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PubMed1992

Nerve growth factor rapidly regulates VGF gene transcription through cycloheximide sensitive and insensitive pathways.

Nerve growth factor (NGF) initiates and maintains a regulatory cascade, involving gene induction, which results in the neuronal differentiation of PC12 cells. The VGF gene encodes one of the most rapidly induced neuronal mRNAs identified in NGF-treated PC12 cells [Science, 229 (1985) 393-395; Mol. Cell Biol., 11 (1991) 2335-2349]. In this communication we show that NGF-treatment for 60-90 min maximally increases VGF gene transcription by 12- to 14-fold. VGF mRNA half-life was found to substantially decrease in PC12 cells treated with NGF for 9-25 h. Partial inhibition of VGF gene transcription and superinduction of cytoplasmic VGF mRNA levels in the presence of both NGF and cycloheximide suggests that the VGF gene may be regulated through multiple pathways, some of which can be activated in the presence of protein synthesis inhibitors as are the immediate early genes, while others require newly synthesized proteins.

Animals↗
PubMed1996

TPA and cycloheximide modulate the activation of NF-kappa B and the induction and stability of nitric oxide synthase transcript in primary neonatal rat hepatocytes.

12-O-Tetradecanoylphorbol 13-acetate (TPA) elicited a transient increase in the transcription of the inducible nitric oxide synthase (iNOS) gene coupled with a shortening of the half-life of its mRNA in primary neonatal rat hepatocytes. These effects of TPA were preceded by a surge in nuclear translocation of the transcription factor NF-kappa B, and followed by a mounting accumulation of NO-2 in the growth medium. Even cycloheximide (CHX) added by itself elicited an early, sustained activation of NF-kappa B followed by an intense induction of iNOS gene expression, irrespective of what degree of protein synthesis inhibition was brought about by the several concentrations tested. When given together, TPA and CHX exerted additive effects on hepatocellular iNOS mRNA levels. These results suggest the likelihood of an ordered sequence of events by which an activated NF-kappa B mediates the induction of iNOS gene expression in TPA- and/or CHX-treated primary hepatocytes.

Animals↗
PubMed1994

The response of brown adipose tissue mitochondrial glycerolphosphate acyltransferase to cold-exposure in hypothyroidism, after adrenalectomy and after treatment with cycloheximide.

1. Exposure to cold has previously been shown to considerably increase the activity of the mitochondrial form of glycerolphosphate acyltransferase (GPAT) in brown adipose tissue (A. C. Darnley, C. A. Carpenter and E. D Saggerson, Biochem. J. 253, 351-355, 1988; J. R. D. Mitchell and E. D. Saggerson. Biochem. J. 277, 665-669, 1991). 2. Both adrenalectomy and chemically-induced hypothyroidism increased mitochondrial GPAT activity in rats maintained at 21 degrees C. This increase was similar to that caused by exposing rats to the cold (4 degrees C) for three days. Whereas exposure of hypothyroid rats to cold (4 degrees C) resulted in a further increase in GPAT activity, no further increase in activity was observed after exposure of adrenalectomized rats to the cold. 3. Administration of triiodothyronine (T3) to rats maintained at 21 degrees C had no effect on mitochondrial GPAT activity. 4. Prior treatment with cycloheximide abolished 60-70% of the increase in GPAT activity caused by cold-exposure.

Acclimatization↗
PubMed1991

Cycloheximide blocks the fall of plasma and tissue tryptophan levels after tryptophan-free amino acid mixtures.

The hypothesis that incorporation of tryptophan (TRY) into proteins is the mechanism underlying the decrease in plasma and tissue TRY levels after a TRY-free amino acid mixture was investigated. Rats fasted 15 hours were pretreated with saline or with the protein synthesis inhibitor cycloheximide (CHEX) and treated with saline or a TRY-free amino acid mixture. In a first experiment, in saline pretreated rats the TRY-free mixture caused a decrease of 49% in total plasma TRY, of 64% in free plasma TRY, of 66% in brain TRY and of 42% in liver TRY. After 5 mg/kg of CHEX the same TRY-free diet caused a decrease of 5% in total plasma TRY, 14% in free plasma TRY, 18% in brain TRY and 9% in liver TRY. In a second experiment, the TRY-free diet caused a 43% decrease of total plasma TRY in saline pretreated animals and a decrease of 15%, 6% and 2% respectively after the pretreatment with 0.3, 1.0 and 5.0 mg/kg of CHEX. In brain TRY, the TRY-free diet caused a 62% decrease in saline pretreated rats and a decrease of 38%, 20% and 19% respectively after the pretreatment with 0.3, 1.0 and 5.0 mg/kg of CHEX. Since 5.0 mg/kg of CHEX almost completely block protein synthesis and since doses of CHEX from 0.3 to 5.0 mg/kg cause a dose-dependent inhibition of protein synthesis, our data support the hypothesis that protein synthesis is the mechanism through which TRY-free mixtures decrease TRY levels.

Amino Acids↗
PubMed1975

Cycloheximide resistance in Chinese hamster cells. II. Induction of Chm resistance in Chinese hamster cells by N-nitrosomethylurea.

Mutant Chinese hamster ovarian (CHO) cells with a resistance to 7-10(-7) and 8-10(-7) M cycloheximide (CHM) were induced at mutation rates of 1.9-5.2-10(-3) and 1.6-1.8-10(-3) respectively after treatment with N-nitrosomethylurea (NMU) at 100 mug/ml. The induced mutation rates differed by two orders of magnitude from the spontaneous rate of mutation to CHM resistance.

Cells, Cultured↗
PubMed1975

Cycloheximide resistance in Chinese hamster cells. I. Spontaneous mutagenesis.

Resistance to cycloheximide (CHM) was studied in cultured Chinese hamster cells. Concentrations of CHM above 5-10-7 M were toxic for the cells. At concentrations above 9-10-7 M no colonies were recovered in selective medium. 15 resistant clones of independent origin were isolated in selective medium containing 7-10-7 M CHM. Resistance was stable when the cells were cultured under non-selective conditions. The spontaneous mutation rate was determined by the fluctuation test. Mutations to CHM resistance arose spontaneously. The spontaneous mutation rate to CHM resistance was about 10-5.

Animals↗
PubMed1982

Antagonization by cycloheximide of ethyl methanesulfonate-induced 6-thioguanine-resistant mutation and sister-chromatid exchanges.

We studied the effect of cycloheximide (CH) on the induction of mutation and sister-chromatid exchanges (SCEs) in ethyl methanesulfonate (EMS)-treated Chinese hamster cells. At 10(-6)M, CH strongly antagonized the induction of mutation and SCEs and cell survival increased. This suggests that protein synthesis is essential for the induction of mutation as well as SCEs. Results of experiments in which CH treatment preceded or followed exposure to mutagens were similar with respect to the response curves obtained for mutation and SCEs.

Animals↗
PubMed1996

Susceptibility of hepatocytes to cell death induced by single administration of cycloheximide in young and old F344 rats. Effect of dietary restriction.

We evaluated the effect of a single dose of 1.0 mg/100 g body weight of cycloheximide (CHX) on the susceptibility of hepatocytes to cell death in young (6 months old) and old (24 months old) F344 rats fed ad libitum (AL) or on dietary restriction (DR), using terminal dUTP nick end labeling (TUNEL). The proportion of TUNEL-positive hepatocytes (TPH) at baseline (without administration of CHX) was significantly higher in advanced age. However, dietary intake did not influence the proportion of TPH at baseline irrespective of age Hepatocytes cell death, detected by TUNEL, was induced in the animal by a single intravenous injection of CHX. The proportion of TPH increased with time and reached a plateau 2.5 h after the administration of CHX in young AL and DR rats and old DR rats, but continued to significantly increase 4 hours after the administration of CHX in old AL rats. Our results indicate that the death of hepatocytes at baseline and susceptibility to cell death was enhanced by CHX in hepatocytes of senile rats. Our results also suggest that dietary restriction does not suppress the enhancement of cell death at baseline, but prevents age-associated increase in the susceptibility to cell death.

Aging↗
PubMed1982

Protein synthesis inhibition and amnesia for saccharin aversion memory in rats after intra-cisternal administration of cycloheximide.

The series of experiments reported further investigated the time course relationship of the amnesia for saccharin aversion memory in rats and the inhibition of protein synthesis resulting from cycloheximide (CXM). The first experiment showed that intraventricular CXM injected rats which had been trained 7 hrs after injection had learned the contingency under a considerable inhibition of protein synthesis. However, 1 hr after CXM injection protein synthesis inhibition was 86% and yet there was no amnesia observed 24 hr after training. It was also apparent that there were no marked regional differences in the extent of protein synthesis inhibition after intraventricular CXM. Finally, intracisternal injection of CXM 1 hr before training resulted in amnesia 24 hrs after training although this effect was greater when the injection was performed 7 hr before training. The findings (1) are consistent with Day et al's [4] suggestion of maximal protein synthesis inhibition at 1 hr post CXM injection with an approximately linear decline thereafter, and (2) provide no support for the involvement of the brain stem nucleus solitarius in taste aversion learning.

Amnesia↗
PubMed1983

Transient aversion and long-lasting amnesia following cycloheximide injection in the rat.

Rats were first trained to press a bar for water reinforcement. The day after reaching criterion, the animals received a subcutaneous injection of cycloheximide (CXM-2.5 mg/kg) or saline, 15 minutes before a single punishment (P) session where bar pressing was followed by a strong inescapable footshock (CXM-P and saline-P groups). No punishment was given to control groups (CXM-NP and saline-NP groups). Retention for this learning experience was tested 24 hr, one week or two weeks later. Performances of the control groups were similar at the three retention intervals although some CXM-induced aversion appeared at 24 hr. The saline-P groups always demonstrated good retention of prior aversive experience. By contrast, a long-lasting CXM-induced amnesia was apparent among the CXM-P groups. This deficit is not easily explained by nonspecific effects of the drug such as altered motor activity or motivational changes. Moreover, CXM-induced amnesia seems to be the result of impaired memory formation rather than impaired memory retrieval.

Amnesia↗
PubMed1986

Effects of methylmercuric chloride, cycloheximide, and colchicine on the reaggregation of dissociated mouse cerebellar cells.

High fetal and neonatal brain levels of methyl mercury (MeHg) have been associated with the abnormal migration of neurons within the cerebellar and cerebral cortices. How MeHg interferes with cellular proliferation, migration, and differentiation is poorly understood. In this study, a cell recognition/cohesion assay based on the ability of dissociated neonatal mouse cerebellar cells to reaggregate was used to test whether MeHg exposure could disrupt cell surface recognition. Reaggregation of dissociated cells was monitored by measuring diameters from low-power photomicrographs. Exposure to 4 mg/kg body wt methylmercuric chloride (MeHgCl) 24 hr prior to the isolation of 3 days postnatal cerebellar cells altered the pattern of reaggregate growth. Between 25 and 51 hr in vitro (hiv), the exposed reaggregates grew at a faster rate than controls. Freshly isolated cells exposed in vitro to 0, 0.5, 1.0, and 4.0 microM MeHgCl initially exhibited a dose-related inhibition in reaggregate growth with an IC50 of 1.5 microM at 24 hiv. Following initial inhibition, exposed groups showed a dose-dependent acceleration in reaggregation similar to that found following in vivo exposure. In contrast, in vitro exposure to cycloheximide resulted in only a dose-related inhibition of reaggregation. No acceleration in growth rate was seen. Colchicine exposure produced no initial inhibition but appeared to mimic the long-term effects seen with both in vivo and in vitro MeHgCl exposure. These studies suggest that MeHgCl alters cerebellar cell recognition through a complex mechanism initially involving depressed synthesis of specific proteins followed by alterations in microtubules. Both effects may involve a disruption in the arrangement of specific cell surface recognition molecules.

Animals↗
PubMed1989

Protein analysis of herpes simplex virus latency in vitro established with cycloheximide.

Herpes simplex virus (HSV)-specific protein synthesis was examined during establishment of HSV latency and reactivation of virus in human embryonic lung cells treated with cycloheximide and incubated at 40.5 degrees. Eight viral proteins, identified during the first two days of establishment of latency at 40.5 degrees, were undetectable by Day 3. At least two synthesized proteins were present during the maintenance phase of latency. Reactivation of HSV (viral protein 135K) was first detected in latently infected cultures between 2 and 3 hr after superinfection with human cytomegalovirus (HCMV). During this period an 82K protein with the same molecular weight as one of the HCMV immediate-early proteins (82 and 75K) was detected in the immunoprecipitates of latently infected cultures with anti-HSV serum. Thus, this HSV latency system can be used to analyze protein synthesis and clarify reactivation of HSV by HCMV superinfection.

Antigens, Viral↗
PubMed1986

Cycloheximide reduces PGD2 or delta 12-PGJ2 cytotoxicity on NCG cells.

To study the precise mechanism of cytotoxic activity of PGD2 or delta 12-PGJ2 (a biologically active metabolite of PGD2), we examined the effect of various compounds on PGD2 or delta 12-PGJ2 cytotoxicity, using a human neuroblastoma cell line (NCG). Cycloheximide (CHM) specifically protected PGD2 cytotoxicity on NCG cells. When delta 12-PGJ2 was tested, CHM exhibited a similar rescue effect. Puromycin, mitomycin C, and alpha-amanitin did not affect PGD2 or delta 12-PGJ2 cytotoxicity. Emetine showed a variable and no consistent rescue effect CHM may have been active at the primary site where PGD2 or delta 12-PGJ2 exerts its cytotoxicity. This is the first report indicating that CHM reduces the cytotoxicity induced by PGD2 or delta 12-PGJ2.

Amanitins↗
PubMed1989

Effect of indomethacin, cycloheximide, and aminoglutethimide on ovarian steroid and prostanoid levels during ovulation in the gonadotropin-primed immature rat.

It has become popular to use the gonadotropin-primed immature rat to study ovulation. The ovarian content of progesterone, estradiol, PGE2, PGF2 alpha, and 6-keto-PGF1 alpha during the ovulatory process was determined in this model. Also, the effect of three anti-ovulatory agents on the ovarian levels of the above substances was determined. At 23 days of age, Wistar rats were primed with pregnant mares serum gonadotropin (PMSG) sc, and two days later the ovulatory process was initiated with human chorionic gonadotropin (hCG) sc. The ovarian follicles began rupturing 12 h later. Ovaries were assayed for the two steroids and prostanoids at 2-h intervals before and several 4-h intervals after ovulation. The ovarian estradiol level increased slightly between 0 and 2 h after hCG, while the progesterone level increased sharply between 2 and 4 h after hCG--at a time when the estradiol declined markedly. All three prostanoids increased concomitantly with progesterone. When the PG synthesis was blocked by indomethacin treatment at 1 h before hCG, ovarian progesterone levels still increased. In contrast, when steroidogenic activity was inhibited by aminoglutethimide, the ovarian prostanoid levels also decreased. Cycloheximide had little effect on the steroids and prostanoids. It is concluded that ovarian prostanoid synthesis might be influenced by ovarian steroid output.

Aminoglutethimide↗
PubMed1976

Cycloheximide-induced amnesia for taste aversion memory in rats.

Male hooded rats were conditioned in one trial to avoid saccharin by pairing saccharin drinking with an intragastric injection of LiC1. A 24 hr water-saccharin preference test showed that conditioned rats exhibited a very low preference for saccharin whereas rats injected intraventricularly with cycloheximide (CXM, 400 mug) 5, 7, or 9 hr before training exhibited a greatly increased saccharin preference which differed significantly from NaC1 injected controls. This 24 hr amnesia was found to be dependent upon the time of administration of CXM, since injection at 1, 3 or 17 hr before training did not confer amnesia. The nature of the task, a control measure and a control experiment indicate that the CXM-induced change in saccharin preference at 24 hr is not due to a CXM-induced aversion, nor a loss in drinking ability nor an inability to retrieve information whilst under the influence of CXM.

Amnesia↗
PubMed1976

Intracranial cycloheximide: effect on male mouse sexual behavior and plasma testosterone.

Cycloheximide (Cyclo), an inhibitor of protein synthesis, infused bilaterally into the preoptic area (POA) of intact B6D2F male mice significantly inhibited male sexual behavior when the males were presented with receptive females 12 hr after treatment. The few males that ejaculated appeared to copulate normally. This finding suggests that Cyclo acts primarily by inhibiting sexual arousal rather than sexual performance. The inhibition of sexual behavior was not observed when the males were tested 84 hr after treatment. After exposure to an estrous female, plasma testosterone levels were measured in males with POA infusions of Cyclo or saline vehicle. No significant difference was found, but both groups had significantly higher levels of plasma testosterone than males not exposed to estrous females. It is suggested that the interference with sexual behavior by Cyclo was not due to interference with the neuroendocrine mechanisms controlling blood andorgen levels, but due to Cyclo acting directly on the neural circuits controlling sexual responsiveness.

Animals↗
PubMed1976

Cycloheximide and passive avoidance memory in mice: time-response, dose-response and short-term memory.

The greatest loss of memory shown by mice 24 hr after learning was found to occur with cycloheximide (CXM) (120 mg/kg) administered subcutaneously 30 min before training. With injection at this time the extent of the amnesia was dose dependent (30-150 mg/kg) and the resultant amnesia was found to be relatively constant when tested at 1, 7 or 14 days. An attempt was made to follow the development of this amnesia with 100 and 120 mg/kg CXM. However, the saline controls showed an unexpectedly low avoidance 6 hr after training. This was interpreted as a possible interaction between the stress of the injection and the 6 hr interval. An experiment designed to test this possibility showed that mice injected with 0.1 ml of 1% lignocaine gave high avoidance at 6 hr but mice receiving only a needle puncture of the skin gave performances similar to mice receiving saline injections. It was felt that these findings cast doubt on the usefulness of the passive avoidance task in the assessment of drug action on short term memory.

Animals↗