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PubMed1984

Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats.

Freely moving rats, chronically implanted with stimulation electrodes in the medial entorhinal cortex and recording electrodes in the dentate gyrus, received two 400 micrograms intraventricular injections of anisomycin during a tetanization procedure that induced a long-lasting potentiation (72 hours) of the monosynaptic field potential. Inhibition of protein synthesis during the tetanization procedure did not immediately influence the induction of long-term potentiation (LTP). However, 3-4 hours after the beginning of tetanization the potentiation effect decayed progressively and was abolished totally during the remaining 7 day observation period. In control experiments anisomycin did not affect the slope of field EPSP's and produced a reversible depression of the population spike amplitude. These data indicate a relatively specific effect of the protein synthesis inhibitor on mechanisms involved in a late phase of LTP stabilization.

Animals↗
PubMed2006

Intra-hippocampal microinjections of anisomycin did not block glucocorticoid-induced impairment of memory retrieval in rats: an evidence for non-genomic effects of glucocorticoids.

Previous findings indicated that intra-cerebral as well as systemic injections of glucocorticoid hormones shortly before retention testing induce impairment of long-term memory retrieval, but the underlying mechanisms (genomic or non-genomic) are not known. To clarify this issue, we investigated the involvement of protein synthesis in the hippocampus in glucocorticoid-induced impairment of memory retrieval. Young rats carrying bilateral cannulae aimed at the hippocampus were trained in a water maze (MWM) task with six trials per day for six consecutive days. Retention of the spatial training was assessed 24h after the last training session with a 60-s probe trial. Corticosterone (1mg/kg) was injected 30 min before retention testing with or without prior bilateral intra-hippocampal injections of anisomycin (80 or 160 microg/mul per site) as an inhibitor of protein synthesis. The control animals received vehicle or saline solutions. The results show that corticosterone-induced impairment of memory retrieval was not blocked by intra-hippocampal infusions of anisomycin. Our data suggest that corticosterone influences memory retrieval via a protein independent mechanism and provide evidence for rapid actions (non-genomic) of glucocorticoids on memory retrieval.

Analysis of Variance↗
PubMed1985

Pharmacological dissociation of memory: anisomycin, a protein synthesis inhibitor, and leupeptin, a protease inhibitor, block different learning tasks.

Inhibition of protein synthesis by anisomycin for a short duration impairs memory of a one-trial inhibitory avoidance task in rats. Memory of escape conditioning involving eight trials is disrupted only if the duration of protein synthesis is prolonged by repeated injections. In marked contrast, olfactory memory of rats trained on two odor discriminations is not affected by anisomycin even if the duration of inhibition is prolonged and the number of trials is reduced to a minimum. In previous work, leupeptin, a thiol proteinase inhibitor, was shown to impair olfactory discrimination learning, but left inhibitory and avoidance conditioning intact. Together, these results provide a pharmacological double dissociation of memory, and suggest that the same chemistries, or mixtures of chemistries, may not be involved in all types of memory.

Animals↗
PubMed1987

Anisomycin impairs long-term working memory in a delayed alternation task.

A long-term temporal component of working memory of rats trained on the radial maze has been shown to be susceptible to disruption by the protein synthesis inhibitor, anisomycin. It is not clear whether protein synthesis played a role in working memory because accurate performance on the radial maze required the storage of a large amount of information, or because the information was to be held in store for relatively long periods of time. This experiment tested these hypotheses by assessing the effect of anisomycin on choice accuracy in a comparatively simple spatial delayed alternation task. Results indicate that under the present training conditions, protein involvement in working memory is related more to the length of the retention interval than to the amount of information retained.

Animals↗
PubMed1983

Structure-activity relationships of synthetic antibiotic analogues of anisomycin.

A general synthetic sequence was used to synthesize a series of analogues of anisomycin, and the biological activities of the new synthetic analogues as antiprotozoals, antifungals, and antibacterials were evaluated. The synthetic antibiotics included 3 beta-acetoxy-4 alpha-hydroxy-2 beta-(p-methylbenzyl)pyrrolidine (1b), 3 beta-acetoxy-2 beta-benzyl-4 alpha-hydroxypyrrolidine (1c), 3 beta-acetoxy-4 alpha-hydroxy-2 beta-(m-methoxybenzyl)pyrrolidine (1d), 3 beta-acetoxy-4 alpha-hydroxy-2 beta-(o-methoxybenzyl)pyrrolidine (1e), 3 beta-acetoxy-4 alpha-hydroxy-2 beta-(alpha-methyl-p-methoxybenzyl)pyrrolidine (1f), and 3 beta-acetoxy-4 alpha-hydroxy-2 beta-(alpha-phenyl-p-methoxybenzyl)pyrrolidine (1g). The anisomycin analogues showed activity against protozoa and fungi, but this activity was restricted primarily to the p-methylbenzyl and benzyl analogues 1b and 1c. The activities dropped dramatically as the methoxy substituent was moved to the meta or ortho positions of the benzyl group (1d and 1e) or a methyl or phenyl group was attached at the alpha-benzyl carbon (1f and 1g).

Animals↗
PubMed2006

The translation inhibitor anisomycin induces Elk-1-mediated transcriptional activation of egr-1 through multiple mitogen-activated protein kinase pathways.

The early growth response-1 gene (egr-1) encodes a zinc-finger transcription factor Egr-1 and is rapidly inducible by a variety of extracellular stimuli. Anisomycin (ANX), a protein synthesis inhibitor, stimulates mitogen-activated protein kinase (MAPK) pathways and thereby causes a rapid induction of immediate-early response genes. We found that anisomycin treatment of U87MG glioma cells resulted in a marked, time-dependent increase in levels of Egr-1 protein. The results of Northern blot analysis and reporter gene assay of egr-1 gene promoter (Pegr-1) activity indicate that the ANX- induced increase in Egr-1 occurs at the transcriptional level. Deletion of the serum response element (SRE) in the 5'-flanking region of egr-1 gene abolished ANX-induced Pegr-1 activity. ANX induced the phosphorylation of the ERK1/2, JNK, and p38 MAPKs in a time-dependent manner and also induced transactivation of Gal4-Elk-1, suggesting that Elk-1 is involved in SRE-mediated egr-1 transcription. Transient transfection of dominant-negative constructs of MAPK pathways blocked ANX-induced Pegr-1 activity. Furthermore, pretreatment with specific MAPK pathway inhibitors, including the MEK inhibitor U0126, the JNK inhibitor SP600125, and the p38 kinase inhibitor SB202190, completely inhibited ANX-inducible expression of Egr-1. Taken together, these results suggest that all three MAPK pathways play a crucial role in ANX-induced transcriptional activation of Pegr-1 through SRE-mediated transactivation of Elk-1.

Anisomycin↗
PubMed1997

Anisomycin and verapamil influence the action of progesterone on regulation of term human myometrial contractile activity.

OBJECTIVE: Progesterone has been shown to have both stimulatory and inhibitory effects on term human myometrial contractile activity. The mechanisms involved in this action of progesterone are still poorly understood. DESIGN: Myometrial tissues were obtained from the lower uterine segment at elective Caesarean section of 30 term pregnant women. The contractile activity of muscle strips was measured by a superfusion technique and protein synthesis evaluated by [3H]-leucine incorporation. RESULTS: [3H]-leucine incorporation into term myometrial strips was not affected by progesterone (10 mumol/l), but was markedly reduced by the protein synthesis inhibitor anisomycin (P < 0.05). However, progesterone increased frequency and tonus of contractions and reduced the activity-area of contractions (P < 0.01). Anisomycin (100 mumol/l) did not change these effects or the spontaneous contractile activity. Removal or extracellular Ca2+ or addition of the L-type calcium channel blocker verapamil prevented the spontaneous as well as the progesterone-induced contractions, but had less pronounced effects on contractions initiated by oxytocin. CONCLUSION: The results indicate that the actions of progesterone on term myometrial contractile activity occur without protein synthesis and that increased Ca2+ influx or decreased outward transport of Ca2+ may play a possible role)

Adult↗
PubMed2002

Transactivation of ErbB2 and ErbB3 by tumor necrosis factor-alpha and anisomycin leads to impaired insulin signaling through serine/threonine phosphorylation of IRS proteins.

The cellular pathways involved in the impairment of insulin signaling by cellular stress, triggered by the inflammatory cytokine tumor necrosis factor-alpha (TNF) or by translational inhibitors like cycloheximide and anisomycin were studied. Similar to TNF, cycloheximide and anisomycin stimulated serine phosphorylation of IRS-1 and IRS-2, reduced their ability to interact with the insulin receptor, inhibited the insulin-induced tyrosine phosphorylation of IRS proteins, and diminished their association with phosphatidylinositol 3-kinase (PI3K). These defects were partially reversed by wortmannin and LY294002, indicating that a PI3K-regulated step is critical for the impairment of insulin signaling by cellular stress. Induction of cellular stress resulted in complex formation between PI3K and ErbB2/ErbB3 and enhanced PI3K activity, implicating ErbB proteins as downstream effectors of stress-induced insulin resistance. Indeed, stimulation of ErbB2/ErbB3 by NDFbeta1, the ErbB3 ligand, inhibited IRS protein tyrosine phosphorylation and recruitment of downstream effectors. Specific inhibitors of the ErbB2 tyrosine kinase abrogated the activation of ErbB2/ErbB3 and in parallel prevented the reduction in IRS protein functions. Taken together, our results suggest a novel mechanism by which cellular stress induces cross-talk between two different signaling pathways. Stress-dependent transactivation of ErbB2/ErbB3 receptors triggers a PI3K cascade that induces serine phosphorylation of IRS proteins culminating in insulin resistance.

Anisomycin↗
PubMed2004

A lipid transfer protein gene BG-14 is differentially regulated by abiotic stress, ABA, anisomycin, and sphingosine in bromegrass (Bromus inermis).

The objective was to investigate the expression of a lipid transfer protein gene (LTP) both in bromegrass (Bromus inermis) cells and seedlings after exposure to abiotic stresses, abscisic acid (ABA), anisomycin, and sphingosine. A full-length cDNA clone BG-14 isolated from bromegrass suspension cell culture encodes a polypeptide of 124 amino acids with typical LTP characteristics, such as a conserved arrangement of cysteine residues. During active stages of cold acclimation LTP expression was up-regulated, whereas at the final stage of cold acclimation LTP transcript level declined to pre-acclimation level. A severe drought stress induced the LTP gene; yet, LTP expression doubled 3 d after re-hydration. Both temperature and heat shock duration influence LTP induction; however temperature is the primary factor. Treatment with NaCl stimulated accumulation of LTP mRNA within 15 min and the transcripts remained at elevated levels for the duration of the salinity stress. Most interestingly, Northern blots showed LTP was rapidly induced not only by ABA, but also by anisomycin and sphingosine in suspension cell cultures. Of the three chemicals, ABA induced the most rapid and highest response in LTP expression as well as highest freezing tolerance, whereas sphingosine was the least active for both LTP expression and freezing tolerance.

Abscisic Acid↗
PubMed1991

A mutation in the large subunit ribosomal RNA gene of Tetrahymena confers anisomycin resistance and cold sensitivity.

Anisomycin, an antibiotic that specifically inhibits the peptidyl transfer function of eukaryotic ribosomes, has been used to select resistant mutants in Tetrahymena thermophila. A mutation conferring anisomycin resistance (an-r) has been localized to a 1.2-kb fragment of the large subunit ribosomal RNA (rRNA) gene by transformation via microinjection. A single base pair change was detected within this region. Nine independently isolated an-r mutants had the same base pair change. T. thermophila strains that are homozygous for this mutation are cold sensitive, unable to mate and grossly abnormal in cell morphology.

Animals↗
PubMed1982

Selective inhibition of adenovirus type 2 early region II and III transcription by an anisomycin block of protein synthesis.

The transcription of adenovirus type 2 genes proceeds through a broad three-phase program. From 1 to 4 h postinfection six early transcription units (EIa, EIb, EII, EIII, EIV, and the promoter-proximal segment of the late transcription unit) are activated. From 4 to 6 h postinfection transcription of the early genes is depressed. After the onset of viral DNA replication at approximately 6 h postinfection, the transcript from the late promoter is antiterminated, and this transcript dominates viral RNA synthesis. The early activation period also proceeds through a series of stages; early regions EIa and EIV are activated first, followed by early region EII. We show that in the presence of anisomycin, a stringent inhibitor of protein synthesis, nuclear RNA and cytoplasmic polyadenylated RNA from regions EIa and EIV accumulate at normal rates, whereas RNAs from regions EII and EIII do not accumulate. We also show that failure to accumulate RNAs from regions EII and EIII is due to reduction of the rate of transcription by greater than 90%. We conclude that the regulation of the promoters for early regions EII and EIII is distinct from the mechanism that operates on the other early transcription units. The promoters for early regions EII and EIII diverge and lie approximately 500 nucleotides apart. We examined the structure of viral chromatin in this region early during infection by mild DNase I digestion in isolated nuclei and indirect end labeling with a DNA probe near these promoters. In control, drug-free cells where EII and EIII are transcribed and in anisomycin-treated cells where EII and EIII are not transcribed we detect the same regular DNase I pattern. We suggest that regulation of EII and EIII is not mediated through a change in gross chromatin structure, but rather by a viral effector, possibly a product of region EIa.

Adenovirus Early Proteins↗
PubMed2001

Reversed effects of RU486 and anisomycin on memory retention of light exposure or corticosterone facilitation in the dark-incubated chicks.

Memory formation for a weak passive avoidance task in the dark-incubated chicks is facilitated by light exposure or corticosterone administration at optimally pre-hatch time points. To explore the potential mechanisms underlying activation of brain memory function development by light or corticosterone exposure during late embryo, steroid receptor antagonist RU486, or protein synthetic inhibitor anisomycin, was administered intraembryonically to the embryos of either only 24-h light-exposure or complete dark-hatched on embryonic day 20 (E20). The results showed that RU486 and anisomycin significantly retarded the facilitated retention both by light and corticosterone exposure in the dark-incubated chicks. They also suggest that the act of corticosterone or light exposure on the development of brain memory function is mediated by the effect of steroid receptor, or afterward on related protein syntheses that is involved in memory formation of post-hatched performance of day-old chicks.

Animals↗
PubMed1976

Effects of anisomycin on brain protein synthesis and passive avoidance learning in newborn chicks.

The effects of anisomycin (ANM) on newborn chicks have been studied with respect to brain protein synthesis, growth, EEG, toxicity, and several passive avoidance learning tasks. It was found that intracerebral ANM (80 nmol) gave a maximum inhibition of brain protein synthesis of 30%, while a combination of subcutaneous (10 mumol; 53 mg/kg) plus intracerebral (80 nmol; 21 mug) ANM inhibited by 91% in the first 2 hr and by 75% in the subsequent 2 hr period. Cycloheximide (CXM) also in combined injections at the same doses as ANM, inhibited by 97% in the 4 hr that followed injection. However, all the CXM-injected chicks were dead by 18 hr, while the lethality of ANM did not differ from that of saline. ANM also did not affect EEG measured at 1, 3, 5, or 24 hr following the subcutaneous plus intracerebral injections, nor did ANM affect body or brain growth curves or brain protein accretion. In the learning experiments, animals were initially trained to peck at water-coated metal spheres (type A learning) or at water imbibed birdseed (types B and C learning) in less than 1 sec, and were exposed to the same lures treated with the aversant methylanthranilate (MeA) one day later on one occasion (types A and B learning) or exposed twice (type C learning) and tested for learning retention one day later. Learning criterion was set as failure to peck at the lure during the first 20 sec of presentation. If ANM was injected 1 hr prior to MeA exposure, large and highly significant memory deficits were found during the retention test, as compared with saline injected controls. No effect of ANM was seen, however, if it was injected one day after learning, indicating that it did not interfere with retrieval mechanisms. ANM also decreased the external manifestations of fear or displeasure that chicks express during retention testing. Such manifestations have a high correlation with pecking suppression (r = 0.88, P less than 0.001).

Amino Acids↗
PubMed1997

Inhibition of male sexual behavior by intracranial implants of the protein synthesis inhibitor anisomycin into the medial preoptic area of the rat.

Castrated male rats received testosterone (T) via silastic capsules and bilateral implants of either anisomycin (ANI) in a cocoa butter/beeswax mixture or cocoa butter/beeswax alone as a control. Cannulae were placed directly into the medial preoptic area (MPOA) to determine if protein synthesis in this brain region is required for the expression of male sexual behavior. In the first experiment, using a restoration paradigm, it was found that a 25% mixture of ANI prevented restoration of male sexual behavior, whereas 4% ANI was only partially effective. In a second experiment, the ability of 25% ANI to suppress male sexual behavior in a maintenance paradigm was tested and found to be completely ineffective. In a third experiment, a 50% ANI dose was used and this dose significantly suppressed male sexual behavior by the fourth week. Sexual behavior returned following ANI discontinuation. Males receiving 50% ANI were also tested for sexual motivation (measured in a place preference test), as well as for scent marking and vocalizations. ANI implanted into the MPOA did not affect sexual motivation, as males in both ANI and control groups spent more time with a sexually receptive female than with a nonreceptive female. ANI in the MPOA did not affect scent marking, but significantly decreased ultrasonic vocalizations. These results suggest that, in rats, protein synthesis in the MPOA is required for the expression of male sexual behavior and vocalizations, but not for sexual preference or scent marking.

Animals↗
PubMed1995

Two time windows of anisomycin-induced amnesia for passive avoidance training in the day-old chick.

The antibiotic anisomycin (ANI), a protein synthesis inhibitor, was used to investigate the time-related changes in protein synthesis following passive avoidance training in the day-old chick. Retention of memory for this simple learning task is known to be prevented by protein synthesis inhibitors within the first hour post-training. Here we report a second, later time window during which inhibition of protein synthesis results in amnesia following one-trial passive avoidance training. Birds were given bilateral intracranial injections of ANI (10 microliters/hemisphere of a 30 mM solution) at various times relative to training and tested 24 h later. Injections given between 0.5 h prior to 1.5 h post-training or 4-5 h post-training, but not at later or at intervening times, resulted in amnesia. These results are discussed in the context of earlier findings, using the inhibitor of glycoprotein synthesis 2-deoxygalactose, that memory formation shows two glycoprotein-synthesis-dependent periods of sensitivity (Scholey, Rose, Zamani, Bock, & Schachner, 1993). The time windows of susceptibility of ANI and 2-Dgal are consistent with a model in which there are two waves of neural activity following training; during the second, commencing 4 h after training, proteins are synthesized and then glycosylated as part of the establishment of an enduring memory trace.

Amnesia↗
PubMed1977

Anisomycin sensitive mutants of Physarum polycephalum isolated by cyst selection.

The haploid myxamoebae of Physarum polycephalum reversibly differentiate to form dormant microcysts under conditions of starvation. The thin-walled cysts can be selective recovered from a cell suspension which has been treated with the surfactant Triton X-100 to lyse amoeboid forms. Excystment, which is initiated by suspension in liquid medium, is inhibited by antibiotics which block protein synthesis. Cysts of drug resistant mutants excyst rapidly in media containing sufficient antibiotic to maintain drug sensitive strains in the encysted state. The selective survival of non-excysted cells following Triton X-100 treatment has been employed to enrich for drug sensitive mutants. Several anisomycin sensitive mutants have been isolated, one of which has been analysed genetically. The possible applications of this mutant enrichment technique are discussed.

Anisomycin↗
PubMed1987

Suppression of antipyretic response in rabbits by intraventricular protein synthesis inhibitor, anisomycin.

Fevers induced by intravenous injection of endogenous pyrogen (EP) and intraventricular prostaglandin E2 (PGE2) were significantly prolonged when protein synthesis inhibitor, anisomycin was administrated intraventricularly 30 min before or 1 hr after injection of EP or PGE2. The present results show that protein synthesis in the central nervous system is involved in the development of antipyresis.

Animals↗
PubMed1988

Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro.

Long-term potentiation (LTP) with its extremely long duration has been frequently regarded as an elementary mechanism of information storage in the nervous system or at least as a suitable model for the study of mechanisms underlying functional plasticity and processes of learning and memory formation. Considering the necessity of an increased protein synthesis for memory consolidation and for the maintenance of LTP in granular synapses in vivo it was of interest to determine whether the LTP of the CA1 region of the hippocampus depends on protein synthesis as well. For the solution of this question anisomycin (ANI), a reversible blocker of protein synthesis, was used at a concentration of 20 microM, which blocked the [3H]leucine incorporation in hippocampal slices by at least 85%. It has been shown that in the CA1 region in vitro the maintenance of LTP (i.e. a late phase greater than 5 h) depends on an ongoing protein synthesis. A 3-h treatment with ANI immediately following multiple tetanization resulted in gradually developing loss of field excitatory postsynaptic potential (EPSP) and population spike (PS) potentiation (15 +/- 19% increase of the PS instead of the 96 +/- 14% increase in non-treated control experiments at the 8th h after tetanization). Furthermore, a late PS potentiation (greater than 6 h) of a second non-tetanized pathway to CA1 pyramidal cells has been observed (increase by 64 +/- 18% at the 8th h) for the first time. This potentiation was ANI-sensitive as well and suggests that the maintenance of LTP is dependent on a postsynaptic mechanism.

Action Potentials↗