The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test

Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10 mg/kg), CORT 108297 (30 mg/kg and 60 mg/kg), imipramine (10 mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60 mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.     

Enzymatic synthesis and anti-coagulant effect of salicin analogs by using the Leuconostoc mesenteroides glucansucrase acceptor reaction

Glucansucrases from Leuconostoc mesenteroides catalyze the transfer of glucosyl units from sucrose to other carbohydrates by acceptor reaction. We modified salicyl alcohol, phenol and salicin by using various glucansucrases and with sucrose as a donor of glucosyl residues. Salicin, phenyl glucose, isosalicin, isomaltosyl salicyl alcohol, and a homologous series of oligosaccharides, connected to the acceptors and differing from one another by one or more glucose residues, were produced as major reaction products. By using salicin and salicyl alcohol as acceptors, B-1355C2 and B-1299CB-BF563 dextransucrases synthesized most widely diverse products, producing more than 12 and 9 different kinds of saccharides, respectively. With phenol, two acceptor products and oligosaccharides were synthesized by using the B-1299CB-BF563 dextransucrase. Salicyl derivatives, as acceptor products, showed higher anti-coagulation activity compared with that of salicin or salicyl alcohol that were used as acceptors.     

Antidepressant-like effects of salvianolic acid B in the mouse forced swim and tail suspension tests

AimsSalvianolic acid B (SalB), one of the most abundant and bioactive compounds extracted from Salvia miltiorrhiza (Danshen), shows neuroprotective and anti-inflammatory activities in vivo and in vitro. This research was intended to investigate the antidepressant effect of SalB by forced swimming test (FST) and tail suspension test (TST).Main methodsSalB was extracted from S. miltiorrhiza roots and followed by HPLC analysis. Thirty five male C57BL/6 mice were divided into five groups: three SalB groups of different doses, one imipramine group, and one control group. The SalB groups received intraperitoneally (i.p.) 5 mg/kg SalB, 10 mg/kg SalB, and 20 mg/kg SalB respectively. At the same time, the imipramine group received 20 mg/kg imipramine, and the control group saline only. The behavioral tests including FST, TST and locomotor activity test were done after administration of drugs for consecutively three times, at 24, 1, and 0.5 h before the tests.Key findingsSalB, from S. miltiorrhiza with purity of 95%, significantly reduced the immobility time in both the FST and TST tests (doses at 5, 10, 20 mg/kg, i.p.), without changing locomotion in spontaneous motor activity.SignificanceThis data suggests that besides neuroprotective and anti-inflammatory activities, SalB has promising therapeutic potential in treatment of depressive disorders.     

Antidepressant effect of Chaihu-Shugan-San extract and its constituents in rat models of depression

Herbal preparations may be effective alternatives in the treatment of depression, which remains difficult to manage. Chaihu-Shugan-San (CSS), an oriental traditional medicine, has been used as a remedy for Hwa-Byung, a Korean culture-bound syndrome resembling depression. We examined whether aqueous extracts of CSS and its constituent herbs exert antidepressant-like effects in two experimental animal models: the forced swimming test (FST) and the chronic mild stress (CMS) model. The herbal extracts were administered orally for 7 days in the FST and for 21 days during the CMS model; imipramine at 20 mg/kg/day was injected intraperitoneally as a positive control. CSS, Radix Bupleuri (one of the most important constituent plants in CSS), and imipramine had significant anti-immobility effects in the FST and reversed the CMS-induced reduction in sucrose consumption. Rhizoma Cyperi, another constituent of CSS, had antidepressant activity in the FST, while it failed in the CMS model. In conclusion, our results suggest that CSS and its constituent herbs exert antidepressant-like effects comparable to those of imipramine in experimental animal models.     

Enzymatic synthesis of two salicin analogues by reaction of salicyl alcohol with Bacillus macerans cyclomaltodextrin glucanyltransferase and Leuconostoc mesenteroides B-742CB dextransucrase

Beta-Salicin is a naturally occurring glycoside found in the bark of poplar and willow trees. Ancient man used it as an analgesic and antipyretic. It has a D-glucopyranose unit attached by a beta-linkage to the phenolic hydroxyl of salicyl alcohol. Two new salicin analogues have been enzymatically synthesized by transglycosylation reactions: (a) by the reaction of Bacillus macerans cyclomaltodextrin glucanyltransferase with cyclomaltohexaose and salicyl alcohol, followed by reactions with alpha amylase and glucoamylase to give D-glucopyranose attached by an alpha-linkage to the phenolic hydroxyl of salicyl alcohol as the major product, alpha-salicin; and (b) by the reaction of Leuconostoc mesenteroides B-742CB dextransucrase with sucrose and salicyl alcohol, followed by reactions with dextranase and glucoamylase to give alpha-d-glucopyranose attached to the primary alcohol hydroxyl of salicyl alcohol as the major product, alpha-isosalicin.     

Characteristics of the combined action of melatonin and imizin on the structure of forced swimming and the circadian rhythm

Acute administration of melatonin (10 mg/kg) produced a depressed effect on the mice behavior. But it's injection after chronic imipramine (10 mg/kg/day, 2 weeks) potentiated antidepressant ability and shortened the duration of immobility in the structure of swimming. In rats, which had a high amplitude of circadian rest-activity rhythm, melatonin produced imipramine effect on circadian mobility, but potentiated antidepressant action in animals with low initial level of locomotor activity.     

Salicyl alcohol oxidase of the chemical defense secretion of two chrysomelid leaf beetles. Molecular and functional characterization of two new members of the glucose-methanol-choline oxidoreductase gene family

Salicyl alcohol oxidase is an extracellular enzyme that occurs in glandular reservoirs of chrysomelid leaf beetle larvae and catalyzes the formation of salicylaldehyde, a volatile deterrent used by the larvae against predators. Salicyl alcohol is the hydrolysis product of salicin, a plant-derived precursor taken up by the beetle larvae from the leaves of willow and poplar trees. The cDNA encoding salicyl alcohol oxidase from two related species Chrysomela tremulae and Chrysomela populi has been identified, cloned, and expressed in an active form in Escherichia coli. The open reading frame of 623 amino acids begins in both enzymes with an N-terminal signal peptide of 21 amino acids. Sequence comparison has revealed that salicyl alcohol oxidase belongs to the family of glucose-methanol-choline oxidoreductase-like sequences with mostly unknown function. Enzymes of this family share similar overall structure with an essentially identical FAD-binding site but possess different catalytic activities. The data suggest that salicyl alcohol oxidase, essential for the activation of the plant-derived precursor salicin, was originally recruited from an oxidase involved in the autogenous biosynthesis of iridoid monoterpenes and found in related chrysomelid leaf beetle species.     

Evaluation of antidepressant-like activity of aqueous and ethanolic extracts of Terminalia bellirica Roxb. fruits in mice

The present study was undertaken to investigate the effect of aqueous and ethanolic extracts of T. bellirica on depression in mice using forced swim test (FST) and tail suspension test (TST). The extracts were administered orally for 10 successive days in separate groups of Swiss young male albino mice. Aqueous extract (50, 100 and 200 mg/kg) in a dose-dependent manner and ethanolic extract (100 mg/kg) significantly reduced the immobility time of mice in both FST and TST. The extracts were without any significant effect on locomotor activity of mice. The efficacies of aqueous extract (200 mg/kg) and ethanolic extract (100 mg/kg) were found to be similar to that of imipramine (15 mg/kg, po) and fluoxetine (20 mg/kg, po) administered for 10 successive days. Both extracts reversed reserpine-induced extension of immobility period of mice in FST and TST. Prazosin (62.5 microg/kg, ip; an alpha1-adrenoceptor antagonist), sulpiride (50 mg/kg, ip; a selective D2 receptor antagonist) and p-chlorophenylalanine (100 mg/kg, ip; an inhibitor of serotonin synthesis) significantly attenuated the aqueous and ethanolic extract-induced antidepressant-like effect in TST. Thus, both the aqueous and ethanolic extracts of T. bellirica elicited a significant antidepressant-like effect in mice by interaction with adrenergic, dopaminergic and serotonergic systems.     

Antidepressant Like Effect of Ascorbic Acid in Mice: Possible Involvement of NO-sGC-cGMP Signaling

The present study was designed to determine the antidepressant like activity of ascorbic acid (AA) in mice. Further the influence of NO-sGC-cGMP signaling in the antidepressant like effect of AA in mice was determined. Male swiss albino mice were used in the present study. Mice in the control group received saline and fluoxetine (10 mg/kg, i.p.) was used as the standard antidepressant drug. AA (50, 100 and 150 mg/kg, i.p.) was administered to the mice and depression related behavior were determined using tail suspension test (TST) and forced swim test (FST). Further the whole brain nitrite and serotonin levels were also determined. It was observed that the administration of AA (100 mg/kg, i.p.) reversed the depression like behavior in mice in TST and FST. AA (100 mg/kg, i.p.) treatment decreased the level of nitrite and increased the level of serotonin in the brain of mice significantly as compared to control. Further the behavioral and neurochemical effect of AA (50 mg/kg, i.p) was studied in NO modulator [NO donor: L-Arginine (50 mg/kg, i.p); NO-sGC inhibitor: methylene blue (1 mg/kg, i.p.) and cGMP modulator: sildenafil (1 mg/kg, i.p.)] pretreated mice. It was observed that the pretreatment of NO donor and cGMP modulator counteracted the effect conferred by AA (50 mg/kg, i.p). While the pretreatment of NO-sGC inhibitor potentiated the effect conferred by AA (50 mg/kg, i.p). The present study suggested that the AA confer antidepressant like effect in mice and NO-sGC-cGMP signaling pathway influence the antidepressant like effect of AA in mice.

     

The involvement of AMPA–ERK1/2–BDNF pathway in the mechanism of new antidepressant action of prokinetic meranzin hydrate

It was recently discovered that ketamine can relieve depression in a matter of hours through an action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This is much more rapid than the several weeks required for the available antidepressants to show therapeutic efficacy. However, ketamine has negative side effects. The aim of this study was to determine whether the natural prokinetic drug meranzin hydrate (MH) has a fast-acting antidepressant effect mediated by AMPA receptors. By means of in vivo and in vitro experiments, we found that (1) treatment of rats with MH at 9 mg/kg decreased immobility time in a forced swimming test (FST), as did the popular antidepressant fluoxetine and the AMPA receptor positive modulator aniracetam. Pretreatment of rats with NBQX (10 mg/kg), an antagonist of AMPA receptors, blocked this effect of MH. (2) MH increased number of crossings of forced swimming rats in the open field test. (3) FST enhanced hippocampal ERK1/2, p-ERK1/2 and BDNF expression levels. MH (9 mg/kg) treatment further up-regulated hippocampal p-ERK1/2 and BDNF expression levels, and this effect was prevented by NBQX. (4) MH-increased BDNF expression corresponded with MH-decreased immobility time in the FST. (5) In vitro experiments, we found that incubation of rats hippocampus slices with MH (10, 20 μM respectively) increased concentrations of BDNF and p-ERK1/2. This effect of MH (20 μM) were prevented by NBQX. In conclusion, in animals subjected to acute stress, the natural prokinetic drug MH produced a rapid effect mediated by AMPA receptors and involving BDNF modulation through the ERK1/2 pathway.     

Characterization of an extracellular salicyl alcohol oxidase from larval defensive secretions of Chrysomela populi and Phratora vitellinae (Chrysomelina)

Larvae of a number of chrysomelid leaf beetles sequester phenol glucosides such as salicin from their food plants, i.e. Salix and Populus spp. Salicin is hydrolyzed in the glandular reservoir of the defensive glands. The resulting salicyl alcohol (saligenin) is oxidized by an extracellular oxidase. The product salicylaldehyde accumulates as major defensive compound. The secretions from Chrysomela populi and Phratora vitellinae were preserved in saturated ammonium sulfate solution and subjected to micro-purification of the oxidase by means of electrophoretic methods. The enzyme from P. vitellinae has a native M(r) of 334,000 and a subunit M(r) of 79,000 indicating a tetrameric enzyme. The isoelectric points of the enzymes from C. populi and P. vitellinae are at pH 5.4 and 5.2, respectively. In the oxidation of salicyl alcohol oxygen functions as electron acceptor yielding hydrogen peroxide as product. Hydrogen peroxide does not accumulate in native secretions but appears to be degraded most likely by a catalase. The oxidases from the two species show broad pH optima in the range 5.5 to 6.5, they oxidize salicyl alcohol as main substrate. Minor substrates are several ortho-substituted and to a lesser extent meta- but not para-substituted benzyl alcohols. In the presence of 8-hydroxygeraniol only trace amounts of the respective aldehyde are formed. The Km values of salicyl alcohol are 132 mM (C. populi) and 63 mM (P. vitellinae). The extracellular enzyme, which is functionally related to fungal aryl alcohol oxidase (EC 1.1.3.7) and vanillyl alcohol oxidase (EC 1.1.3.38) was named salicyl alcohol oxidase. The continuous formation of salicylaldehyde in the glandular reservoir can be compared to the operation of an enzyme reactor. Due to its low aqueous solubility the produced aldehyde steadily leaves the aqueous reaction fluid and builds up an organic phase which may account for 15% of the total liquid volume of the secretion.     

Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress

Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic–pituitary–adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague–Dawley rats treated with vehicle, 1 mg of testosterone propionate, 10 mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis.     

The antidepressant-like effects of Aloysia polystachya (Griseb.) Moldenke (Verbenaceae) in mice

The aim of the present work is to evaluate the putative antidepressant-like effects of a hydro-ethanolic extract (CEAp) and their fractions from the aerial parts of Aloysia polystachya (Griseb.) Moldenke (Verbenaceae) on the performance of male mice in the forced swimming test (FST). A single dose (100.0 mg/kg p.o.) of CEAp, in male mice provoked a significant reduction of the immobility time (p<0.01). Such effect was also observed with short-term treatment (7 days) with single doses of 1.0 (p<0.01), 10.0 (p<0.05) and 100.0 (p<0.05) mg/kg/day of CEAp. Additionally, in a different set of experiments, repeated administration in a 24-h period (24, 18 and 1 h before swimming test) with doses of 1.0 (p<0.05) and 10.0 (p<0.05) mg/kg p.o., of CEAp and 10.0 mg/kg p.o., (p<0.05) of ethyl acetate fraction, provoked significant reduction of the immobility time of male mice in the FST. Moreover, it was noted important differences in the onset of the antidepressant-like effect in the FST, depending on the modality of treatment with CEAp (acute, short-term or repeated). Both, efficacy and potency were higher when repeated administration of CEAp was used, and surprisingly the dose of 10 mg/kg (24, 18 and 1 h before swimming test) was more effective than imipramine. In the same way, the short term administration (7 days) improved significantly efficacy and potency of the CEAp in comparison to a single dose treatment. The ethyl acetate fraction submitted to TLC demonstrated that main and minor components are phenolics and terpenes, respectively. In addition, this fraction gives a negative Shinoda's test for flavonoids. These results indicate an antidepressant-like profile of action for the hydro-ethanolic extract and the component(s) of the ethyl acetate fraction obtained from A. polystachya, which deserve further investigation.     

Involvement of nitric oxide (NO) signalling pathway in the antidepressant activity of essential oil of Valeriana wallichii Patchouli alcohol chemotype

Valeriana wallichii DC (Valerianaceae), popularly named as Indian valerian has been shown to exist as three chemotypes. The present study evaluated the antidepressant like effect of root essential oil of Valeriana wallichii patchouli alcohol chemotype in both acute and chronic treatment study using forced swim test (FST). Mice (n = 6 per group) received 10, 20 and 40 mg/kg p.o. doses of test drug. Single administration of oil significantly inhibited the immobility period (57.6% and 46.9%) at doses 20 and 40 mg/kg respectively without changing the motor function (p < 0.05). Similarly, daily administration of essential oil (20 mg/kg) for 14 days significantly reduced the immobility period (69.9%) in FST (p < 0.05). The neurotransmitter levels in mouse brain were estimated on day 14 after the behavioral study. Significant increase in the level of norepinephrine (29%) and serotonin (19%) (p < 0.05) was found at 20 mg/kg dose, while no change was observed at 10 and 40 mg/kg doses. The antidepressant-like effect of essential oil (20 mg/kg) was prevented by pretreatment of mice with l-arginine (750 mg/kg i.p.) and sildenafil (5 mg/kg i.p). On the contrary, pretreatment of mice with l-NAME (10 mg/kg i.p.) or methylene blue (10 mg/kg i.p.) potentiated the antidepressant action of essential oil (10 mg/kg). Taken together, these findings demonstrated that nitric oxide pathway is involved in mediating antidepressant like effect of essential oil from this chemotype.     

Automated experimental system capturing three behavioral components during murine forced swim test

AimsAn automated experimental system applying a commercially available video image analyzer was developed for the simultaneous detection and measurement of three behavioral components; immobility, swimming (horizontal movements) and climbing (vertical movements) that occur in the murine forced swim test (FST). The system was validated using four typical antidepressants.Main methodsSystem validity was confirmed by demonstrating no significant difference in 6 min time course of control group and imipramine-dosed group (30 mg/kg) between manual examinations and automated digital analysis for all the three behaviors (i.e., correlation coefficients were 0.96, 0.83 and 0.94 for immobility, swimming and climbing, respectively). The effects of acute single treatment with four antidepressants in clinical use, i.e., imipramine, desipramine, bupropion and fluvoxamine were evaluated at doses of 15, 30 and 60 mg/kg using the system.Key findingsIn 2–4 min time span analysis, all four antidepressants reduced immobility and increased climbing significantly, desipramine and bupropion increased swimming significantly, while imipramine and fluvoxamine did not.SignificanceThe automated experimental system enabled efficient and accurate analysis of the three murine behaviors during FST at once. Climbing could be more sensitive parameter to detect anti-depressant-like effect than immobility in this system.     

Antidepressant-like profile of action of two 4-amine derivatives of 10,11-dihydro-5H-dibenzo [a,d] cycloheptane in mice evaluated in the forced swimming test

This study investigated the antidepressant-like effect of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one (ADDCH1) and 1,2,3,4,8,9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2), in a validated experimental model of depression, the forced swimming test (FST) in mice. Female adult mice were sub-chronically (three doses in 24 h) or repeatedly (once a day for 10 days) treated with either of the compounds and evaluated in the FST. The sub-chronic treatment promoted a dose-dependent reduction in the immobility time in the FST with the doses of 50 mg/kg (ADDCH1) and 30 mg/kg (ADDCH2) ip being the most effective (33% and 37% of reduction, respectively). A similar profile of action was observed in the animals repeatedly treated with ADDCH1 50 mg/kg or ADDCH2 30 mg/kg ip (for 10 days) and there was no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. These findings suggest that these amine derivatives of the system dibenzocycloheptane have an antidepressant-like action which could be of clinical interest and, therefore, deserves further investigation. In addition, putative underlying mechanisms of action are discussed.     

Antihistamine, anticholinergic and cardiovascular effects of 2-substituted-4-phenylquinoline derivatives

Eleven new derivatives of 4-phenylquinoline, having various substituents at the 2-position of the quinoline ring, were previously synthesized. The antidepressant activities of these derivatives were demonstrated by their antagonism to reserpine-induced hypothermia in mice. The ED50 values were found to be in the range of 12-42 mg/kg (imipramine is 21.0 mg/kg). In the present work, comparative studies of the effects of these new drugs on the cholinergic and histaminergic (H1) systems, as well as their effects on the cardiovascular system, are presented. Both imipramine and trazodone were utilized as standards representing typical and atypical antidepressant drugs, respectively. All these new compounds have very low antihistaminic (H1) activities, as compared to imipramine. In addition, a clear cut separation of the antidepressant activity from the antihistaminic (H1) activity was observed. These compounds have weak anticholinergic (atropine-like properties) activity as compared to imipramine, using the isolated guinea-pig ileum. Animal studies of the cardiac toxicity of these compounds showed reduced lethality for some of them as compared to imipramine. Arrhythmias commonly associated with imipramine were absent for most of these compounds. The effects of these compounds on the heart conduction were determined by electrocardiographic studies. Although some of these compounds do not interfere with heart conduction, as compared to imipramine most were inferior to trazodone. Correlation between the pharmacological activities and structural modifications of these derivatives has also been observed.     

Glucosylation of Salicyl Alcohol by Gardenia jasminoides Cell Cultures

Cultured cells of Gardenia jasminoides produced both salicinand isosalicin from exogenously supplied salicyl alcohol. Theglucosylation activity of the cells was highest in the exponentialphase of growth and ca. 70% of the added substrate was convertedto the glucosides within 4 days. The rate of glucosylation wasalso dependent on the medium composition such as auxin and sucroseconcentrations. The ratio of salicin to isosalicin formed fromsalicyl alcohol was influenced by the growth stage of the culturedcells. Salicin was converted to isosalicin when exogenouslyadded to the culture. (Received October 11, 1985; Accepted March 10, 1986)