BMC Pharmacology - Latest articles

RU486 did not exacerbate cytokine release in mice challenged with LPS nor in db/db mice

2008-05-12

Background: Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerbation have limited the development and clinical use of GR antagonists in the treatment of diabetes and depression. We investigated the effects of RU486 on serum cytokines in db/db mice and on lipopolysaccharide (LPS)-induced circulating TNFalpha levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice. Results: Chronic treatment of db/db mice with RU486 dose-dependently decreased blood glucose, increased serum corticosterone and ACTH, but did not affect serum MCP-1 and IL-6 levels. LPS dose-dependently increased serum TNFalpha in both AKR and C57BL/6 DIO mice, along with increased circulating corticosterone and ACTH. Pretreatment of the mice with RU486 dose-dependently suppressed the LPS induced increases in serum TNFalpha and further increased serum corticosterone. Conclusions: RU486 at doses that were efficacious in lowering blood glucose did not exacerbate cytokine release in these three mouse models. RU486 actually suppressed the lower dose LPS-mediated TNFalpha release, possibly due to the increased release of glucocorticoids.

Antidepressant drugs modulate growth factors in cultured cells

2008-03-04

Background: Different classes of antidepressant drugs are used as a treatment for depression by activating the catecholinergic system. In addition, depression has been associated with decrease of growth factors, which causes insufficient axonal sprouting and reduced neuronal damage repair. In this study, antidepressant treatments are analyzed in a cell culture system, to study the modulation of growth factors. Results: We quantified the transcription of several growth factors in three cell lines after application of antidepressant drugs by real time polymerase chain reaction. Antidepressant drugs counteracted against phorbolester-induced deregulation of growth factors in PMA-differentiated neuronal SY5Y cells. We also found indications in a pilot experiment that magnetic stimulation could possibly modify BDNF in the cell culture system. Conclusion: The antidepressant effects antidepressant drugs might be explained by selective modulation of growth factors, which subsequently affects neuronal plasticity.

A global view of drug-therapy interactions

Jose C Nacher and Jean-Marc Schwartz — 2008-03-04

Background: Network science is already making an impact on the study of complex systems and offers a promising variety of tools to understand their formation and evolution in many disparate fields from technological networks to biological systems. Even though new high-throughput technologies have rapidly been generating large amounts of genomic data, drug design has not followed the same development, and it is still complicated and expensive to develop new single-target drugs. Nevertheless, recent approaches suggest that multi-target drug design combined with a network-dependent approach and large-scale systems-oriented strategies create a promising framework to combat complex multi-genetic disorders like cancer or diabetes. Results: We here investigate the human network corresponding to the interactions between all US approved drugs and human therapies, defined by known relationships between drugs and their therapeutic applications. Our results show that the average paths in this drug-therapy network are shorter than three steps, indicating that distant therapies are separated by a surprisingly low number of chemical compounds. We also identify a sub-network composed by drugs with high centrality measures in the drug-therapy network, which represent the structural backbone of this system and act as hubs routing information between distant parts of the network. Conclusion: These findings provide for the first time a global map of the large-scale organization of all known drugs and associated therapies, bringing new insights on possible strategies for future drug development. Special attention should be given to drugs which combine the two properties of (a) having a high centrality value in the drug-therapy network and (b) acting on multiple molecular targets in the human system.

Role of sulphated polysaccharides from Sargassum Wightii in Cyclosporine A-induced oxidative liver injury in rats

2008-02-20

Background: Seaweeds or marine algae have long been made up a key part of the Asian diet, and as an antioxidant, sulphated polysaccharides have piqued the interest of many researchers as one of the ocean's greatest treasures. The present investigation suggests the therapeutic potential of sulphated polysaccharides from marine brown algae "Sargassum wightii" in Cyclosporine A (CsA)- induced liver injury. CsA is a potent immunosuppressive agent used in the field of organ transplantations and various autoimmune disorders. However, hepatotoxicity due to CsA remains to be one of the major clinical challenges. Methods: The effect of sulphated polysaccharides on CsA-induced hepatotoxicity was studied in adult male albino rats of Wistar strain, and the animals were randomized into four groups with six rats in each. Group I served as vehicle control. Group II rats were given CsA at a dosage of 25 mg/kg body weight, orally for 21 days. Group III rats were given sulphated polysaccharides at a dosage of 5 mg/kg body weight, subcutaneously for 21 days. Group IV rats were given sulphated polysaccharides simultaneously along with CsA, as mentioned in Group II for 21 days. Results: CsA provoked hepatotoxicity was evident from the decreased activities of hepatic marker enzymes. A significant rise in the level of oxidants, along with a striking decline in both the enzymic and non-enzymic antioxidants, marks the severity of oxidative stress in CsA-induced rats. This in turn led to enhanced levels of lipid peroxidation, 8-hydroxy-2-deoxy guanosine and protein carbonyls, along with a decrease in ATPase activities and alterations in lipid profile. Histopathological changes also strongly support the above aberrations. However, concomitant treatment with sulphated polysaccharides restored the above deformities to near control and prevented the morphological alterations significantly. Conclusion: Thus, the present study highlights that sulphated polysaccharides can act therapeutically against CsA-induced hepatotoxicity.Key WordsCyclosporine A; hepatic markers; antioxidants; hyperlipidemia; macromolecules; sulphated polysaccharides.

Inhibition of 11βHSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice

2008-02-12

Background: A substantial body of evidence indicates that reduced plasma adiponectin levels may be key in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. Glucocorticoids decrease the levels of adiponectin in animals and humans. Cortisone is transformed to its active form cortisol, via 11β-hydroxysteroid dehydrogenase (HSD) type 1. This study sought to ascertain if inhibition of 11β HSD1 with a new selective inhibitor, BVT116429, affects the concentrations of circulating adiponectin with concomitant effects on glucose homeostasis in diabetic mice. Results: KKAy mice were treated with BVT116429 (3, 10, 30 mg/kg), rosiglitazone (5 mg/kg) or vehicle once daily for ten days. Plasma adiponectin levels rose in mice treated with BVT116429 and this was found to be both the hexameric and the high molecular weight multimeric forms of adiponectin. Seven days of treatment with the 11β HSD1-inhibitor BVT116429 decreased basal insulin levels but no changes in glucose tolerance were seen. After ten days of treatment, fasting blood glucose level was decreased by BVT116429 comparable to the effects of rosiglitazone. Another 11β HSD1 inhibitor, BVT2733, improved HbA1c but had no effect on adiponectin. Conclusion: Inhibition of 11β HSD1 can be expected to be beneficial for treating the pathology of type 2 diabetes mellitus. The differences seen in adiponectin between BVT116429 and BVT2733 could be explained by different pharmacodynamics exerted by the compounds in different tissues in the body. Increases in adiponectin concentrations may be an integral component in the mechanism of action of this new11β HSD1 inhibitor and may be a useful marker of efficacy during the clinical development of 11β HSD1 inhibitor compounds.

Comparative study of the antimutagenic properties of vitamins C and E against mutation induced by norfloxacin

2008-02-11

Background: Norfloxacin like other fluoroquinolones, is known to be mutagenic for Salmonella typhimurium TA102 strain. This mutagenic effect is due to free oxygen radicals (ROS), because it is inhibited by antioxidants such as β-carotene and naturally occurring antioxidants of Roheo discolor and other plants. The aim of this work was to evaluate combination therapy with norfloxacin and vitamins C and E, to reduce the possible genotoxic risk associated with fluoroquinolones.MethodThe antimutagenicity of α-tocoferol (Vitamin E) and ascorbic acid (Vitamin C) against norfloxacin-induced mutation was evaluated on S. typhimurium TA102, using the aroclor-1254-induced S9 rat liver homogenate. The minimum inhibitory concentration (MIC) a measure of the bactericidal effect of norfloxacin, was obtained in vitro by the plate dilution method. Results: Vitamin E (0.5 mg per Petri dish) induced a statistically significant reduction (P < 0.001) in the mutagenicity of norfloxacin, whereas Vitamin C (1 mg per Petri dish) had no such effect. Neither of these vitamins altered the MIC for norfloxacin against 25 uropathogenic strains of Escherichia coli. Conclusion: These results suggest that Vitamin E is a potent antimutagen that would be worthwhile being used in conjunction with fluoroquinolone treatment. The minimal antimutagenic effect of Vitamin C observed under these experimental conditions may have been because Vitamin C in the Ames test induces a Fenton reaction, and if divalent cations are present, it can act as a pro-oxidant rather than an antioxidant. Ascorbic acid should be further evaluated in the presence of different divalent cations concentrations.

Dicholine salt of succinic acid, a neuronal insulin sensitizer, ameliorates cognitive deficits in rodent models of normal aging, chronic cerebral hypoperfusion, and beta-amyloid peptide-(25–35)-induced amnesia

2008-01-23

Background: Accumulated evidence suggests that insulin resistance and impairments in cerebral insulin receptor signaling may contribute to age-related cognitive deficits and Alzheimer's disease. The enhancement of insulin receptor signaling is, therefore, a promising strategy for the treatment of age-related cognitive disorders. The mitochondrial respiratory chain, being involved in insulin-stimulated H2O2 production, has been identified recently as a potential target for the enhancement of insulin signaling. The aim of the present study is to examine: (1) whether a specific respiratory substrate, dicholine salt of succinic acid (CS), can enhance insulin-stimulated insulin receptor autophosphorylation in neurons, and (2) whether CS can ameliorate cognitive deficits of various origins in animal models. Results: In a primary culture of cerebellar granule neurons, CS significantly enhanced insulin-stimulated insulin receptor autophosphorylation. In animal models, CS significantly ameliorated cognitive deficits, when administered intraperitoneally for 7 days. In 16-month-old middle-aged C57Bl/6 mice (a model of normal aging), CS enhanced spatial learning in the Morris water maze, spontaneous locomotor activity, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to the age-matched control (saline). In rats with chronic cerebral hypoperfusion, CS enhanced spatial learning, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to control rats (saline). In rats with beta-amyloid peptide-(25–35)-induced amnesia, CS enhanced passive avoidance performance and increased activity of brain choline acetyltransferase, as compared to control rats (saline). In all used models, CS effects lasted beyond the seven-day treatment period and were found to be significant about two weeks following the treatment. Conclusion: The results of the present study suggest that dicholine salt of succinic acid, a novel neuronal insulin sensitizer, ameliorates cognitive deficits and neuronal dysfunctions in animal models relevant to age-related cognitive impairments, vascular dementia, and Alzheimer's disease.

The presence of β2-adrenoceptors sensitizes α2A-adrenoceptors to desensitization after chronic epinephrine treatment

2007-12-20

Background: In addition to the regulation of blood pressure, α2- and β-adrenoceptor (AR) subtypes play an important role in the modulation of noradrenergic neurotransmission in the human CNS and PNS. Several studies suggest that the α2-AR responsiveness in cells and tissues after chronic epinephrine (EPI) or norepinephrine (NE) exposure may vary, depending on the β-AR activity present there. Recently, we reported that in BE(2)-C human neuroblastoma cells (endogenously expressing α2A- and β2-AR), chronic EPI treatment (300 nM) produced a dramatic β-adrenoceptor-dependent desensitization of the α2A-AR response. The aim of this study is to determine if stable addition of a β2-AR to a second neuroblastoma cell line (SH-SY5Y), that normally expresses only α2A-ARs that are not sensitive to 300 nM EPI exposure, would suddenly render α2A-ARs in that cell line sensitive to treatment with the same EPI concentration. Methods: These studies employed RT-PCR, receptor binding and inhibition of cAMP accumulation to confirm α2-AR subtype expression. Stable clones of SH-SY5Y cells transfected to stably express functional β2-ARs (SHβ2AR4) were selected to compare sensitivity of α2-AR to EPI in the presence or absence of β2-ARs. Results: A series of molecular, biochemical and pharmacological studies indicated that the difference between the cell lines could not be attributed to α2-AR heterogeneity. We now report that after transfection of functional β2-AR into SH-SY5Y cells (SHβ2AR4), chronic treatment with modest levels of EPI desensitizes the α2A-AR. This effect results from a β2-AR dependent down-regulation of native α2A-ARs by EPI accompanied by enhanced translocation of GRK2 and GRK3 to the membrane (required for GRK-mediated phosphorylation of agonist-occupied receptors). Conclusion: This study further supports the hypothesis that the presence of the β-AR renders the α2A-AR more susceptible to desensitization with physiological levels of EPI.

Chlorin e6 – polyvinylpyrrolidone mediated photosensitization is effective against human non-small cell lung carcinoma compared to small cell lung carcinoma xenografts

William WL Chin, Paul WS Heng and Malini Olivo — 2007-12-01

Background: Photodynamic therapy (PDT) is an effective local cancer treatment that involves light activation of a photosensitizer, resulting in oxygen-dependent, free radical-mediated cell death. Little is known about the comparative efficacy of PDT in treating non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), despite ongoing clinical trials treating lung cancers. The present study evaluated the potential use of chlorin e6 – polyvinylpyrrolidone (Ce6-PVP) as a multimodality photosensitizer for fluorescence detection and photodynamic therapy (PDT) on NSCLC and SCLC xenografts. Results: Human NSCLC (NCI-H460) and SCLC (NCI-H526) tumor cell lines were used to establish tumor xenografts in the chick chorioallantoic membrane (CAM) model as well as in the Balb/c nude mice. In the CAM model, Ce6-PVP was applied topically (1.0 mg/kg) and fluorescence intensity was charted at various time points. Tumor-bearing mice were given intravenous administration of Ce6-PVP (2.0 mg/kg) and laser irradiation at 665 nm (fluence of 150 J/cm2 and fluence rate of 125 mW/cm2). Tumor response was evaluated at 48 h post PDT. Studies of temporal fluorescence pharmacokinetics in CAM tumor xenografts showed that Ce6-PVP has a selective localization and a good accuracy in demarcating NSCLC compared to SCLC from normal surrounding CAM after 3 h post drug administration. Irradiation at 3 h drug-light interval showed greater tumor necrosis against human NSCLC xenografts in nude mice. SCLC xenografts were observed to express resistance to photosensitization with Ce6-PVP. Conclusion: The formulation of Ce6-PVP is distinctly advantageous as a diagnostic and therapeutic agent for fluorescence diagnosis and PDT of NSCLC.

Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779

Michael P Messina, Aubrey Rauktys, Laifong Lee and Sandra L Dabora — 2007-11-06

Background: Tuberous Sclerosis Complex (TSC) is an autosomal dominant hamartoma disorder with variable expression for which treatment options are limited. TSC is caused by a mutation in either the TSC1 or TSC2 genes, whose products, hamartin and tuberin, function as negative regulators in the highly-conserved mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin (also known as sirolimus), an mTOR inhibitor, has been shown to reduce disease severity in rodent models of TSC and is currently being evaluated in clinical trials in human populations. The cytokine interferon-gamma (IFN-γ) is also a potential therapeutic agent for TSC. A high-expressing IFN-γ allele has been associated with reduced disease severity in human TSC patients and it has been shown in mouse models that treatment with exogenous IFN-γ reduces disease severity. Results: Here, we examine the effects of treating Tsc2+/- mice at different time points with a rapamycin analog (CCI-779) as a single agent or with a combination of CCI-779 and IFN-γ. We observed that administering a short course of CCI-779 or CCI-779 plus IFN-γ reduced the severity of kidney lesions if administered after such lesions develop. As long as treatment is given after lesions arise, altering the time period during which treatment was given did not significantly impact the effect of the treatment on disease severity. We did not observe a significant benefit of combination therapy relative to treatment with a rapamycin analog alone in Tsc2+/- mice. We also compared timing of treatment and two mTOR inhibitors (rapamycin and CCI-779) in nude mice bearing Tsc2-/- tumors. Conclusion: Preventing the genesis of TSC-related kidney lesions in Tsc2+/- mice is not an effective treatment strategy; rather, the presence of growing tumors appears to be the most important factor when determining an appropriate treatment schedule. Treatment with rapamycin was more effective in reducing tumor growth and improving survival in nude mice bearing Tsc2-/- tumors and also resulted in higher rapamycin levels in blood, brain, and kidney tissue than treatment with an equal milligram dose of CCI-779. We anticipate these results will influence future preclinical and clinical trials for TSC.