European Journal of Pharmacology (v.729, #C)

Ameliorative effect of acetyl-l-carnitine and/or nifedipine against selenite-induced cataractogenesis in young albino rats by Lamiaa M. Farghaly; Waleed A. Ghobashy; Youssef Shoukry; Mona F. El-Azab (1-9).
Free radical toxicity and calcium ion overload have been identified as the major two players in the causation of cataract. The current study was carried out to investigate the anti-cataractogenic effect of single and combined treatment with acetyl-l-carnitine and nifedipine in sodium selenite-induced cataract. Rat pups were divided into 5 groups; 1st group received intraperitoneal injection (i.p.) of saline and served as normal control, 2nd group received single subcutaneous injection of sodium selenite 30 nmol/g body weight on p10 (postpartum day 10), 3rd and 4th groups received either acetyl-l-carnitine (200 mg/kg, i.p.) or nifedipine (0.1 mg/kg, i.p.) on p9, respectively, before the administration of sodium selenite, and the treatment continued till p14. Last group received the combined treatments of acetyl-l-carnitine and nifedipine in the same regimen. All animals were examined using a slit lamp and retroillumination then sacrificed on p30. Lenses were removed and processed for biochemical analyses, histopathological and electron microscopic examination. Selenite-treated groups showed significantly (P≤0.05) lower values of redox system components (glutathione and glutathione reductase activity) and anti-oxidant enzymes׳ activities (superoxide dismutase and catalase) along with increased lipid peroxidation that was accompanied by 100% opacified crystalline lenses (mature cataract) with abnormal structure as detected by electron microscopy. It is concluded that acetyl-l-carnitine or nifedipine was able to partially protect against selenite-induced abnormalities. While, combined treatment with acetyl-l-carnitine and nifedipine was superior to individual treatments in slowing down the development of cataract by restoring the anti-oxidant defense and mitigating lipid peroxidation in the lens and hence represents an attractive anti-cataractogenic remedy.
Keywords: Cataract; Calcium channel blockers; l-Carnitine; Oxidative stress; Selenite;

Effect of azithromycin on Prevotella intermedia lipopolysaccharide-induced production of interleukin-6 in murine macrophages by Eun-Young Choi; Ji-Young Jin; Jeom-Il Choi; In Soon Choi; Sung-Jo Kim (10-16).
Interleukin-6 (IL-6) is a key proinflammatory cytokine which plays a central role in the pathogenesis of periodontal disease. Host modulatory agents targeting at inhibiting IL-6, therefore, appear to be beneficial in slowing the progression of periodontal disease and potentially reducing destructive aspects of the host response. The present study was designed to investigate the effect of the macrolide antibiotic azithromycin on IL-6 generation in murine macrophages treated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in inflammatory periodontal disease, and its mechanisms of action. Azithromycin significantly suppressed IL-6 production as well as its mRNA expression in P. intermedia LPS-activated RAW264.7 cells. LPS-induced activation of JNK and p38 was not affected by azithromycin treatment. Azithromycin failed to prevent P. intermedia LPS from degrading IκB-α. Instead, azithromycin significantly diminished nuclear translocation and DNA binding activity of NF-κB p50 subunit induced with LPS. Azithromycin inhibited P. intermedia LPS-induced STAT1 and STAT3 phosphorylation. In addition, azithromycin up-regulated the mRNA level of SOCS1 in cells treated with LPS. In conclusion, azithromycin significantly attenuated P. intermedia LPS-induced production of IL-6 in murine macrophages via inhibition of NF-κB, STAT1 and STAT3 activation, which is possibly related to the activation of SOCS1 signaling. Further in vivo studies are required to better evaluate the potential of azithromycin in the treatment of periodontal disease.
Keywords: Azithromycin; Lipopolysaccharide; Interleukin-6; NF-κB; STAT; SOCS1;

The present study evaluated the effects of morphine treatments on elevated plus maze test parameters, oxidative stress markers and Hsp70 expression in normal and stressed rats. Acute and chronic stress caused neurobehavioral suppression, altered prooxidant–antioxidant balance and increased Hsp70 expression in brain homogenates in a differential manner. Morphine (1 and 5 mg/kg) attenuated RS induced anxiogenesis, changes in MDA and GSH but further enhanced Hsp70 expression. Similar anxiolytic and Hsp70 enhancing effects were seen after morphine in normal rats (no RS). Exposure to chronic RS did not elicit any appreciable neurobehavioral response in EPM but enhanced MDA, lowered GSH and exaggerated the Hsp70 expression. Pretreatment with morphine did not affect the neurobehavioral response to chronic RS, but reverted the GSH and Hsp70 expression. The results suggest that morphine differentially influences acute and chronic stress induced changes in anxiety behavior and complex interactions between oxidative stress markers and Hsp70 expression which may contribute to these effects.
Keywords: Restraint stress; Anxiety; Morphine CID: 5288826; Oxidative stress; Hsp70 CID: 5461444;

The wide range of inflammation mechanisms under control by NF-κB makes this pathway as an attractive target for new anti-inflammatory drugs. Herein, we showed that a new dibenzocyclooctadiene lignan analog XLYF-104-6, with a chemical name of 1,2,3,10,11-pentamethoxydibenzocycloocta-6,7-[c] pyrrole-1,3-dione, inhibited lipopolysaccharide (LPS)-induced NF-κB activation in RAW264.7 cells through preventing IκBα degradation and p65 nuclear translocation. The inhibitory activity of this compound on NF-κB activation contributes to the reduction of LPS-induced TNF-α and IL-6 productions. Notably, XLYF-104-6 suppressed LPS-induced iNOS expression and NO production in a NF-κB independent manner, since IKK inhibitor BAY 11-7082 has failed to exert similar inhibitory effect on iNOS expression and NO production. In addition, XLFY-104-6 also exerted anti-inflammatory action in endotoxemic mice by decreasing plasma LPS-induced TNF-α and IL-1β levels as well as increasing plasma LPS-induced IL-10 concentrations. These findings suggest XLYF-104-6 could act as a leading compound for developing a potential anti-inflammatory drug.
Keywords: Anti-inflammatory drug; NF-κB; Dibenzocyclooctadiene lignin; iNOS expression and NO production; Lipopolysaccharide; Sepsis;

New cyclopentaquinoline derivatives with fluorobenzoic acid induce G1 arrest and apoptosis in human lung adenocarcinoma cells by Paulina Olszewska; Jacek Szymański; Elżbieta Mikiciuk-Olasik; Paweł Szymański (30-36).
Non-small cell lung cancer accounts for 80–85% of all lung cancer cases and is the leading cause of cancer death indicating inefficient current treatment. Acridine derivatives interact with DNA and inhibit topoisomerase leading to cell growth arrest or cell death. The aim of this study was to evaluate the effects of new synthesized sixteen 2,3-dihydro-1H-cyclopenta[b]quinoline derivatives (cyclopentaquinoline), a member of acridine-based compounds, on the survival and growth of human lung adenocarcinoma, A549 cells. Anticancer activity of eight new cyclopentaquinoline derivatives with hydrazinonicotinic acid (compounds 18) and eight with fluorobenzoic acid (compounds 916) were screened using WST-1 assay. Interestingly, cyclopentaquinoline derivatives with fluorobenzoic moiety were found to have a higher anticancer activity than derivatives with hydrazinonicotinic acid. Four out of eight tested compounds with fluorobenzoic acid inhibited 50% cancer cell growth at concentration below 20 μM. Moreover, the efficacy of cyclopentaquinoline derivatives containing fluorobenzoic acid correlated with increasing number of carbon atoms in the aliphatic chain. The most effective compounds (6, 15, 16) were selected to determine molecular mechanisms of their anticancer action. The results indicated that inhibition of A549 cell growth by compounds 15 and 16 was associated with a cell cycle arrest at G0/1 phase and with induction of caspase 3-dependent apoptosis. Compound 6 also caused A549 cells death due to apoptosis, however, it had no significant effect on a cell cycle progression. These findings suggest that cyclopentaquinoline derivatives containing fluorobenzoic acid with 8 and 9 carbon atoms in aliphatic chain may be promising candidate for treatment of lung cancer.
Keywords: Cyclopentaquinoline derivatives; Acridine derivatives; Anticancer drug; Lung cancer; DNA intercalation;

Anti-diabetic properties of a non-conventional radical scavenger, as compared to pioglitazone and exendin-4, in streptozotocin-nicotinamide diabetic mice by Michela Novelli; Donatella Canistro; Manuela Martano; Niccola Funel; Andrea Sapone; Simone Melega; Matilde Masini; Vincenzo De Tata; Anna Pippa; Cecilia Vecoli; Daniela Campani; Rocco De Siena; Antonio Soleti; Moreno Paolini; Pellegrino Masiello (37-44).
We previously showed that the innovative radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) improves metabolic dysfunctions in a diabetic mouse model. Here, we compared the in vivo effects of IAC with those of the anti-diabetic drugs pioglitazone (PIO) and exendin-4 (EX-4). Diabetes was induced in C57Bl/6J mice by streptozotocin and nicotinamide administration. Paralleled by healthy controls, diabetic animals (D) were randomly assigned to four groups and treated daily for 7 consecutive weeks: D+saline, ip; D+IAC 30 mg/kg b.w., ip; D+PIO 10 mg/kg b.w. per os; and D+EX-4, 50 μg/kg b.w., ip. Our results show that IAC reduced basal hyperglycemia and improved glucose tolerance better than PIO or EX-4. Interestingly, in the heart of diabetic mice, IAC treatment normalized the increased levels of GSSG/GSH ratio and thiobarbituric acid reactive substances, indexes of oxidative stress and damage, while PIO and EX-4 were less effective. As supported by immunohistochemical data, IAC markedly prevented diabetic islet β-cell reduced density, differently from PIO and EX-4 that had only a moderate effect. Interestingly, in diabetic animals, IAC treatment enhanced the activity of pancreatic-duodenal homeobox 1 (PDX-1), an oxidative stress-sensitive transcription factor essential for maintenance of β-cell function, as evaluated by quantification of its nuclear immunostaining, whereas PIO or EX-4 treatments did not. Altogether, these observations support the improvement of the general redox balance and β-cell function induced by IAC treatment in streptozotocin-nicotinamide diabetic mice. Furthermore, in this model, the correction of diabetic alterations was better obtained by treatment with the radical scavenger IAC than with pioglitazone or exendin-4.Display Omitted
Keywords: Type 2 diabetes mellitus; Oxidative stress; Radical scavengers; PDX-1; Pioglitazone; Exendin-4;

The dual PI3K/mTOR inhibitor NVP-BEZ235 prevents epithelial–mesenchymal transition induced by hypoxia and TGF-β1 by Guanyu Lin; Renhua Gai; Zibo Chen; Yijie Wang; Sida Liao; Rong Dong; Hong Zhu; Yongchuan Gu; Qiaojun He; Bo Yang (45-53).
Epithelial–mesenchymal transition (EMT) is regarded as the most important mechanism behind the initiation of cancer metastasis. Though there has been great interest in developing therapies aimed at impairing the process of EMT, only few molecules have been identified to orchestrate it so far. Here we report that the dual PI3K/mTOR inhibitor NVP-BEZ235 is capable of preventing human ovarian cancer cell line SKOV-3 and prostatic cancer cell line PC-3 from hypoxia- and TGF-β1-induced EMT. The addition of NVP-BEZ235 reverses the EMT-like morphologic changes, down-regulation of E-cadherin, and enhancement of cell migration induced by 1% O2 partially through interfering with the expression and transcriptional activity of Hif-1α via PI3K/mTOR pathway. In addition, NVP-BEZ235 inhibits TGF-β1-induced phosphorylation of Smad2/3 and Akt/GSK-3β, reduces the expression of Snail both in transcriptional and post-translational level, and consequently prevents the repression of E-cadherin expression as well as the increase of cell motility caused by TGF-β1. Moreover, in nude mice bearing SKOV-3 ovarian cancer xenografts, NVP-BEZ235 significantly increases the mRNA level of E-cadherin. Taken together, our study demonstrates, for the first time, NVP-BEZ235 can prevent microenvironment and growth factor induced EMT, which suggests this agent as a potential candidate for cancer metastasis treatment.
Keywords: NVP-BEZ235; EMT; Hypoxia; TGF-β1; PI3K/mTOR;

Chlorogenic acid attenuates lipopolysaccharide-induced mice mastitis by suppressing TLR4-mediated NF-κB signaling pathway by Gao Ruifeng; Fu Yunhe; Wei Zhengkai; zhou Ershun; Li Yimeng; Yao Minjun; Song Xiaojing; Yang Zhengtao; Zhang Naisheng (54-58).
Chlorogenic acid (CGA), one of the most abundant polyphenols in the diet, has been reported to have potent anti-inflammatory properties. However, the effect of CGA on lipopolysaccharide (LPS)-induced mice mastitis has not been investigated. The purpose of the present study was to elucidate whether CGA could ameliorate the inflammation response in LPS-induced mice mastitis and to clarify the possible mechanism. The mouse model of mastitis was induced by injection of LPS through the duct of mammary gland. CGA was administered intraperitoneally with the dose of 12.5, 25, and 50 mg/kg respectively 1 h before and 12 h after induction of LPS. In this study, the effect of CGA on LPS-induced mice mastitis was assessed through histopathological examination, ELISA assay, and western blot analysis. The results showed that CGA significantly reduced TNF-α, IL-1β, and IL-6 production compared with LPS group. Besides, western blot analysis showed that CGA could inhibit the expression of TLR4 and the phosphorylation of NF-κB and IκB induced by LPS. These results suggested that anti-inflammatory effects of CGA against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-κB signaling pathway. Therefore, CGA may be a potent therapeutic reagent for the prevention of the immunopathology encountered during Escherichia coli elicited mastitis.
Keywords: Chlorogenic acid; LPS; Mastitis; NF-κB; TLR4; Inflammation;

Effect of linagliptin, alone and in combination with voglibose or exendin-4, on glucose control in male ZDF rats by Robert B. Jones; Steven P. Vickers; Sharon C. Cheetham; Katie R. Headland; Michael Mark; Thomas Klein (59-66).
The effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, alone and in combination with voglibose or exendin-4, on glycaemic control and body weight were assessed in an animal model of type 2 diabetes. Voglibose is an α-glucosidase inhibitor but also increases glucagon-like peptide 1 (GLP-1). Exendin-4 is a GLP-1 receptor agonist. Male Zucker Diabetic Fatty (ZDF) rats were dosed for 3 days, fasted overnight and a sucrose/glucose tolerance test was performed. Linagliptin (1 mg/kg po) improved glucose tolerance by increasing plasma GLP-1 (active) and insulin secretion, whilst having no effect on body weight. Voglibose (1 and 10 mg/kg po) reduced body weight, improved glycaemic control, reduced plasma insulin and increased total but not active GLP-1. The combination of linagliptin and voglibose significantly reduced body weight, improved glycaemic control and reduced plasma insulin compared to linagliptin alone. Furthermore, linagliptin plus voglibose produced a marked increase in GLP-1 (active) at 5 min post-sucrose, compared to linagliptin, possibly because linagliptin prevented the degradation of GLP-1 secreted in response to voglibose. Exendin-4 (10 μg/kg sc) significantly reduced body weight, improved glucose tolerance but reduced GLP-1 (active). The combination of linagliptin and exendin-4 significantly reduced body weight and improved glycaemic control but had no effect on plasma GLP-1. Overall it did not markedly improve glycaemic control compared to the individual drugs. The improved glucose control, reduced body weight and markedly increased plasma GLP-1 levels in animals given linagliptin with voglibose, suggests that this combination may be particularly beneficial in the treatment of type 2 diabetes.
Keywords: Linagliptin; Voglibose; Exendin-4; GLP-1; Glucose control; Type 2 diabetes;

Interstitial cystitis is a debilitating bladder inflammation disorder. To date, the understanding of the causes of interstitial cystitis remains largely fragmentary and there is no effective treatment available. Recent experimental results have shown a functional role of the endocannabinoid system in urinary bladder. In this study, we evaluated the anti-inflammatory effect of selective cannabinoid CB1 and CB2 receptor agonists in a mouse model of interstitial cystitis. Bladder inflammation was induced in mice by lipopolysaccharide (LPS) and whole bladders were removed 24 h later. LPS induced a significant increase of the contractile amplitude in spontaneous activity and a hypersensitivity to exogenous acetylcholine-induced contraction of whole-isolated bladder. Next, we evaluated the anti-inflammatory activity of cannabinoidergic compounds by pretreating mice with CB1 or CB2 selective agonist compounds, respectively ACEA and JWH015. Interestingly, JWH015, but not ACEA, antagonized LPS-induced bladder inflammation. Additionally, anti-inflammatory activity was studied by evaluation, leukocytes mucosa infiltration, myeloperoxidase activity, and mRNA expression of pro-inflammatory interleukin (IL-1α and IL-1β), tumor necrosis factor-alpha (TNF-α) and cannabinoid CB1 and CB2 receptors. JWH015 significantly decreased leukocytes infiltration in both submucosa and mucosa, as well as the myeloperoxydase activity, in LPS treated mice. JWH015 reduced mRNA expression of IL-1α, IL-1β, and TNF-α. LPS treatment increased expression of bladder CB2 but not CB1 mRNA. Taken together, these findings strongly suggest that modulation of the cannabinoid CB2 receptors might be a promising therapeutic strategy for the treatment of bladder diseases and conditions characterized by inflammation, such as interstitial cystitis.Display Omitted
Keywords: Intestitial cystitis; JWH015; Isolated bladder assay; Mast cells; Leukocytes infiltration; Myeloperoxidase activity;

Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists by Laura Ajram; Malcolm Begg; Robert Slack; Jenni Cryan; David Hall; Simon Hodgson; Alison Ford; Ashley Barnes; Dawid Swieboda; Aurelie Mousnier; Roberto Solari (75-85).
The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to β-arrestin and stimulated GTPγS binding however CCL17 did not couple to β-arrestin and only partially stimulated GTPγS binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target.
Keywords: Chemokine; CCR4; MDC; TARC; CCL22; CCL17;

Effects of acute and chronic administration of venlafaxine and desipramine on extracellular monoamine levels in the mouse prefrontal cortex and striatum by Kosuke Higashino; Yukio Ago; Masato Umehara; Yuki Kita; Kazumi Fujita; Kazuhiro Takuma; Toshio Matsuda (86-93).
Prefrontal catecholamine neurotransmission plays a key role in the therapeutic actions of drugs for attention-deficit/hyperactivity disorder (ADHD). We have recently shown that serotonin/noradrenaline reuptake inhibitors and the noradrenaline reuptake inhibitor desipramine attenuated horizontal hyperactivity in spontaneously hypertensive rats, an animal model of ADHD, and that these drugs are potential pharmacotherapeutics for ADHD. In this study, we used in vivo microdialysis to study the effects of acute and chronic (once daily for 3 weeks) administration of the serotonin/noradrenaline reuptake inhibitor venlafaxine and the noradrenaline reuptake inhibitor desipramine on noradrenaline, dopamine, and serotonin levels, and the expression of the neuronal activity marker c-Fos in the mouse prefrontal cortex and striatum. Both acute and chronic venlafaxine administration increased prefrontal noradrenaline, dopamine, and serotonin levels and striatal noradrenaline and serotonin levels. Both acute and chronic desipramine administration increased prefrontal noradrenaline and dopamine levels and striatal noradrenaline levels, with chronic administration yielding stronger increase. Chronic desipramine did not affect striatal dopamine and serotonin levels. Both acute and chronic venlafaxine administration increased the expression of c-Fos in the prefrontal cortex, whereas chronic, but not acute, desipramine administration increased the expression of c-Fos in the prefrontal cortex. Both acute and chronic venlafaxine administration increased the striatal c-Fos expression to some degree, whereas desipramine administration did not. These results suggest that acute and chronic venlafaxine and chronic desipramine administration maximally activate the prefrontal adrenergic and dopaminergic systems without affecting striatal dopaminergic systems in mice.
Keywords: Venlafaxine; Desipramine; Attention-deficit/hyperactivity disorder (ADHD); Noradrenaline; Dopamine; Mouse;

Exogenous administration of spermine improves glucose utilization and decreases bodyweight in mice by Satish Kumar Sadasivan; Balamuralikrishna Vasamsetti; Jaideep Singh; Venkataranganna V. Marikunte; Anup Mammen Oommen; M.R. Jagannath; Raghavendra Pralhada Rao (94-99).
Polyamines are highly charged low molecular weight aliphatic polycations and are ubiquitously present in all living cells. In addition to their previously reported role in cell proliferation and cancer, recent studies support their role in energy homeostasis and glucose metabolism. In the present study we have evaluated a polyamine—spermine for its effect on glycemic, lipid and body weight parameters. High fat diet induced obese mice (6 week old male C57B6/J mice fed on high fat diet for 22 weeks) were dosed with spermine intraperitoneally at two different doses (5 mg/kg and 10 mg/kg body weight) for 4 weeks and its effect on body weight, glycemic and lipid parameters was monitored. We found that at a dose of 10 mg/kg bodyweight, spermine treatment resulted in a 24% reduction in the body weight and 18% reduction in the fasting glucose compared to untreated controls. Besides, spermine treated mice exhibited improved glucose utilization associated with improved fat oxidation and loss of white adipose mass. Our study is promising in the direction of exploring the spermine and their analogs for treatment of metabolic syndrome.
Keywords: Spermine; Polyamines; Obesity; Metabolic disorder; Diabetes; Body weight;

Cannabinoids are key regulators of vascular tone, some of the mechanisms involved include the activation of cannabinoid receptor types 1 and 2 (CB); the transient receptor potential cation channel, subfamily V, member 1 (TRPV1); and non-(CB1)/non-CB2 receptors. Here, we used the potent, selective CB1 agonist arachidonylcyclopropylamide (ACPA) to elucidate the mechanism underlying vascular tone regulation. Immunohistochemistry and confocal microscopy revealed that CB1 was expressed in smooth muscle and endothelial cells in rat aorta. We performed isometric tension recordings in aortic rings that had been pre-contracted with phenylephrine. In these conditions, ACPA caused vasorelaxation in an endothelium-independent manner. To confirm that the effect of ACPA was mediated by CB1 receptor, we repeated the experiment after blocking these receptors with a selective antagonist, AM281. In these conditions, ACPA did not cause vasorelaxation. We explored the role of K+ channels in the effect of ACPA by applying high-K+ solution to induce contraction in aortic rings. In these conditions, the ACPA-induced vasorelaxation was about half that observed with phenylephrine-induced contraction. Thus, K+ channels were involved in the ACPA effect. Furthermore, the vasorelaxation effect was similarly reduced when we specifically blocked calcium-activated potassium channel subunit alpha-1 (KCa1.1) (MaxiK; BKCa) prior to adding ACPA. Finally, ACPA-induced vasorelaxation was also diminished when we specifically blocked the calcium channel, voltage-dependent, L type, alpha 1C subunit (Cav1.2). These results showed that ACPA activation of CB1 in smooth muscle caused vasorelaxation of aortic rings through a mechanism involving the activation of KCa1.1 and the inhibition of Cav1.2.
Keywords: CB1 receptors; Cannabinoids; ACPA; Aorta; MaxiK channels; Ca2+ channels;

1,2,3,4-Tetrahydroisoquinoline produces an antidepressant-like effect in the forced swim test and chronic mild stress model of depression in the rat: Neurochemical correlates by Edyta Możdżeń; Mariusz Papp; Piotr Gruca; Agnieszka Wąsik; Irena Romańska; Jerzy Michaluk; Lucyna Antkiewicz-Michaluk (107-115).
1,2,3,4-Tetrahydroisoquinoline (TIQ) is an exo- and endogenous amine naturally present in mammalian brain which displays antidepressant-like effect in various animal models: the forced swim test (FST) and chronic mild stress (CMS) paradigm in rats. To elucidate this action we compared the effects of TIQ with imipramine, a classic antidepressant drug and one of the most clinically effective. Applied behavioral tests showed that TIQ produced an antidepressant-like effect with a potency comparable to that of imipramine. TIQ (25–50 mg/kg i.p.), similarly to imipramine (10–30 mg/kg i.p.), reduced the immobility time in FST and completely reversed the decrease in sucrose intake caused by CMS in the rat. In addition, in order to avoid the possible psychostimulating effect of TIQ we examined the influence of its administration on locomotor activity in rats. TIQ, like imipramine, produced a reduction in horizontal locomotor activity. This suggested that TIQ did not have psychostimulant properties and that prolonged swimming in the FST was a result of an increased motivation to escape from the stressful situation. The biochemical analyses have shown that TIQ activates monoaminergic systems as a reversible monoamine oxidase (MAO) inhibitor and free radical scavenger. Beyond the activation of noradrenaline and serotonin systems, TIQ also moderately affects the dopamine system. On the basis of the presented behavioral and biochemical studies we suggest that TIQ is a potential new antidepressant which may be effective for the depression therapy in a clinical setting.
Keywords: 1,2,3,4-Tetrahydroisoquinoline; Forced swimming test; Chronic mild stress; Models of depression; Imipramine; Metabolism of monoamines; Rat brain;

Synergistic efficacy of meropenem and rifampicin in a murine model of sepsis caused by multidrug-resistant Acinetobacter baumannii by Yuan Sun; Lei Wang; Jiankang Li; Chongbo Zhao; Jinyi Zhao; Meiyou Liu; Shan Wang; Chengtao Lu; Gangwei Shang; Yanyan Jia; Aidong Wen (116-122).
Multidrug-resistant Acinetobacter baumannii becomes an increasing challenge due to the overuse of antibiotics. Combination therapies are considered as effective options to overcome this matter. The present study was to investigate the synergistic activity of meropenem combined with other antibiotics in vitro and in vivo. Checkerboard assay and time-kill assay were performed to study the combination effects in vitro. For the animal model, a murine sepsis model injected with inoculums intraperitoneally was used. Susceptibility test showed that all the twelve strains in this study were resistant to most of the antibiotics except rifampicin. In combination, meropenem plus rifampicin exhibited synergistic activity against six of twelve strains. In the sepsis model, meropenem monotherapy had no therapeutic effect in this model while it can enhance the activity of rifampicin in both survival rate and bacterial clearance from blood. Moreover, combination therapy significantly reduced plasma IL-6 levels compared with rifampicin monotherapy. Pharmacokinetic analysis of rifampicin was also performed in this study. These data above showed that there was synergistic activity between meropenem and rifampicin against multidrug-resistant Acinetobacter baumannii both in vitro and for experimental model of sepsis. It suggested that combining meropenem with rifampicin may be appropriate in treating multidrug-resistant Acinetobacter baumannii infections.
Keywords: Acinetobacter baumannii; Meropenem; Rifampicin; Murine sepsis model; Combination;

Effects of dopamine D2-like receptor agonists in mice trained to discriminate cocaine from saline: Influence of feeding condition by Gregory T. Collins; Jonathan A. Jackson; Wouter Koek; Charles P. France (123-131).
In rats, the discriminative stimulus effects of direct- and indirect-acting dopamine receptor agonists are mediated by multiple dopamine receptor subtypes and the relative contribution of dopamine D2 and D3 receptors to these effects varies as a function of feeding condition. In these studies, free-fed and food-restricted mice were trained to discriminate 10.0 mg/kg cocaine using a two-lever discrimination procedure in which responding was maintained by food. Both groups of mice acquired the discrimination; however, free-fed mice responded at lower rates than food-restricted mice. Dopamine D3 receptor agonists, pramipexole and quinpirole, increased cocaine-appropriate responding (>85%) in food-restricted, but not in free-fed mice. The dopamine D2 receptor agonist, sumanirole, and the nonselective dopamine receptor agonist, apomorphine, failed to increase cocaine-appropriate responding in either group. Free-fed mice were more sensitive than food-restricted mice to the rate-decreasing effects of dopamine receptor agonists and these effects could not be overcome by increasing the magnitude of reinforcement. Because feeding condition did not alter quinpirole-induced hypothermia, it is unlikely that differences in the discriminative stimulus or rate-decreasing effects of dopamine D2-like receptor agonists were due to differences in the pharmacokinetic properties of the drugs. Although these results suggest that the discriminative stimulus effects of cocaine are mediated by both dopamine D2 and D3 receptors in food-restricted mice, the increased sensitivity of free-fed mice to the rate-decreasing effects of dopamine D2-like receptor agonists limited conclusions about the impact of feeding conditions on the relative contribution of dopamine D2 and D3 receptors to the discriminative stimulus effects of cocaine.
Keywords: Mice; Cocaine; Drug discrimination; Dopamine D2 receptors; Dopamine D3 receptors; Free-feeding; Food-restriction;

Metabolomic evaluation of the response to endocrine therapy in patients with prostate cancer by Gang Huang; Xinru Liu; Li Jiao; Chuanliang Xu; Zhongxiao Zhang; Linhui Wang; Yun Li; Chun Yang; Weidong Zhang; Yinghao Sun (132-137).
Timely evaluation of the response to endocrine therapy in patients with prostate cancer (PCa) may optimize treatment regimens and improve long-term prognosis. We used the liquid chromatography–mass spectrometry (LC–MS)-based metabolomic technique to identify serum biomarkers indicative of disease progression and therapeutic benefit.The mean serum levels of seven metabolites, including deoxycholic acid (DCA), glycochenodeoxycholate (GCDC), l-tryptophan, docosapentaenoic acid (DPA), arachidonic acid, deoxycytidine triphosphate, and pyridinoline, differed significantly between untreated PCa patients and healthy controls. In patients who did not develop castration-resistant prostate cancer (CRPC) for at least 2 years (good responders), these metabolite levels reverted to near healthy control levels during endocrine therapy. In contrast, the metabolite levels remained abnormal in patients who developed CRPC within 1 year (poorly responsive patients). Three of these biomarkers (DCA, GCDC, and DPA) are mainly involved in cholesterol metabolism, underscoring the importance of elevated cholesterol to PCa progression. These metabolites may serve as predictive biomarkers for assessing the therapeutic response of PCa patients to endocrine therapy.Display Omitted
Keywords: Prostate cancer; Endocrine therapy; Metabolomics; DCA; GCDC; DPA;

Arginine NO-dependent and NO-independent effects on hemodynamics by Jorge Guridi; Conrado Borgatello; Oscar U. Scremin (138-143).
l-arginine administration decreases mean arterial blood pressure (MABP), presumably by excess nitric oxide (NO) synthesis. However, some reports indicate that d-arginine, not a substrate of NO synthase (NOS), also induces hypotension. To clarify this phenomenon, the hemodynamic effects of l- and d-arginine and their modification by NOS inhibition with l-nitroarginine methyl ester (l-NAME) were assessed. MABP, cardiac output, stroke volume, heart rate and systemic vascular resistance were recorded in Sprague-Dawley rats under urethane or ketamine/diazepam anesthesia, with or without blockade of NO synthesis by l-NAME. Both stereoisomers of arginine induced a dose-related drop in MABP of similar magnitude and time course, but recovery from hypotension was slower in l-arginine than in d-arginine. The hypotension induced by both stereoisomers was due to a decrease in systemic vascular resistance (SVR) with increase in cardiac output (CO) and stroke volume (SV). Administration of l-NAME induced a pronounced increase in MABP and SVR, with decreases in CO and heart rate (HR). Infusion of l-arginine after l-NAME significantly decreased MABP and SVR at the highest dose while d-arginine failed to do so. After l-NAME, MABP was significantly lower under l-arginine than under d-arginine at all doses. These experiments suggest a dual mechanism in the hypotensive effect of l-arginine: a NO independent action on vascular resistance shared with d-arginine, and a NO dependent mechanism that becomes evident in the presence of NOS inhibition with l-NAME. Cardiac effects of NO do not appear to play a role in l-arginine hypotension.
Keywords: l-NAME; Nitric oxide synthase; Arterial blood pressure; Cardiac output; Systemic vascular resistance;

Retinoid signaling in pathological remodeling related to cardiovascular disease by Daisuke Kotake; Taiki Sato; Noriyasu Hirasawa (144-147).
Retinoids, the active derivatives of vitamin A, are critical signaling molecules in crucial biological processes such as embryonic development, the maintenance of immune function, and cellular differentiation and proliferation. Preclinical studies have shown that retinoids also regulate morphological changes during the progression of cardiovascular disease (CVD). CVD is complexly formed in a mutual chain reaction of various modern lifestyle-related risk factors such as dyslipidemia, hypertension, diabetes, and obesity. These factors induce the pathological remodeling of adipose tissue, the vasculature, and the ventricles, which are a potential target for retinoid signaling. This perspective highlights emerging topics and future prospectives on the relationship between CVD and retinoid signaling.
Keywords: Retinoid; RAR; RXR; Cardiovascular disease; Remodeling;