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PubMed2006

Feeding behavior of lambs in relation to kinetics of 1,8-cineole dosed intravenously or into the rumen.

The monoterpene 1,8-cineole is a major constituent of the essential oils that adversely influence intake of sage brush by herbivores, but little is known about the mechanisms of its action. We investigated the influence of 1,8-cineole on the feeding behavior of two groups of sheep, one group dosed intravenously and the other intra-ruminally. In the first study, we infused 40 mg/kg BW of 1,8-cineole intravenously into four lambs on wk 1, 2, and 4. In the second, we administered 125 mg/kg BW of 1,8-cineole into the rumen of four lambs as a single-bolus dose in wk 1 and 2. Lambs dosed intravenously spent less time feeding than controls (28 vs. 60 min; P<0.05), as did lambs dosed intra-ruminally (35 vs. 60 min; P<0.05). Dosed lambs ate less than controls during rumen dosing studies (P<0.05). For the intravenous infusion studies, rates of elimination did not differ among weeks (P<0.05). For the rumen infusion studies, however, the absorption rate constant increased from 0.035/min to 0.076/min from wk 1 to 2, while the absorption half-life declined from 24 to 10 min (P<0.05). Maximum plasma concentrations and time to reach maximum plasma concentrations were no faster in wk 2 than wk 1, but the primary elimination rate constant was 2.3 times higher in wk 2 (0.058/min) than in wk 1 (0.025/min) (P<0.05). Dosed lambs exhibited clinical effects-licking of lips, drowsiness, staggering, and 1,8-cineole-smelling breath-that were much more pronounced with intravenous than rumen infusions. Dosing did not affect the acid-base balance. Collectively, these data suggest 1) rapid absorption and distribution of 1,8-cineole was responsible for initiating satiety, while more prolonged excretion was responsible for the duration of the satiety effect, and 2) lambs more readily adapted to 1,8-cineole in the rumen-dose study than in the intravenous-dose study.

Animals↗
PubMed2006

UV-induced mortality in encapsulated intertidal embryos: are mycosporine-like amino acids an effective sunscreen?

Mycosporine-like amino acids (MAAs) are believed to protect a variety of marine organisms against the negative effects of ultraviolet radiation (UVR). However, their role in protecting developing intertidal encapsulated embryos remains untested. In the present study, we focused on the UV protective role of natural concentrations of MAAs for two intertidal gastropod species, Bembicium nanum and Siphonaria denticulata, which lay egg masses in habitats exposed to direct sunlight. We predicted that in both species, a higher concentration of MAAs within the egg mass would increase the likelihood of embryonic survivorship in the presence of UVR. Egg masses from both species were collected along the rocky shores of southeastern New South Wales, and a portion from each was subjected to one of three separate spectral treatments: full spectrum, UV-B block, and UV block. Proportions of surviving embryos were recorded following 72 hr exposure to spectral treatment. In addition, MAAs in each egg mass were quantified. Levels of variation in MAA concentration were striking, with S. denticulata egg masses showing more intraspecific variation than those of B. nanum. Surprisingly, survivorship under all spectral treatments was extremely high for both species, irrespective of MAA concentration. Under full spectrum treatments, B. nanum survivorship and total MAA concentration were significantly and positively correlated; however, MAA accounted for just 23.6% (R = 0.486) of the variation in survivorship. In contrast, survivorship in S. denticulata was not correlated with MAA concentration under full spectrum light. We conclude that the dependence on MAAs as photoprotection may be species-specific; however, it is likely that both species possess alternative mechanisms that minimize the negative effects of UVR.

Amino Acids↗
PubMed2005

Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression--evolution of antidepressants and the role of the "neuro-immune" system.

Antidepressive drugs offer considerable symptomatic relief in mood disorders and, although commonly discovered by screening with single biological targets, most interact with multiple receptors and signaling pathways. Antidepressants require a treatment regimen of several weeks before clinical efficacy is achieved in patient populations. While the biochemical mechanisms underlying the delayed temporal profile remain unclear, molecular adaptations over time are likely involved. The selective serotonin and noradrenaline reuptake inhibitor, venlafaxine, offers a dual antidepressive action. Its pharmacological behavior, however, is unknown at the genetic level, and it is difficult to monitor in human brain samples. Because the hypothalamic-pituitary-adrenal axis is often severely disrupted in mood disorders, lymphocytes may serve as models of neuropsychiatric conditions. As such, we examined the role of venlafaxine on the gene expression profile of human lymphocytes. DNA microarray was used to measure the expression patterns of multiple genes in human lymphocytes from depressed patients treated with this mood stabilizer. In this self-controlled study, RNAs of control and treated samples were purified, converted into cDNA and labeled with either Cy3 or Cy5, mixed and hybridized to DNA microarrays containing human oligonucleotides corresponding to more than 8,000 genes. Genes that were differentially regulated in response to treatment were selected for follow up on the basis on novelty, gene identity, and level of over-expression/repression, and selected transcripts were profiled by real-time PCR (data have been normalized to beta-actin). Using software analysis of the microarray data, a number of transcripts were differentially expressed between control and treated samples, of which only 57 were found to significantly vary with the "P" value of 0.05 or lower as a result of exposure to venlafaxine. Of these, 31 genes were more highly expressed and 26 transcripts were found to be significantly less abundant. Most selected genes were verified with QRT-PCR to alter. As such, independent verification using QRT-PCR demonstrated the reliability of the method. Genes implicated in ionic homeostasis were differentially expressed, as were genes associated with cell survival, neural plasticity, signal transduction, and metabolism. Understanding how gene expression is altered over a clinically relevant time course of administration of venlafaxine may provide insight into the development of antidepressant efficacy as well as the underlying pathology of mood disorders. These changes in lymphocytes are thought to occur in the brain, and a "neuro-immune system" is proposed by this study.

Aged↗
PubMed2004

Management of hot flashes in breast cancer survivors and men with prostate cancer.

Hot flashes are a significant complaint among many breast cancer survivors and many men undergoing androgen deprivation therapy for prostate cancer. Several therapeutic approaches are available to the suffering man or woman. Many of these individuals have tried nonpharmacologic and nonconventional approaches. However, most nonpharmacologic treatments have not been compared with placebo or were not more effective than placebo in prospective, randomized clinical trials. The most effective nonhormonal treatments for hot flashes include agents from the selective serotonin or noradrenergic reuptake inhibitor (SSRI/SNRI) family. Paroxetine, 10 mg/d, or venlafaxine, 37.5 mg/d, are reasonable initial dosages, and if symptoms do not improve within a week or two, the dosage can be doubled. Gabapentin appears to provide similar benefits, but direct comparisons have not been reported. Because of the strong association between gonadal hormones and breast and prostate cancer, the use of hormonal agents to treat hot flashes in these patients has been limited. However, such hormonal therapies as depomedroxyprogesterone acetate can be prescribed for an informed individual who experiences bothersome symptoms despite nonhormonal treatments.

Amines↗
PubMed2002

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system. In the present studies, we attempted to answer the question of whether or not this deamplification is reflected beyond the second messenger system. Nuclear CREB-P was determined in frontal cortex of rats following acute and chronic administration of desipramine (DMI) or reboxetine and in human fibroblasts following incubation for 48 hours with DMI, reboxetine or venlafaxine. Nuclear CREB-P in the frontal cortex was significantly decreased following chronic administration of DMI or reboxetine. Moreover, incubation of human fibroblasts with DMI or reboxetine, but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P suggesting that the noradrenergic antidepressants exert direct effects beyond beta adrenoceptors. The results are consistent with the view that chronic treatment with antidepressants causes a net deamplification of the norepinephrine mediated signal transduction cascade which might "normalize" the increased noradrenergic activity evident in major depression.

Animals↗
PubMed1990

Effects of bepridil and CERM 4205 (ORG 30701) on the relation between cardiac cycle length and QT duration in healthy volunteers.

Bepridil is a calcium antagonist that prolongs the duration of ventricular repolarization, whereas CERM 4205, another calcium antagonist, seems to be devoid of any effect on QT interval. The aim of this study was to compare the effects of bepridil and CERM 4205 on the QT-RR relation at different heart rates during rest and exercise and the results of pharmacologic tests designed to vary neurovegetative tone. Twelve healthy men (21 to 37 years) participated in a placebo-controlled, randomized, crossover, double-blind study and received either bepridil (200 mg/day twice daily) or CERM 4205 (200 mg/day twice daily), or matching placebo during three 14-day treatment periods at 2-week intervals. Bepridil, but not CERM 4205, caused a significant prolongation of resting QT interval. The RR-QT relation was monoexponential for all subjects during resting and exercising physiologic conditions and remained unchanged after 14 days with placebo or CERM 4205. Bepridil significantly shifted the relation upward, resulting in a rate-dependent QT prolongation that predominated during bradycardia. After isoprenaline, QT no longer adapted to changes in heart rate, whereas atropine resulted in a rate-dependent shortening in QT. These results suggest that bepridil and CERM 4205 exert different effects on ventricular repolarization, since only bepridil significantly prolonged QT duration. Bepridil-induced prolongation of QT increased at slow heart rates, which could explain the greater incidence of torsades de pointes in bradycardia.

Adult↗
PubMed1992

Inhibition of glucocerebrosidase and induction of neural abnormality by cyclophellitol in mice.

Cyclophellitol, a cyclitol with an epoxide, is a novel microbial secondary metabolite that inhibits beta-glucosidase and beta-glucocerebrosidase. Daily administration of cyclophellitol induces a severe abnormality of the nervous system in mice while it has no toxicity in various cultured cells. It was shown to inhibit glucocerebrosidase in vivo significantly in mice and the content of glucocerebroside in liver, spleen, and brain was increased markedly. The enzyme activity was completely suppressed in brain, liver, spleen, kidney, and muscle. On the other hand hexosaminidase activity was not affected in all tissues. After a single administration of cyclophellitol the maximal inhibition of glucocerebrosidase was observed within 30 min in brain and liver, and the inhibition lasted for 2-4 days. A single administration of cyclophellitol also induced a severe abnormality of the nervous system known as Gaucher's-like disease in mice. Conduritol B epoxide is also known to inhibit glucocerebrosidase and induce Gaucher's like-disease in mice by repetitive injection. Cyclophellitol was shown to be more potent than conduritol B epoxide in inhibition of glucocerebrosidase and in induction of the neural abnormality.

Animals↗
PubMed1987

Ion transport across the frog olfactory mucosa: the basal and odorant-stimulated states.

The Ussing method was adapted to study the basal electrolyte transfer as well as the events that occur upon odorant stimulation in frog olfactory mucosa. The unstimulated short-circuit current was due mainly to a furosemide-sensitive ion transport system on the apical side of the olfactory mucosa. This current was not amiloride sensitive. The current-voltage relationship of the unstimulated state was linear. That of the odorant-evoked current was non-linear and amiloride-sensitive. Ouabain caused collapse of both the unstimulated and odorant-stimulated short-circuit current. In this case, voltage-clamping the tissue to non-zero values restored the odorant-evoked current with polarity depending on that of the clamping voltage. This suggested that the direction of the current is determined by that of the sodium electrochemical potential difference. Our results indicate that the unstimulated short-circuit current occurs through an apical sodium cotransport system, while the odorant-evoked current is due to odorant-activated, passive sodium channels that are amiloride sensitive.

Amiloride↗
PubMed1991

Cyclophellitol: a naturally occurring mechanism-based inactivator of beta-glucosidases.

The natural product cyclophellitol, isolated from the culture filtrate of a mushroom, Phellinus sp. is found to be a highly specific and effective irreversible inactivator of beta-glucosidases. It inactivates the beta-glucosidases from both almond emulsin and Agrobacter sp. according to pseudo-first order kinetics with inactivation constants of Ki = 0.34 mM, ki = 2.38 min-1, and Ki = 0.055 mM, ki = 1.26 min-1 respectively. No reactivation of the inactivated enzyme is seen upon dialysis, thus providing evidence for the irreversibility of the inactivation. The high specificity of this inactivator is evidenced by the fact that even at very high (12 mM) concentrations of cyclophellitol, no inactivation of yeast alpha-glucosidase was observed, and only extremely slow (t1/2 greater than 5 hours) inactivation of E. coli beta-galactosidase could be detected.

Alcaligenes↗
PubMed1983

The inhibition of hepatic S-3-hydroxy-3-methylglutaryl-CoA reductase by 3,3,5-trimethylcyclohexanol and its mandelic acid ester, cyclandelate.

Rat hepatic HMGCoA reductase was found to be at least 50% inhibited 17 hr after administration of a single oral dose of 3,3,5-trimethylcyclohexanyl mandelate (cyclandelate), a vasoactive substance. This inhibition was also found in rats given the 3,3,5-trimethylcyclohexanol component but only slight inhibition was seen after an equimolar dose of mandelate. The inhibition of HMGCoA was observed both around the high point and near the low point of the diurnal activity cycle. The effect did not persist to 41 hr after treatment. There was no direct inhibition of HMGCoA reductase by trimethylcyclohexanol when added to the assay system in vitro. The in vivo effect of these inhibitors was specific for HMGCoA reductase. There was no change, neither elevation nor depression, of the amount of microsomal membrane components cytochromes b5 and P-450, not was the activity of another microsomal enzyme, arylesterase, affected by dosing with cyclandelate or trimethylcyclohexanol.

Administration, Oral↗
PubMed1993

A novel role for carboxylesterase in the elevation of cellular cysteine by esters of cysteine.

Esters of cysteine, such as cysteine isopropylester (CIPE) or cysteine cyclohexylester (CCHE), are efficient delivery systems for cysteine to cells. After enzymic cleavage, the esters of cysteine provide a source of cellular cysteine, which may support reduced glutathione (GSH) synthesis and/or act as a direct chemoprotectant. Reducing esterase activity of rat lung slices or isolated hepatocytes with paraoxon or bis(4-nitrophenyl) phosphate or by reducing the temperature to 4 degrees dramatically altered the metabolism of esters of cysteine; the initial increase in cellular cysteine was slowed, the residency time of cysteine esters in the extracellular pool was prolonged without substantially enhancing the levels of intracellular ester. Incubation of lung slices with CIPE at 4 degrees led to a marked increase in cellular cysteine, which prior inhibition of esterase activity abolished. Inhibiting the neutral amino acid uptake systems, ASC and L, while effecting the uptake of cysteine, did not reduce the elevation of cellular cysteine by CIPE. We propose that the elevation of cellular cysteine by esters of cysteine may be mediated by membrane associated esterase activity.

Animals↗
PubMed1994

Evidence for the direct interaction of reduced metronidazole derivatives with DNA bases.

The electrochemical behaviour of the bioreductive redox active nitroimidazole drug metronidazole has been examined in the presence and absence of the DNA bases using three electrochemical techniques, all of which indicate the capacity for interaction between reduced products and DNA bases. The 4-electron metronidazole (RNO2) metronidazole-hydroxylamine (RNHOH) couple in an aqueous medium shows a positive shift in reduction potential upon addition of thymine, adenine and guanine, but a negative shift for cytosine. Interpretation of these results for an irreversible process is, however, inconclusive. In dimethylformamide/H2O the presence of DNA base on the one-electron addition product, the nitro radical anion, was examined by cyclic voltammetry. All except guanine resulted in interaction with the metronidazole nitro radical anion (RNO2-), as measured by the decrease in the return-to-forward peak current ratio, in the following order of increasing reactivity: cytosine, adenine and thymine (at a metronidazole: base ratio of 1:1). The increase in the stability of the radical anion by increasing the pH of the dimethylformamide/H2O medium resulted in a decreased reaction with thymine.

Adenine↗
PubMed1994

Demonstration of ternary immunophilin-calcineurin complexes with the immunosuppressants cyclosporin and macrolide FK506.

The specificity of cyclosporin A (CsA) binding to the major intracellular receptor proteins, cyclophilin A and B, as well as the interaction of CsA with the phosphatase calcineurin were investigated. Binding of photoaffinity-labeled CsA (PL-CS), a photoaffinity probe of CsA, to recombinant human cyclophilin A and B is saturable and specific. Non-specific PL-CS binding to calcineurin is observed in the absence of cyclophilin and calmodulin. In the presence of cyclophilin, cyclosporin-calcineurin binding becomes specific. Ternary complexes containing an equimolar ratio of cyclophilin A or B, PL-CS and calcineurin are resolved using the chemical-crosslinking technique. The formation of these complexes is specific, calcium- but not calmodulin-dependent, and is only inhibitable by cyclosporins, which bind cyclophilin. The drug-immunophilin complex binds to the calcineurin A subunit. The proteolytic 43 kDa product of calcineurin A retains binding properties, suggesting that the C-terminal domains are not necessary for complex formation. A trimeric complex of FKBP-calcineurin is also formed with FK506, but not with rapamycin. As expected, these complexes are only competed with by homologous derivatives. Chemical crosslinking of photolabeled Jurkat T-cells strongly suggests that drug-calcineurin complexes are of biological relevance.

Affinity Labels↗
PubMed1985

Intracellular potentials of salamander mitral/tufted neurons in response to odor stimulation.

Intracellular responses of salamander mitral/tufted neurons to defined odor pulses are described. Responses to odor stimulation, which generally are more complex than responses to olfactory nerve or tract electrical stimulation, show periods of depolarization and hyperpolarization that are influenced by odor concentration and quality. The way these periods coincide with different types of spike patterns in individual cells supports the hypothesis that the temporal patterning of odor responses is generated by differential activation of bulbar circuits.

Animals↗
PubMed1991

Neuronal localization of cannabinoid receptors and second messengers in mutant mouse cerebellum.

Four lines of mutant mice were used to investigate (1) the neuronal localization of cannabinoid receptors in the cerebellar molecular layer and (2) the anatomical association of these receptors with elements of the two second messenger systems in the brain. Two of the mutant lines--Purkinje cell degeneration and nervous--are selectively deficient in Purkinje cells; the other two--weaver and reeler--are deficient in granule cells. In the heterozygous mice, [3H]CP 55,940 binding to cannabinoid receptors was discretely and densely localized to the molecular layer, as was [3H]forskolin binding to adenylate cyclase and [3H]phorbol 12,13-dibutyrate binding to protein kinase C, a component of the phosphoinositide cycle. [3H]CP 55,940 and [3H]forskolin binding was selectively reduced in weaver and reeler homozygous mice but unchanged in Purkinje cell deficient and nervous homozygotes. No decreases in [3H]phorbol 12,13-dibutyrate binding were found in any of the homozygous mutants relative to the heterozygous littermates. The results suggest that cannabinoid receptors and adenylate cyclase are localized to granule cell axons in the molecular layer, whereas protein kinase C is equally distributed in parallel fibers and Purkinje cell dendrites.

Adenylyl Cyclases↗
PubMed1991

Chronic exposure to delta 9-tetrahydrocannabinol fails to irreversibly alter brain cannabinoid receptors.

The effects of chronic delta 9-tetrahydrocannabinol (delta 9-THC) and marijuana administration on the properties of brain cannabinoid receptor populations of the rat and monkey, respectively, were examined in this study. It was determined that the properties of the cannabinoid receptors in the striatum, cerebral cortex, cerebellum, hippocampus, and brainstem/spinal cord of the rat do not appear to be irreversibly altered by chronic exposure to delta 9-THC. Similarly, the cannabinoid receptors in the caudate, prefrontal cortex, and cerebellum of the monkey do not appear to be irreversibly altered by chronic exposure to marijuana smoke.

Analgesics↗
PubMed1993

Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study.

The active ingredient of marijuana is (-)-delta 9-tetrahydrocannabinol (delta 9-THC). delta 9-THC and other natural and synthetic cannabinoids such as CP-55,940 inhibit spontaneous activity and produce catalepsy in animals in a receptor-mediated fashion. Tolerance develops to the motor effects of delta 9-THC after repeated administration. To test the hypothesis that tolerance is mediated by changes in cannabinoid receptor binding characteristics, we used quantitative in vitro autoradiography of [3H]CP-55,940 binding to striatal brain sections from rats treated either chronically or acutely with delta 9-THC, CP-55,940, or the inactive natural cannabinoid cannabidiol. In the chronic conditions, rats were given daily i.p. injections of delta 9-THC (10 mg/kg), cannabidiol (10 mg/kg), or CP-55,940 (1, 3, or 10 mg/kg) for 2 weeks and sacrificed 30 min after the last injection. In the acute condition, animals received a single dose (10 mg/kg) prior to sacrifice. Rats developed tolerance to the inhibitory effects of delta 9-THC and CP-55,940, assayed in an open field on days 1, 7, and 14. Cannabidiol had no effect on behavior. Densitometry of [3H]CP-55,940 binding to brain sections showed that delta 9-THC- and CP-55,940-treated animals had homogeneous decreases in binding in all structures measured at the selected striatal levels. Cannabidiol had no effect on binding. Analysis of binding parameters showed that alterations in the acute condition were attributed to changes in affinity (KD), whereas the major changes in the chronic condition were attributed to a lowering of capacity (Bmax). The effects in the 1, 3, and 10 mg/kg CP-55,940 conditions were dose-dependent and paralleled the behavioral data showing that the animals given the highest dose developed the greatest degree of tolerance. The data suggest that tolerance to cannabinoids results at least in part from agonist-induced receptor down-regulation.

Animals↗