnion-derived WISH cells in culture.

Amnion↗