MH_dev_237

A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl - extrusion in osteoclasts . DB09152 - containing bisphosphonates have been well known to be inhibited farnesyl diphosphate synthase ( P14324 REA ) , an enzyme in mevalonic acid metabolism , resulting in disturbance in polymerization of cytoskeleton structure in bone resorption and promotion of apoptosis in mature osteoclasts . Although bisphosphonates have been reported to activate ion transporters in native epithelium and Xenopus oocytes , little is known whether bisphosphonates affect acid hydrochronic acid extrusion in osteoclasts during bone resorption . The aim of this study was to determine the role of bisphosphonates on inhibition of hydrochronic acid extrusion in osteoclasts . Effects of zoledronic acid , a nitrogen-containing bisphosphonate , on the Cl ( - ) current activated by extracellular acidification were examined in two types of osteoclasts derived from RAW 264.7 cells and mouse bone marrow macrophages ( BMMs ) . Extracellular acidification induced outwardly rectifying Cl ( - ) currents in mouse osteoclasts . DB00399 MEN dose-dependently inhibited the acid-activated Cl ( - ) current . The non-nitrogen bisphosphonate etidronic acid had no effect on the acid-activated Cl ( - ) current . DB00759 - induced P14324 REA silencing caused a significant decrease in the Cl ( - ) current . The inhibitor of geranylgeranyl transferase suppressed the Cl ( - ) current . By contrast , the inhibitory action of zoledronic acid was rescued by addition of geranylgeranyl acid , a derivative of mevalonic acid . The activity of acid-activated Cl ( - ) currents was dependent on expression of P51798 REA during osteoclastogenesis . These results suggest that nitrogen-containing bisphosphonates suppress the activity of osteoclastic acid-activated Cl ( - ) currents through P14324 REA inhibition , suggesting the inhibition of Cl ( - ) extrusion activity .

New-generation Q13639 REA receptor agonists : potential for treatment of gastrointestinal motility disorders . IMPORTANCE OF THE FIELD : Gastrointestinal ( GI ) dysmotility is an important mechanism in functional GI disorders ( FGIDs ) including constipation , irritable bowel syndrome , functional dyspepsia , and gastroparesis . 5 - hydroxytryptamine ( 4 ) ( 5 - HT ( 4 ) ) receptors are targets for the treatment of GI motility disorders . However , older 5 - HT ( 4 ) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac Q12809 REA potassium channel . AREAS COVERED IN THIS REVIEW : We conducted a PubMed search using the following key words alone or in combination : 5 - HT ( 4 ) , safety , toxicity , pharmacokinetics , pharmacodynamics , clinical trial , cardiac , hERG , arrhythmia , potassium current , elderly , prucalopride , ATI - 7505 , and velusetrag ( DB05655 MEN ) , to review mechanisms of action , clinical efficacy , safety and tolerability of three new-generation 5 - HT ( 4 ) receptor agonists . WHAT THE READER WILL GAIN : DB06480 , ATI - 7505 , and velusetrag ( DB05655 MEN ) are highly selective , high-affinity 5 - HT ( 4 ) receptor agonists that are devoid of action on other receptors within their therapeutic range . Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and , to a variable degree , in clinical trials that significantly relieve chronic constipation . Currently available evidence shows that the new 5 - HT ( 4 ) receptor agonists have safe cardiac profiles . TAKE HOME MESSAGE : New-generation 5 - HT ( 4 ) receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility , particularly colonic diseases .

[ Serotonin transporter gene and stress reactivity in unipolar depression . Role of the Q9Y251 REA system as endophenotype of the P31645 REA gene ] . BACKGROUND : A length polymorphism in the promoter region of the serotonin transporter gene ( 5 - HTTLPR ) is associated with both depression and hypothalamic-pituitary-adrenal ( Q9Y251 REA ) system activity . A dysregulation of the Q9Y251 REA system is considered to be a candidate endophenotype of depression . The objective of the present study was an investigation of a possible gene-endophenotype-interaction between 5 - HTTLPR and Q9Y251 REA system activity in a sample of inpatients with major depression . MATERIALS AND METHODS : A total of 237 inpatients with major depression were genotyped for 5 - HTTLPR and participated in a combined dexamethasone-corticotropin-releasing hormone test ( DB00514 SUB - P06850 REA test ) as well as using the Hamilton score ( Hamilton rating scale for depression ) to determine the severity of the psychopathology . RESULTS : Patients with the ss-genotype showed a significantly higher Q9Y251 REA - system activity in comparison to patients with the lI-genotype , but no association between 5 - HTTLPR and the severity of psychopathology could be detected . CONCLUSIONS : The results of the current study demonstrate an influence of 5 - HTTLPR on dysregulation of the Q9Y251 REA system in patients with major depression and support the hypothesis that 5 - HTTLPR - and Q9Y251 REA - system-interaction constitutes an important component in the pathogenesis of depression .

Identification of a potential molecular link between the glucocorticoid and serotonergic signaling systems . P04150 REA ( GR ) and serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) signaling systems play a pivotal role in the regulation of the hypothalamic-pituitary-adrenal ( Q9Y251 REA ) axis , but the molecular nature of interactions between these two systems remain largely unidentified . We used computational and experimental approaches to evaluate if DNA-protein interactions would provide a molecular link for the interaction between 5 - HT and GR systems . Bioinformatic analysis identified nine binding sites in various serotonin receptors ( P28221 REA , P30939 REA , P28223 REA , P46098 REA , and P50406 REA ) for transcription factors in the GR family . Electrophoretic mobility shift assays ( EMSA ) using HeLa nuclear extract and purified full-length GR verified most of the predicted DNA-protein interactions . Six binding sites verified by EMSA results were evolutionarily conserved in multiple species . Multiple lines of evidence from computational and experimental analyses in this study support the potential of a molecular link between 5 - HT and GR signaling systems . This finding provides new approaches to studies directed at mechanisms for glucocorticoid negative feedback regulation of the Q9Y251 REA axis involving 5 - HT and interventional studies directed to neuropsychiatric diseases .

DB01892 MEN is a dual inhibitor of cyclooxygenase - 1 and P09917 REA . The acylphloroglucinol derivative hyperforin is the major lipophilic constituent in the herb Hypericum perforatum ( St . John ' s wort ) . The aim of the present study was to investigate if hyperforin as well as extracts of H . perforatum can suppresses the activities of P09917 REA ( P09917 REA ) and cyclooxygenases ( P36551 REA ) , key enzymes in the formation of proinflammatory eicosanoids from arachidonic acid ( AA ) . In freshly isolated human polymorphonuclear leukocytes stimulated with Ca ( 2 + ) ionophore A23187 , hyperforin inhibited P09917 REA product formation with IC ( 50 ) values of about 1-2 microM , in the absence or presence of exogenous AA ( 20 microM ) , respectively , being almost equipotent to the well-documented P09917 REA inhibitor zileuton ( IC ( 50 ) = 0.5- 1 microM ) . Experiments with purified human P09917 REA demonstrate that hyperforin is a direct P09917 REA inhibitor ( IC ( 50 ) approximately 90 nM ) , acting in an uncompetitive fashion . In thrombin - or ionophore-stimulated human platelets , hyperforin suppressed P23219 REA product ( 12 ( S ) - hydroxyheptadecatrienoic acid ) formation with an IC ( 50 ) of 0.3 and 3 microM , respectively , being about 3 - to 18 - fold more potent than aspirin . At similar concentrations , hyperforin suppressed P23219 REA activity in platelets in presence of exogenous AA ( 20 microM ) as well as in cell-free systems . DB01892 MEN could not interfere with P35354 REA product formation and did not significantly inhibit 12 - or 15 - LO in platelets or leukocytes , respectively . We conclude that hyperforin acts as a dual inhibitor of P09917 REA and P23219 REA in intact cells as well as on the catalytic activity of the crude enzymes , suggesting therapeutic potential in inflammatory and allergic diseases connected to eicosanoids .

DB09210 defines a new binding site for allosteric modulators of alpha-amino - 3 - hydroxy - 5 - methyl - 4 - isoxazole-propionic acid ( AMPA ) receptors . Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia . Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation . The pyrrolidine allosteric modulators , piracetam and aniracetam , were among the first of this class of drugs to be discovered . We have determined the structure of the ligand binding domain of the AMPA receptor subtypes P42262 REA and P42263 REA with piracetam and a corresponding structure of P42263 REA with aniracetam . Both drugs bind to P42262 REA and P42263 REA in a very similar manner , suggesting little subunit specificity . However , the binding sites for piracetam and aniracetam differ considerably . DB04599 MEN binds to a symmetrical site at the center of the dimer interface . DB09210 binds to multiple sites along the dimer interface with low occupation , one of which is a unique binding site for potential allosteric modulators . This new site may be of importance in the design of new allosteric regulators .

Nongenomic , glucocorticoid receptor-mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus-pituitary-adrenal ( Q9Y251 REA ) - axis and the serotonergic system . The Q9Y251 REA - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid-glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor-based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( DB00514 SUB ) resulted in enhanced , dose-dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR-antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid-GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 REA interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .

The kinase inhibitor staurosporine induces P55008 arrest at two points : effect on retinoblastoma protein phosphorylation and cyclin-dependent kinase 2 in normal and transformed cells . DB02010 MEN ( ST ) , a protein kinase inhibitor , at a concentration of 20 nM arrests normal diploid fibroblasts 3 h into P55008 ( H . A . Crissman et al . , Proc . Natl . Acad . Sci . USA , 88 : 7580-7584 , 1991 ; K . Abe et al . , Exp . Cell Res . , 192 : 122-127 , 1991 ) . ST ( 2 nM ) induces a new P55008 arrest point at 6 h into P55008 . Partial phosphorylation of the retinoblastoma protein was observed at the 2 nM ST arrest point , whereas the retinoblastoma protein was unphosphorylated or underphosphorylated at the 20 nM arrest point . This correlated with the activity of the cyclin-dependent kinase 2 ( P24941 REA ) and the phosphorylation of the Thr 160 residue of p33CDK2 . The cyclin E and cyclin D1 / 2 levels were reduced at the 20 nM ST arrest point . In HeLa cells that do not arrest in P55008 in response to 2 or 20 nM ST , the retinoblastoma protein and P24941 REA phosphorylations and P24941 REA activity were not affected by ST . These results suggest that ST inhibits one or more P55008 - regulating protein kinases , which lie upstream of P24941 REA .

Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression - - no influence of celecoxib treatment . OBJECTIVES : The involvement of an immune process in the pathophysiology of major depression disorder ( MDD ) was substantiated by studies demonstrating elevated levels of proinflammatory cytokines and prostaglandin E ( 2 ) ( PGE ( 2 ) ) . P35354 REA ( P35354 REA ) inhibitors lead to a reduced production of PGE ( 2 ) and have been shown to improve depressive symptoms . We investigated the three immune parameters macrophage migration inhibitory factor ( MIF ) , transforming growth factor-β ( TGF-β ) and soluble P08571 REA ( sCD 14 ) in a randomized , placebo-controlled trial of the P35354 REA inhibitor celecoxib as add-on therapy in patients with MDD treated with reboxetine . METHODS : Thirty-two patients with depression and 20 healthy controls participated in the study . The patients were treated with reboxetine and celecoxib or placebo . Immune parameters were measured from serum at baseline , after three and five weeks using ELISA . RESULTS : Celecoxib as add-on strategy resulted in a significant reduction of Hamilton Depression Scale scores compared to placebo . Depressed patients showed significantly elevated MIF ( p < 0.001 ) and reduced TGF-β ( p = 0.006 ) concentrations at baseline . There was no difference in sCD 14 - concentrations . There was no difference between the placebo and the celecoxib group and no change over time . LIMITATIONS : Limitations of the study are the relatively small sample size and lack of functional assessment of Q9Y251 REA axis in parallel . CONCLUSIONS : MIF is a promising new candidate in the neuro-immune interplay that may link depressive symptoms , altered immune state and Q9Y251 REA - axis dysregulation . Reduced levels of TGF-β replicate previous findings and support the importance of this regulatory cytokine in major depressive disorder .

DB01079 MEN and other serotonergic agents : what is the evidence ? Through effects on gastrointestinal motor and secretory function as well as visceral sensation , serotonin ( 5 - HT ) plays a key role in the pathogenesis of irritable bowel syndrome ( IBS ) . In particular , 5 - Q9H205 REA and Q13639 REA receptors appear to be very important in IBS . This article critically appraises the evidence supporting the use of the 5 - Q9H205 REA receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS . The safety profile and restricted-use program for alosetron is also reviewed . This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS .

P04141 REA - 1 ( P09603 REA ) delivers a proatherogenic signal to human macrophages . P09603 REA / P09603 REA supports the proliferation and differentiation of monocytes and macrophages . In mice , P09603 REA also promotes proinflammatory responses in vivo by regulating mature macrophage functions , but little is known about the acute effects of this growth factor on mature human macrophages . Here , we show that in contrast to its effects on mouse bone marrow-derived macrophages , P09603 REA did not induce expression of urokinase plasminogen activator mRNA , repress expression of apolipoprotein E mRNA , or prime LPS-induced P01375 REA and P05231 REA secretion in human monocyte-derived macrophages ( HMDM ) from several independent donors . Instead , we show by expression profiling that P09603 REA modulates the HMDM transcriptome to favor a proatherogenic environment . P09603 REA induced expression of the proatherogenic chemokines P02778 REA / IFN-inducible protein 10 , P13500 REA , and P8 0098 but repressed expression of the antiatherogenic chemokine receptor P61073 REA . P09603 REA also up-regulated genes encoding enzymes of the cholesterol biosynthetic pathway ( P04035 REA , P53602 REA , Q13907 REA , P14324 REA , Q14534 REA , Q16850 REA , EBP , Q15738 REA , Q9UBM7 , and Q15392 REA ) , and expression of P45844 REA , encoding a cholesterol efflux transporter , was repressed . Consistent with these effects , P09603 REA increased levels of free cholesterol in HMDM , and the selective P07333 REA kinase inhibitor GW2580 ablated this response . These data demonstrate that P09603 REA represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which P09603 REA , which is known to be present in atherosclerotic lesions , may contribute to plaque progression .

The receptor tyrosine kinase inhibitor amuvatinib ( DB05216 MEN ) sensitizes tumor cells to radio - and chemo-therapies in part by inhibiting homologous recombination . BACKGROUND AND PURPOSE : Q06609 REA is a key protein involved in homologous recombination ( HR ) and a potential target for radiation - and chemotherapies . Amuvatinib ( formerly known as DB05216 MEN ) is a novel receptor tyrosine kinase inhibitor that targets c - P10721 REA and PDGFRα and can sensitize tumor cells to ionizing radiation ( IR ) . Here , we studied amuvatinib mechanism on Q06609 REA and functional HR . MATERIALS AND METHODS : Protein and RNA analyses , direct repeat green fluorescent protein ( DR-GFP ) assay and polysomal fractioning were used to measure HR efficiency and global translation in amuvatinib-treated H1299 lung carcinoma cells . Synergy of amuvatinib with IR or mitomycin c ( DB00305 ) was assessed by clonogenic survival assay . RESULTS : Amuvaninib inhibited Q06609 REA protein expression and HR . This was associated with reduced ribosomal protein S6 phosphorylation and inhibition of global translation . Amuvatinib sensitized cells to IR and DB00305 , agents that are selectively toxic to HR-deficient cells . CONCLUSIONS : Amuvatinib is a promising agent that may be used to decrease tumor cell resistance . Our work suggests that this is associated with decreased Q06609 REA expression and function and supports the further study of amuvatinib in combination with chemotherapy and radiotherapy .

A population-based association study of candidate genes for depression and sleep disturbance . The clinical manifestation of depression comprises a variety of symptoms , including early morning awakenings and fatigue , features also indicating disturbed sleep . The presence or absence of these symptoms may reflect differences in neurobiological processes leading to prolonged depression . Several neurobiological mechanisms have been indicated in the induction of depression , including disturbances in serotonergic and glutamatergic neurotransmission and in the action of the hypothalamic-pituitary-adrenal ( Q9Y251 REA ) axis . The same transmitters have also been linked to sleep regulation . We hypothesized that depression without simultaneous symptoms of disturbed sleep would partly have a different genetic background than depression with symptoms of disturbed sleep . We tested this hypothesis using a systematic population-based association study of 14 candidate genes related to depression and disturbed sleep . Association of genetic variants with either depression alone , depression with early morning awakenings , or depression with fatigue was investigated using permutation-based allelic association analysis of a sample of 1,654 adults recruited from Finland ' s population-based program . The major findings were associations of Q8IWU9 ( rs12229394 ) with depression accompanied by fatigue in women and P16220 REA ( rs11904814 ) with depression alone in men . We also found suggestive associations in women for Q99259 REA , P42263 REA , and P23560 REA with depression accompanied by fatigue , and for P34998 REA with depression accompanied by early morning awakenings . The results indicate sex-dependent and symptom-specific differences in the genetic background of depression . These differences may partially explain the broad spectrum of depressive symptoms , and their systematic monitoring could potentially be used for diagnostic purposes .

The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non-infected groups , interleukin ( IL ) - 4 ( p < 0.001 ) , P05113 REA , P22301 REA , IL - 1beta , tumor necrosis factor ( P01375 REA ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 REA , P05113 REA , P22301 REA and Ig A expression increased , but IL - 1beta and P01375 REA ( p < 0.001 ) decreased , and the number of goblet cells ( p < 0.001 ) and helix pomatia agglutinin ( Q9Y251 REA ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0.05 ) . On the other hand , the expression of all the cytokines except P22301 REA in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 REA ) in the small intestine but not on the systemic immune response .

P08908 REA receptor responsivity in unipolar depression . Evaluation of ipsapirone-induced DB01285 and cortisol secretion in patients and controls . The selective P08908 REA receptor ligand ipsapirone ( IPS ) induces corticotropin ( DB01285 ) and cortisol secretion in humans . To explore P08908 REA receptor-mediated hypothalamic-pituitary-adrenal ( Q9Y251 REA ) system activation in depression , 24 subjects ( 12 patients with unipolar depression and 12 individually matched controls ) were given 0.3 mg / kg IPS or placebo in random order . Compared with controls , the depressed patients exhibited significantly decreased DB01285 and cortisol responses to IPS in association with increased basal cortisol secretion . The impaired Q9Y251 REA response following P08908 REA receptor challenge in unipolar depression could have resulted from glucocorticoid-dependent subsensitivity of the ( post-synaptic ) P08908 REA receptor itself and / or from a defective postreceptor signaling pathway [ inhibitory guanine nucleotide-binding protein ( Gi ) - adenylate cyclase complex function ] , thus supporting the hypothesis that a disintegrated 5 - HT and Q9Y251 REA system interaction may be present in depression . Future studies of the Q9Y251 REA response to direct-acting P08908 REA ligands , such as IPS , should facilitate the assessment of 5 - HT / Q9Y251 REA system integrity in various affective disorders and its involvement in psychotropic drug effects .

Putative role of HIF transcriptional activity in melanocytes and melanoma biology . Hypoxia-inducible factor - 1α ( HIF - 1α ) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric Q9BYW2 transcription factor . Under hypoxic stress , Q9BYW2 activity is induced to control expression of multiple downstream target genes , including vascular endothelial growth factor ( P15692 REA ) . The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF - 1α and HIF - 2α . Expression of HIF - 1α and / or HIF - 2α has been suggested to correlate with the increased malignant potential of melanocytes , therefore , failures of melanoma therapies may be partially linked to high HIF activity . Notably , melanomas that have the V600E P15056 REA mutation exhibit increased HIF - 1α expression . We have utilized a bioinformatics approach to identify putative hypoxia response elements ( HREs ) in a set of genes known to participate in the process of melanogenesis ( includingTRPM 1 , Q9UMX9 , P01112 REA , C - P10721 REA , P40967 and P06850 REA ) . While some of the mechanistic links between these genes and the HIF pathway have been previously explored , others await further investigation . Although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma , there are currently no clinical trials in progress to test their efficacy in melanoma .

Oncostatin M and interleukin 6 inhibit cell cycle progression by prevention of p27kip1 degradation in HepG 2 cells . We analysed the regulation of P55008 - phase progression in relation to cytokine receptor signalling in HepG 2 hepatoma cells , stably transduced with the P22301 REA receptor after stimulation with Oncostatin M ( P13725 REA ) , P05231 REA , Leukaemia Inhibitory Factor ( P15018 REA ) and P22301 REA . All cytokines induced P40763 REA phosphorylation to approximately the same level , but only P13725 REA , and to a lesser extent P05231 REA , induced P42229 REA phosphorylation . The cytokines also stimulated phosphorylation of P29323 REA in the order of decreasing effectiveness : P13725 REA > P05231 REA > P15018 REA > P22301 REA . The same order of activity of the cytokines was observed on inhibition of DNA synthesis and accumulation of cells in the P55008 - phase of the cell cycle . These processes were accompanied by a decrease in cyclin A expression and P24941 REA activity , and enhanced accumulation of p27kip1 . The level of p27kip1 mRNA expression was unaffected by the cytokines , and maintenance of the elevated level of p27kip1 occurred independently of de novo protein synthesis . Furthermore , inhibition of proteasomal activity increased the level of p27kip1 in the unstimulated cells to the same level as in P13725 REA - treated cells . Inhibition of MEK activation completely abrogated P13725 REA and P05231 REA induced p27kip1 accumulation , while expression of dominant negative P42229 REA decreased the P13725 REA and P05231 REA mediated inhibition of DNA-synthesis and partially inhibited p27kip1 accumulation .

Effects of lesopitron on the central nervous system arising from its interaction with P08908 REA receptors . DB04970 MEN acts as a ligand for central serotonin P08908 REA receptors . Ki obtained from [ 3H ]8 - OH-DPAT competition studies was 104.8 + / - 10.6 nmol / l . As lesopitron did not affect the binding of [ 3H ] paroxetine , involvement of the serotonin reuptake system in the effects of lesopitron is rejected . DB04970 MEN inhibits haloperidol-induced catalepsy that is the consequence of its action on P08908 REA autoreceptors . The ability of lesopitron to induce 5 - HT syndrome reflects post-synaptic P08908 REA receptor activation and the reversion of 8 - OHDPAT-induced 5 - HT syndrome by lesopitron suggests a partial agonist effect on this receptor-type . DB04970 MEN induced a hypothermic effect due to the enhanced activation of post-synaptic P08908 REA receptors . The agonist effect of lesopitron on P08908 REA receptors and its marked hypothermic effect is an added value for this drug and a stimulus to the study of its possible neuroprotective action .

Changes in Q13639 REA receptor and 5 - HT transporter binding in olfactory bulbectomized and glucocorticoid receptor heterozygous mice . The 5 - HT ( 4 ) receptor is a new potential target for antidepressant treatment and may be implicated in the pathogenesis of depression . This study investigated differences in 5 - HT ( 4 ) receptor and 5 - HT transporter ( 5 - HTT ) binding by quantitative autoradiography of [ ( 3 ) H ] SB207145 and ( S ) - [ N-methyl - ( 3 ) H ] citalopram in two murine models of depression-related states , olfactory bulbectomy and glucocorticoid receptor heterozygous ( GR ( + / - ) ) mice . The olfactory bulbectomy model is characterized by 5 - HT system changes , while the GR ( + / - ) mice have a deficit in hypothalamic-pituitary-adrenal ( Q9Y251 REA ) system control . The olfactory bulbectomized mice displayed increased activity in the open field test , a characteristic depression-like feature of this model . After bulbectomy , 5 - HT ( 4 ) receptor binding was increased in the ventral hippocampus ( 12 % ) but unchanged in the dorsal hippocampus , frontal and caudal caudate putamen . Among post hoc analyzed regions , there was a 14 % decrease in 5 - HT ( 4 ) receptor binding in the olfactory tubercles . The 5 - HTT binding was unchanged in the hippocampus and caudate putamen of bulbectomized mice but post hoc analysis showed small decreases in lateral septum and lateral globus pallidus . In comparison , GR ( + / - ) mice had increased 5 - HT ( 4 ) receptor ( 11 % ) binding in the caudal caudate putamen and decreased 5 - HTT binding in the frontal caudate putamen but no changes in dorsal and ventral hippocampus . Post hoc analysis showed increased 5 - HT ( 4 ) receptor binding in the olfactory tubercles of GR ( + / - ) mice . In conclusion , we have found brain regional changes in 5 - HT ( 4 ) receptor and 5 - HTT transporter binding in two murine models of depression-related states , characterized by 5 - HT and Q9Y251 REA system changes .

Changes in single symptoms and separate factors of the schizophrenic syndrome after treatment with risperidone or haloperidol . DB00734 MEN , a rather selective blocker of D - 2 and P28223 REA receptors , was , in the doses 1 mg , 4 mg , 8 mg , 12 mg and 16 mg a day , compared to the rather selective D - 2 blocker haloperidol in the dose of 10 mg a day , in 88 chronic schizophrenic patients . After one week placebo wash-out , the patients were randomly assigned to one of the six treatment groups and the study was performed as a double blind parallel-group study for 8 weeks . In the present analysis , a special emphasis has been laid on the effects on single symptoms and separate factors in the schizophrenic syndrome . Overall , risperidone in a dose of 4 mg a day was comparable to haloperidol in a dose of 10 mg a day . DB00734 MENMAX DB00734 MEN was found to have a curvilinear dose-response curve with an optimum effect of 4 mg day on the negative , anxious / depressive and cognitive factors and with an optimum effect of 8 mg day on the positive and excited factors . While haloperidol had significant effects on the negative and anxious / depressive factors , risperidone had significant effects on all five factors - the positive , the negative , the excited , the anxious / depressive and the cognitive . The fact that the novel drug had significant effects on the cognitive factor might be of great importance as concerns the possibilities for rehabilitation of chronic schizophrenic patients .