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PubMed1984

The lethal syndrome following intravenous injection of Ehrlich ascites tumour cells in cycloheximide-treated mice and its prevention by heparin.

Heparin was shown to be a life-saving treatment in the otherwise lethal syndrome following intravenous injection of Ehrlich ascites tumour cells in cycloheximide-treated mice, and in mice treated with cycloheximide 2 h after injection of Ehrlich tumour cells. The effectiveness of heparin cannot be attributed to interference with initial arrest of tumour cells. A similar lethal syndrome, again prevented by heparin treatment, occurs in mice given intravenous colloidal carbon and cycloheximide. It is suggested that large doses of intravenous particulates bring about changes in plasma composition which are rapidly rectified in an otherwise normal mouse, but which persist under the influence of cycloheximide and lead to the irreversible and fatal outcome. Finally, evidence is presented which suggests that liver protein synthesis may play an essential role in the period following intravenous injection of tumour cells in an otherwise normal mouse.

Animals↗
PubMed1988

Fatal susceptibility to cycloheximide of mice bearing Ehrlich ascites tumours and of animals pretreated with cell-free Ehrlich ascites tumour fluid.

Soluble, but unidentified, factors in cell-free Ehrlich ascites tumour fluid induced, after a delay period, a fatal heparin- and ancrod-resistant susceptibility to a normally tolerated dose of cycloheximide. The evidence suggests that production of such factors is dependent upon interaction of tumour cells with the intravascular or the intraperitoneal compartment. The factors are considered likely also to play a crucial role in the similar heparin and ancrod-resistant fatalities which follow cycloheximide challenge of mice bearing established Ehrlich ascites tumours and in the deaths of mice challenged with cycloheximide 24 h after an intravenous injection of washed Ehrlich ascites tumour cells. These factors play no part in the heparin- and ancrod-preventable fatal syndrome following cycloheximide challenge either 2 h before or 2 h after intravenous injection of washed Ehrlich ascites tumour cells.

Ancrod↗
PubMed1989

Factors involved in the fatal susceptibility to submicrogram doses of endotoxin in cycloheximide-treated mice.

Analysis of fatal sensitivity to 0.2 microgram of S. enteritidis lipopolysaccharide in cycloheximide-treated mice identified two independent lethal elements. First, an absolute requirement for steroid supplementation to ensure survival suggests a crucial role for cycloheximide-mediated inhibition of steroidogenesis. The second factor is the development of virtually total bilateral renal cortical necrosis, itself a consequence of glomerular capillary occlusion with fibrin-like material. The survival of cycloheximide and endotoxin-challenged mice requires both hydrocortisone treatment and defibrination with ancrod. Cycloheximide and a smaller dose of endotoxin (0.1 microgram per mouse) is also fatal, but here steroid deficiency is not a crucial factor, protection being conferred by ancrod defibrination alone.

Ancrod↗
PubMed1982

The effect of ether stress and cycloheximide treatment on cholesterol binding and enzyme turnover of adrenal cortical cytochrome P450scc.

Relative rate constants for the formation of pregnenolone from cytochrome P450scc bound cholesterol in adrenal cortical mitochondria of stressed, stressed plus cycloheximide treated and dexamethasone treated rats were calculated from the ratios of initial rates of pregnenolone formation and the pregnenolone induced difference spectrum. In mitochondria from adrenals removed under aerobic conditions in vivo, the rate constant for the enzyme in stressed rats is twice a high as the rate constant for the enzyme from the stressed plus cycloheximide group, and four times as high as that for the enzyme from dexamethasone treated rats. Anoxia for 5 min in the intact gland increases the rate constant in all groups. Pregnenolone difference spectra are higher in mitochondria from stressed plus cycloheximide treated rats than in mitochondria from stressed rats, when adrenals are removed aerobically. It is concluded that ACTH increases cholesterol binding to cytochrome P450scc, by increasing either the enzymes affinity for its substrate or the availability of cholesterol and in addition promotes turnover of the enzyme. Both of these effects of ACTH are inhibited by cycloheximide.

Adrenal Cortex↗
PubMedDate not supplied

Timing of cycloheximide administration and inhibition of the development of analgesic tolerance to morphine.

A single injection of cycloheximide (10 mg/kg, i.p.) partially prevented the development of analgesic tolerance to morphine (10 mg/kg, i.p. daily for 5 days). The inhibitory effect of cycloheximide was strictly dependent on the time of its administration, and only effective when it was administered 2 hrs before or 1 hr after morphine injection. Daily repeated treatment with cycloheximide 2 hrs before and/or 1 hr after morphine also prevented the tolerance development. However, the pre or post treatment with cycloheximide differed in the duration of the effect, and the discrepancies between two treatments suggest the importance of timing of the administration of inhibitor in the underlying mechanisms.

Analgesia↗
PubMed1990

Inhibition by protein kinase-C inhibitor and cycloheximide of phorbol ester- and epidermal growth factor-induced arachidonic acid metabolism in cultured porcine thyroid cells.

In an attempt to elucidate possible mechanism(s) for stimulated arachidonic acid metabolism by phorbol 12-myristate 13-acetate (PMA) and epidermal growth factor (EGF) in porcine thyroid cells, we examined the effects of protein kinase inhibitors, isoquinolinesulfonamide derivatives (H-7 and HA-1004), and cycloheximide. The production of PGE2 stimulated by either PMA or EGF was strongly inhibited by H-7, with an ID50 value of approximately 20 to 25 mumol/L in each case, as well as by cycloheximide, with an ID50 value of less than 0.5 micrograms/mL in each case. In contrast, 100 mumol/L of HA-1004 showed less inhibition of PGE2 production provocated by either PMA or EGF. On the other hand, PGE2 production in basal or stimulated condition by exogenously added arachidonic acid, was inhibited to an even lesser extent by both H-7 and cycloheximide. The EGF- and PMA-stimulated release of 3H-arachidonic acid from the cells was also strongly inhibited by H-7 and cycloheximide. These results suggest an induction of synthesis of some proteins responsible for the release of arachidonic acid, which might be attributed to protein kinase-C activation in arachidonic acid metabolism stimulated by PMA or EGF. Moreover, PGE2 production was potently induced by PMA and slightly by EGF in the cyclooxygenase-inactivated cells by acetyl salicylate pretreatment, which also suggests that both agents might induce the synthesis of cyclooxygenase in cultured porcine thyroid cells, although we did not measure its activity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Effects of cycloheximide on the retention of olfactory learning and maternal experience effects in postpartum rats.

We have previously shown that cycloheximide, a protein synthesis inhibitor, blocks retention of experimentally based material responding in postpartum rats. In the following study, we investigated further the effect of this drug on maternal experience effects and, in particular, on the retention of olfactory learning. Dams were injected SC with cycloheximide or saline following a one-hour maternal experience with pups scented with one of two artificial odorants. When tested eight days later, saline but not cycloheximide animals demonstrated a preference for the odor which they had experience on pups. Animals were then tested for maternal responsiveness with pups that were scented with an odor that was either the same or different from the one used in the maternal experience. All animals receiving cycloheximide, regardless of the pup odor at testing, exhibited long latencies to become maternal, replicating our earlier finding that the retention of learning in maternal behavior is susceptible to disruption by protein synthesis inhibitors. A similar disruption of the experience effect was found when the pup odor at testing was different from the exposure odor. This suggests that olfactory learning may normally play a role in the mediation of postpartum experience effects.

Animals↗
PubMed1987

Interaction of cycloheximide and diisopropylphosphorofluoridate (DFP) during subchronic administration in rat.

Male Sprague-Dawley rats daily treated with DFP (0.5 mg/kg/day, sc) exhibited signs of cholinergic toxicity such as tremors and muscle fasciculations between Days 3 and 5 comparable to those observed 15 min after a single acute signs-producing dose (1.5 mg/kg, sc). Further administration of DFP (0.5 mg/kg/day, sc) for 6-14 days led to tolerance development as evidenced by disappearance of the described toxicity signs. The protein synthesis inhibitor cycloheximide, when given in a nontoxic dose (0.5 mg/kg/day, sc) 1 hr before DFP (0.5 mg/kg/day, sc) administration, potentiated the DFP toxicity and rats died after the fifth injection. DFP-tolerant rats developed toxicity signs when subsequently treated with cycloheximide (0.5 mg/kg/day, sc) and DFP (0.5 mg/kg/day, sc). Each drug when given alone for 4 days caused 30-50% reduction of [14C]valine uptake in vivo into the free amino acids pool as well as its incorporation into proteins of brain and skeletal muscles. A combination of these drugs caused a significantly greater inhibitory effect on [14C]valine incorporation into proteins. Cycloheximide (0.5 mg/kg/day, sc) administered for 4 days did not significantly alter the levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), or carboxylesterase (CarbE) activities but potentiated the DFP-induced inhibition of the activities of these enzymes. It is concluded that the cycloheximide pretreatment potentiates DFP toxicity by a mechanism that is related to inhibition of the synthesis of proteins such as AChE, BuChE, and CarbE.

Acetylcholinesterase↗
PubMed1983

Reversible inhibition of poxvirus replication by cycloheximide during the early phase of infection.

Infection of primary chick embryo fibroblasts with Vaccinia WR, IHD-W, and cowpox virus even at high m.o.i. does not cause drastic early inhibition of host cell protein synthesis. This contrasts with the infection by these viruses of many eucaryotic cells. Cellular protein synthesis of mouse L cells is also only partially inhibited after infection with cowpox virus up to a m.o.i. of 2500 e.b. As predicted by Moss and Filler (1970, J. Virol. 5, 99-108) no irreversible inhibition of poxvirus replication is observed in these cells following the addition of cycloheximide early after infection. The viral cores which accumulate in chick embryo fibroblasts in the presence of cycloheximide are further uncoated after removal of the protein synthesis inhibitor. These poxvirus host cell systems can be used to identify in vivo immediate and putative delayed early viral gene products. Formation of progeny virus, viral DNA synthesis, the sequential formation of viral proteins, and sensitivity to interferon has been demonstrated in chick embryo fibroblasts after reversal of the cycloheximide block. These studies indicate a synchronized replication cycle of poxvirus after reversal of the cycloheximide block.

Animals↗
PubMed1980

Effect of cycloheximide and d-amphetamine on brain catecholamines in two mouse strains.

The ability of cycloheximide to inhibit brain catecholamine synthesis in C57BL/6J and DBA/2J mice was studied to determine whether differences exist in these two strains with regard to this action and whether such effects correlate with previously reported differences in sensitivity to the amnesic effects. Administration of cycloheximide caused a dose-dependent inhibition of norepinephrine and dopamine synthesis in both strains. There was a significant effect due to strain on dopamine synthesis in drug-treated animals. d-Amphetamine partially prevented the decrease in the rate of synthesis of norepinephrine, dopamine and normetanephrine caused by cycloheximide in the C57 strain but enhanced the inhibition of synthesis of these compounds in the DBA strain. The results suggest that the reported differences in sensitivity to the behavioral effects of cycloheximide may be associated with the degree of inhibition of catecholamine synthesis in these two mouse strains.

Animals↗
PubMed1994

Ethanol-induced reduction of the amount of stimulatory GTP-binding regulatory protein, Gs, in wild-type S49 murine lymphoma cells: effect of cycloheximide and puromycin.

The activity and the amount of Gs in wild-type S49 murine lymphoma cells decreased by 16-18% and by 29%, respectively, after 24 h treatment of the cells with 50 mM ethanol, through a transient increase of the Gs activity with no alteration in its content after 4 and 8 h treatment. No decrease of the Gs activity was noted when membranes from S49 cells were treated with 50-500 mM ethanol. To study the role of protein metabolism in the ethanol-induced reduction in the amount of Gs, S49 cells were treated with ethanol for 24 h in the presence of inhibitor of protein synthesis. Cycloheximide at concentrations of 0.05-0.15 micrograms/ml and puromycin at 0.15-0.60 micrograms/ml caused a dose-dependent inhibition of cell division in S49 cells to a similar degree. The ethanol-induced reduction of the activity and the amount of Gs was completely abolished by those concentrations of cycloheximide, but not by puromycin. Cycloheximide itself caused no alteration in the Gs activity of S49 cell membranes. These results indicate that the process of the ethanol-induced event of Gs involves cycloheximide-sensitive protein synthesis.

Animals↗
PubMed1987

Action mechanism of inhibin in vitro--cycloheximide mimics inhibin actions on pituitary cells.

The effects of inhibin on gonadotropin secretion from cultured rat anterior pituitary cells were examined by using purified porcine follicular fluid (pFF) 32 kDa inhibin. pFF 32 kDa inhibin suppressed the basal FSH secretion as well as cell content of FSH with identical ED50 values (ED50 = 1.0 ng/ml) in a dose-dependent manner, but did not alter either basal secretion or cell content of LH. On the other hand, pretreatment of the pituitary cells with pFF 32 kDa inhibin during the first 3 days resulted in suppression of subsequent LH-RH-stimulated release of both FSH and LH in a dose-dependent manner, indicating that the suppression of LH-RH-stimulated release of LH is one of the intrinsic inhibin actions on pituitary cells. The marked difference between ED50 values for FSH (ED50 = 1.1 ng/ml) and LH (ED50 = 2.5 ng/ml) in the suppression of LH-RH-stimulated release of gonadotropins, together with the fact that the total amount of LH (cell content plus released) after LH-RH stimulation remained unchanged following inhibin treatment suggests that the suppression of LH-RH-stimulated release of LH by inhibin is quite different from that of FSH regarding the action mechanism. Similarly, cycloheximide, an inhibitor of protein biosynthesis, suppressed both basal secretion and cell content of FSH with almost the same ED50 values (ED50 = 22.5 ng/ml) but did not alter either basal secretion or cell content of LH. Cycloheximide also suppressed LH-RH-stimulated release of both FSH and LH, and the ED50 values were different from each other (ED50 = 25.0 ng/ml for FSH and 60.0 ng/ml for LH suppression, respectively). Our finding that cycloheximide completely mimicked the action of inhibin on gonadotropin secretion strongly suggests that LH is quite insensitive to biosynthetic inhibition, and that preferential effects of inhibin or cycloheximide on FSH in appearance may reflect the difference between LH and FSH in susceptibility to biosynthetic inhibition.

Animals↗
PubMed1989

Effects of cycloheximide on hepatic and uterine insulin-like growth factor-I mRNA.

To investigate differences in growth hormone (GH) and estrogen activation of insulin-like growth factor-I (IGF-I) expression, we have examined the effects of cycloheximide on hepatic and uterine IGF-I mRNA abundance in response to GH and 17 beta-estradiol (E2) respectively. In hypophysectomized (hypox) rats a single injection of GH significantly increased hepatic IGF-I mRNA 3.65 +/- 0.68-fold, P less than 0.005, 6 h after injection. Administration of cycloheximide 30 min prior to GH injection completely abolished this response. In contrast, in pituitary intact rats killed 6 h after administration of cycloheximide, hepatic IGF-I mRNA abundance was not significantly different from untreated control rats although the serum IGF-I concentration was significantly reduced; 119.9 +/- 11.8 vs. 270.2 +/- 48.7 ng/ml, P less than 0.005. In immature rats, injection of E2 (1 micrograms/100 g body weight) significantly increased uterine IGF-I mRNA 4.1 +/- 0.4-fold. Cycloheximide did not block the E2-induced increase in IGF-I mRNA but rather significantly enhanced the IGF-I response. These data indicate that continuing protein synthesis is required for GH induction of hepatic IGF-I mRNA in the hypox rat but is not required for E2 induction of uterine IGF-I mRNA. Furthermore, in pituitary-intact rats protein synthesis is not required for maintenance of hepatic IGF-I mRNA levels.

Animals↗
PubMed1996

Cycloheximide enhances ACTH-receptor mRNA through transcriptional and post-transcriptional mechanisms in bovine adrenocortical cells.

We have previously shown that ACTH is one of the few polypeptide hormones having a positive trophic effect, not only on the number, but also on the expression of its own receptors. In the present study, we investigated whether the constitutive and ACTH-induced expression of ACTH-receptor (ACTH-R) mRNA in bovine adrenocortical cells (BAC) requires new protein synthesis. The results show that cycloheximide alone, an inhibitor of protein synthesis, induced a time- and dose-dependent increase in the constitutive level of the ACTH-R major transcript of 3.6 kb in BAC. The maximal stimulation (5.17 +/- 1.15 fold, n = 4) was obtained after 24 h treatment with 5 micrograms/ml cycloheximide. The effect of cycloheximide was specific and not directly related to translational arrest since other protein synthesis inhibitors acting through different mechanisms, emetine and puromycin, were unable to reproduce such an effect at concentrations inhibiting protein synthesis. The effect of cycloheximide involved an increase in the half-life and the transcription rate of the major transcript of ACTH-R (2- and 8.4-fold respectively). In addition, the results also demonstrated that neither the constitutive nor the ACTH-induced expression of ACTH-R require new protein synthesis.

Adrenocorticotropic Hormone↗
PubMed1983

Effect of cycloheximide on ionic channels in neuroblastoma cell membrane.

The effect of cycloheximide (an inhibitor of protein synthesis) on the ionic currents through sodium and potassium channels was investigated in dialysed voltage-clamped N18 A-1 neuroblastoma cells. The cycloheximide concentration needed for half-inhibition of sodium peak conductance was about 0.5 micrograms/ml for 24 h of incubation. Half-inhibition time of the sodium peak conductance in cells incubated with 15.0 micrograms/ml of cycloheximide was about 9 h. Sodium against potassium ion selectivity, the activation and inactivation parameters were shown to be not affected by cycloheximide. Potassium conductance in similarly treated cells exhibited no consistent changes. The main conclusion is that the decay in peak sodium conductance is caused by diminishing the sodium channel density in the membrane (from 25 to 2.2 channels per micron2). The inhibition effect was evidently mediated by block of protein synthesis and was not the result of direct drug-channel interaction. The half-decay time of sodium peak conductance is interpreted as a possible life-time characteristic of sodium channels in the neuroblastoma cell membrane.

Animals↗
PubMed1983

Inhibition of sexual receptivity after intracranial cycloheximide infusions in female hamsters.

Female hamsters were ovariectomized and one week later stereotaxically infused with 20 micrograms cycloheximide (20 micrograms/microliter, 0.6 microliter/min) or 1 microliter saline bilaterally into one of several brain sites. Thirty min after the infusion, the animals were injected with 5 micrograms estradiol benzoate (EB) then 44 hr later with 500 micrograms progesterone and tested with a male for receptivity at hour 48. One week later the animals were retested with EB and progesterone but without any intracranial infusion to investigate the possibility of permanent lesion effects. The greatest inhibition of receptivity occurred in females which received cycloheximide in the ventromedial hypothalamus (VMH) or lateral to the VMH. Saline infusions into the VMH had no inhibitory effects. Inhibition was rarely seen after infusion into the preoptic area, anterior hypothalamus, dorsomedial hypothalamus, cortico-medial amygdala, or septal area. Moderate inhibition was found after infusion of cycloheximide into the third ventricle. The inhibition following cycloheximide infusion was not permanent or irreversible. On the retest one week later the animals were sexually receptive. These results suggest that protein synthesis within the VMH is an essential part of the initial action of estrogen for the induction of sexual receptivity in hamsters.

Amygdala↗
PubMed1992

Morphometric and time lapse analyses of rapid-onset neurites stimulated by cycloheximide in NG108-15 cells.

We previously reported that the laminin-induced outgrowth of neurites in the first 4 hr after plating ('rapid-onset neurites') is markedly stimulated by inhibitors of protein and RNA synthesis, including cycloheximide, puromycin and actinomycin D. Our original interpretation of this finding was that inhibiting protein synthesis led to metabolic changes in the cell which converged upon the intracellular pathway used by laminin to stimulate neurite formation. Alternatively, Preston et al. (1987, Proc. natn. Acad. Sci. U.S.A. 84, 5247-5251) suggested that cycloheximide acts by inhibiting neurite retraction. In order to resolve these conflicting interpretations, we decided to re-examine the effects of cycloheximide using time lapse analyses of NG108-15 cells grown on laminin, together with morphometric analyses of cultures fixed at 1.5 or 3 hr after plating. Cycloheximide was found to cause both an increase in neurite initiation within the first 1.5 hr after plating, and a decrease in the occurrence of neurite retractions between 1 and 3 hr. Investigators should be aware of the effects of biosynthetic inhibitors on neurite growth, since these agents are employed widely in studies of cultured neural cells, particularly those involving receptor metabolism and phenotypic differentiation.

Cells, Cultured↗
PubMed2006

Parthenogenetic activation of domestic cat oocytes using ethanol, calcium ionophore, cycloheximide and a magnetic field.

The objective of this study was to evaluate parthenogenetic activation of domestic cat oocytes after being exposed to either ethanol, magnetic field, calcium ionophore A23187, or cycloheximide and a combination of these agents. We also wished to evaluate the usefulness of the magnetic field for oocyte activation. In vitro matured oocytes subjected to artificial activation were randomly assigned into eight groups according to activating agents: (1) 10% ethanol; (2) the magnetic field (slow-changing, homogenous magnetic field with low values of induction); (3) 10% ethanol plus magnetic field; (4) 10 microM calcium ionophore A23187; (5) 10 microM calcium ionophore A23187 plus magnetic field; (6) 10% ethanol and 10 microg/mL of cycloheximide; (7) 10% ethanol and 10 microg/mL of cycloheximide plus magnetic field; (8) oocytes were not exposed to any of the activating agents. After activation oocytes were stained with Hoechst 33258 and parthenogenetic activation was defined as oocytes containing pronuclei and second polar bodies or two to four or six nuclei (embryonic cleavage). The total activation rate by using different activation treatments was 40%. The addition of the magnetic field to ethanol or calcium ionophore treatments resulted in increased parthenogenetic activation rates from 47% to 75%, and from 19% to 48%, respectively (P<0.001). Instead, when the magnetic field was added to ethanol and cycloheximide treatment, activation rate decreased from 48% to 30%. Oocytes activated with magnetic field only gave the lowest activation rate (12%). We concluded that a magnetic field can be used as an activating agent, and the combination of ethanol and magnetic field is an effective method for domestic cat oocyte activation.

Animals↗