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ABSTRACT: Aims To identify by a molecular genetic approach potential targets in mast cells at which 1,4-benzodiazepines may cause their inhibitory effect on mast cell activity. Main methods Gene expression analyses with microarray gene chip and/or quantitative PCR were perfomed using 1,4-benzodiazepine-treated human mast cell leukemia HMC-1.2 cells, promyelocytic leukemia HL-60 cells and human mast cells from healthy volunteers and patients with mast cell activation disease (MCAD). Pathway analysis was applied to search for enriched biological functions and canonical pathways within differentially regulated genes. Key findings Both neoplastic and normal human mast cells express several GABA(A) receptor subunits at the mRNA level. In mast cells from MCAD patients expression of some GABA(A) receptor subunits and of the translocator protein TSPO are increased compared with those from healthy controls. Expression of the protein tyrosine kinases Lyn, Fgr and Yes1 was increased in HMC-1.2 cells as compared with the ontogenetically related HL60 cells. Differences in gene regulation in HMC-1.2 cells after treatment with the 1,4-benzodiazepines clonazepam, flunitrazepam and 4-chlorodiazepam suggested that signalling and gene expression induced by clonazepam was similar to that of flunitrazepam but different from that of 4-chlorodiazepam. This conclusion is supported by the results of the pathways analysis. Significance A novel type of GABA(A) receptors on mast cells appears to be involved in the inhibition of mast cell activity by 1,4-benzodiazepines. These receptors seem to be composed without γ subunits suggesting unique pharmacological properties. An action at Src-kinases, or at TSPO located in the plasma membrane may also be involved.
Life sciences 01/2013; · 2.56 Impact Factor
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ABSTRACT: Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease-associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized.
Immunology 09/2012; 137(3):197-205. · 3.32 Impact Factor
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Britta Haenisch,
Stefan Herms,
Manuel Mattheisen,
Michael Steffens,
Rene Breuer,
Jana Strohmaier,
Franziska Degenhardt,
Christine Schmäl,
Susanne Lucae,
Wolfgang Maier,
Marcella Rietschel,
Markus M Nöthen,
Sven Cichon
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ABSTRACT: BACKGROUND: Dysfunctions of serotonergic neurotransmission are supposed to be involved in the pathogenesis of psychiatric disorders such as major depressive disorder (MDD). The concentration of serotonin (5-hydroxytryptamine, 5-HT) in the synaptic cleft is essentially regulated by the 5-HT transporter (5-HTT). A length polymorphism repeat in the 5-HTT promoter region, termed 5-HTTLPR, has been commonly investigated for an association with psychiatric disorders. METHODS: Genotyping of the 5-HTTLPR is time-consuming and technically challenging. Recently, a two-SNP haplotype was identified that tags the 5-HTTLPR at r(2)=0.775. This allows extraction of 5-HTTLPR genotype information from large genome-wide association study (GWAS) data sets. In the present study we performed haplotype analysis using a German GWAS case-control dataset to test for an association between MDD and the two-SNP tagging haplotype for 5-HTTLPR. RESULTS: We detected a significant association between the TA haplotype (tagging the S-allele of the 5-HTTLPR) and MDD. Our result is consistent with previous findings of an association between the 5-HTTLPR S-allele and MDD. LIMITATIONS: Using the two-SNP tagging haplotype did not allow testing of the tri-allelic genotype (but only the two-allelic genotype). This and the fact that the haplotype tags the 5-HTTLPR with an imperfect linkage disequilibrium of r(2)=0.775 may lead to some loss of power. CONCLUSIONS: Our results provide further support for an involvement of the 5-HTTLPR in MDD and represent the first example of demonstrating association between MDD and the S-allele of the length polymorphism repeat using common SNP information from SNP-array data.
Journal of affective disorders 08/2012; · 3.76 Impact Factor
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ABSTRACT: Agmatine, a cationic amine formed by decarboxylation of l-arginine by the mitochondrial enzyme arginine decarboxylase (ADC), is widely but unevenly distributed in mammalian tissues. Agmatine in the tissues originates from cellular enzymatic de novo synthesis and from agmatine absorbed from the lumen of the gut. Absorption from the gut and accumulation in the tissues and cells must occur via a specific carrier mechanism because the compound is charged at physiologic pH and, hence, biological membranes are almost completely impermeable to the organic cation in the absence of an uptake system. Agmatine initially attracted attention as an endogenous ligand at imidazoline receptors and α(2)-adrenoceptors. However, independent of binding to those receptors, agmatine induces a variety of physiological and pharmacological effects exhibiting a great therapeutic potential of the compound. Although the precise function of endogenous agmatine is presently still unclear, this review summarizes the current knowledge concerning the physiological and pathophysiological function of agmatine.
Pharmacology [?] Therapeutics 12/2011; 133(3):351-65. · 8.56 Impact Factor
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ABSTRACT: We aimed at identifying transcripts whose expression is regulated by a SNP-SNP interaction. Out of 47,294 expression phenotypes we used 3107 transcripts that survived an extensive quality control and 86,613 linkage disequilibrium-pruned SNP markers that have been genotyped in 210 individuals. For each transcript we defined cis-SNPs, tested them for epistasis with all trans-SNPs, and corrected all observed cis-trans-regulated expression effects for multiple testing. We determined that the expression of about 15% of all included transcripts is regulated by a significant two-locus interaction, which is more than expected (P = 2.86 × 10(-144)). Our findings suggest further that cis-markers with so called 'marginal effects' are more likely to be involved in two-locus gene regulation than expected (P = 8.27 × 10(-05)), although the majority of interacting cis-markers showed no one-locus regulation. Furthermore, we found evidence that gene-mediated trans-effects are not a major source of epistasis, as no enrichment of genes has been found in close vicinity of trans-SNPs. In addition, our data support the notion that neither chromosomal regions nor cellular processes are enriched in epistatic interactions. Finally, some of the cis-trans regulated genes have been found in genome-wide association studies, which might be interesting for follow-up studies of the corresponding disorders. In summary, our results provide novel insights into the complex genome-transcriptome regulation.
European journal of human genetics: EJHG 08/2011; 20(1):97-101. · 3.56 Impact Factor
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ABSTRACT: Sumatriptan, an antimigraine drug, causes contraction of human coronary arteries through activation of 5-HT1B receptors which couple to Gi/Go inducing inhibition of adenylate cyclase. At a rare, naturally occurring human receptor variant (124Cys-h5-HT1B), sumatriptan has previously been shown to act as a more potent agonist than at wild-type receptor. Tegaserod, a 5-HT4-receptor agonist, developed for the treatment of functional gastrointestinal disorders, has been suspected to be involved in very rare cardiac ischemic events in patients with cardiovascular risk factors. In this study, we examined the potential agonist-like effects of tegaserod in comparison with sumatriptan at heterologously expressed human wild type and 124Cys-variant 5-HT1B receptors, using assays addressing G-protein coupling and inhibition of forskolin-stimulated cyclic AMP accumulation. Sumatriptan exhibited agonist effects as previously reported, whereas tegaserod acted as partial agonist at both wild type and 124Cys-variant h5-HT1B receptors (expressed in rat C6 glioma cells). Sumatriptan and tegaserod were more potent at the 124Cys-variant h5-HT1B receptor. It remains to be shown whether the very rare cardiovascular side effects reported with these drugs are predominantly observed in patients homozygously expressing the variant receptor.
Pharmacogenetics and Genomics 07/2011; 21(7):432-5. · 3.48 Impact Factor
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ABSTRACT: The antidepressant trimipramine shows an atypical pharmacological profile and its mechanism of action is still obscure.
The present study investigated whether trimipramine and three of its metabolites interact with targets of other antidepressants, namely, the human monoamine transporters for noradrenaline (hNAT), serotonin (hSERT), and dopamine (hDAT), and with the human organic cation transporters (hOCT1, hOCT2, and hOCT3) which are expressed in the brain and are known to be involved in the uptake of monoamines.
HEK293 cells heterologously expressing the abovementioned transporters were used to determine the inhibition of [(3)H]MPP(+) uptake by trimipramine and its main metabolites.
At concentrations up to 30 μM, all transporters, except hOCT3, were inhibited by all examined substances. With IC(50) values between 2 and 10 μM, trimipramine inhibited hSERT, hNAT, hOCT1, and hOCT2, whereas clearly higher concentrations were needed for half-maximal inhibition of hDAT. Desmethyl-trimipramine showed about the same potencies as trimipramine, whereas 2-hydroxy-trimipramine was less potent at hNAT, hSERT, and hOCT1. Trimipramine-N-oxide preferentially inhibited hSERT.
Neither trimipramine nor its metabolites are highly potent inhibitors of the examined monoamine transporters. However, since at a steady state the sum of the concentrations of the parent compound and its active metabolites is almost two times higher than the plasma concentration of trimipramine and since it is known that tricyclic antidepressants accumulate in the brain (up to tenfold), at least partial inhibition by trimipramine and its metabolites of hSERT and hNAT (but not of hOCT3) may contribute to the antidepressant action of trimipramine.
Psychopharmacologia 04/2011; 217(2):289-95. · 4.08 Impact Factor
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ABSTRACT: Major depressive disorder (MDD) which is supposed to result from a complex interaction of genetic and epigenetic, environmental and developmental factors is one of the most common debilitating public health problems. The molecular mechanisms underlying this disease are still largely unclear. Identifying common pathways for diverse antidepressants (ADs) as well as new drug targets and thereby developing more effective treatments are primary goals of research in this field. Major targets of ADs are the serotonin transporter (SERT), the noradrenaline transporter (NAT) and also the dopamine transporter (DAT) located in the plasma membrane of corresponding neurons. These monoamine transporters (MATs) are important regulators of the extracellular neurotransmitter concentration. Among the clinically important ADs are tricyclic ADs (e.g. imipramine), selective serotonin re-uptake inhibitors (SSRIs, e.g. fluoxetine), selective noradrenaline (NA) re-uptake inhibitors (SNRIs, e.g. reboxetine) and NAT/DAT inhibitors like bupropion. This review is focussing on brain changes in monoamine neurotransmitter systems, downstream targets of monoaminergic neurotransmission as well as of behaviours of mice with a conventional knockout (KO) of either the SERT, DAT or NAT. MAT knockout induces changes in behaviour and brain neurochemistry. Although at least NATKO and SERTKO mice were expected to show a phenotype like AD-treated wild-type mice, this holds true only for the NATKO mice whereas SERTKO mice show an anxiety-like phenotype. Chronic social or restraint stress-induced depression-like behaviour and concomitant changes in brain neurotrophins are prevented by pharmacologically diverse ADs and by NATKO. Thus, NATKO mice are an interesting tool to investigate the mechanisms beyond monoamines responsible for depression as well as for AD actions.
Pharmacology [?] Therapeutics 03/2011; 129(3):352-68. · 8.56 Impact Factor
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Sven Cichon,
Thomas W Mühleisen,
Franziska A Degenhardt,
Manuel Mattheisen,
Xavier Miró,
Jana Strohmaier,
Michael Steffens,
Christian Meesters,
Stefan Herms,
Moritz Weingarten, [......],
Joanna Hauser,
Andreas Zimmer,
Mark Lathrop,
Thomas G Schulze,
Thomas F Wienker,
Johannes Schumacher,
Wolfgang Maier,
Peter Propping,
Marcella Rietschel,
Markus M Nöthen
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ABSTRACT: We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.
The American Journal of Human Genetics 02/2011; 88(3):372-81. · 10.60 Impact Factor
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ABSTRACT: Impairment of agmatine homeostasis is involved in the regulation of cell proliferation in malignant solid tumors. The present study aimed at analyzing the relevance of agmatine homeostasis in pathophysiology of human leukemia. Proliferation of the human leukemia cells HMC-1 and HL-60 was determined in the absence or presence of agmatine. Apoptosis and cell cycle distribution was investigated by determination of caspase-3 activity and/or flow cytometry after staining with propidium iodide. Expression analysis was performed by qPCR and by a microarray genechip. Exogenous agmatine inhibited proliferation of both HMC-1 and HL-60 cells. The antiproliferative effect was due to interference of agmatine with the cell cycle with no evident signs of apoptosis. Comparative analysis of expression of mRNA in untreated HMC-1 cells and in non-leukemic human mast cells revealed a much lower expression of agmatinase and diamine oxidase in HMC-1 cells indicating a significantly reduced agmatine catabolism in the leukemic cells. At the mRNA level, inhibition of proliferation of both cell lines by agmatine was associated with cell type-specific alterations of the expression of enzymes of the polyamine pathway. The present results point to a significant role of agmatine homeostasis in the (patho)physiology of cell proliferation of leukemic cells, at least in HMC-1 and HL-60 cells, that may serve as a potential target for an adjuvant therapy in the treatment of human leukemia.
Leukemia research 01/2011; 35(9):1248-53. · 2.36 Impact Factor
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ABSTRACT: We report on the outcome of 4 patients with therapy-resistant systemic mast cell activation disease (MCAD) treated with the anti-IgE monoclonal antibody omalizumab in compassionate use. Two patients achieved an impressive persistent clinical response to treatment with omalizumab. In the third patient symptoms gradually improved. In the fourth patient omalizumab treatment had to be discontinued due to intolerable mast cell mediator-induced symptoms. In conclusion, omalizumab can lessen the intensity of the symptoms of systemic MCAD. Hence, omalizumab should be considered as a therapeutic option in cases of systemic MCAD that are resistant to evidence-based therapy.
Internal Medicine 01/2011; 50(6):611-5. · 0.94 Impact Factor
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ABSTRACT: Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH(3) for the interaction with BCRP.
Bioorganic & medicinal chemistry 12/2010; 19(6):2090-102. · 2.82 Impact Factor
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ABSTRACT: Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline.
Fundamental and Clinical Pharmacology 12/2010; 24(6):729-39. · 1.80 Impact Factor
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Marcella Rietschel,
Manuel Mattheisen,
Josef Frank,
Jens Treutlein,
Franziska Degenhardt,
René Breuer,
Michael Steffens,
Daniela Mier,
Christine Esslinger,
Henrik Walter, [......],
Christine Schmäl,
Andreas Zimmer,
Dilafruz Juraeva,
Benedikt Brors,
Thomas Bettecken,
Andreas Meyer-Lindenberg,
Bertram Müller-Myhsok,
Wolfgang Maier,
Markus M Nöthen,
Sven Cichon
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ABSTRACT: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.
We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects.
Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 (p(combined) = 3.24E-6) located upstream of the carboxypeptidase M (CPM) gene and 2) rs7713917 (p(combined) = 1.48E-6), located in a putative regulatory region of HOMER1. Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 (p(combined) = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward.
Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes.
Biological psychiatry 09/2010; 68(6):578-85. · 8.93 Impact Factor
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ABSTRACT: Monoamine neurotransmission is efficiently terminated through synaptic reuptake of released neurotransmitters by high-affinity Na(+)- and Cl(-)-dependent neuronal monoamine transporters of the SLC6A family located in the plasma membrane of presynaptic nerve terminals. Recently, a low-affinity, high-capacity Na(+)- and Cl(-)-independent plasma membrane monoamine transporter (PMAT) belonging to the SLC29 solute carrier family has been cloned. PMAT was shown to transport monoamine neurotransmitters as well as organic cations such as 1-phenyl-4-methyl-pyridinium (MPP(+)). Thus, the PMAT which is highly expressed in the human brain may be involved in the modulation of central monoaminergic neurotransmission and it may be a target for drugs used to treat depression and schizophrenia, i.e., dysregulations of the monoamine homeostasis in the central nervous system (CNS). Therefore, we examined in transfected cells the influence on [(3)H]-MPP(+) transport by the human PMAT (hPMAT) of nine monoamine transport inhibiting antidepressants (ADs) belonging to pharmacologically diverse classes (imipramine, desipramine, amitriptyline, bupropion, fluoxetine, sertraline, paroxetine, reboxetine, and venlafaxine), of the atypical ADs tianeptine and trimipramine and of five antipsychotics (levomepromazine, haloperidol, clozapine, olanzapine, and risperidone). All examined drugs inhibited the hPMAT; however, half-maximum inhibition (IC(50)) was observed at concentrations which were much higher than reported clinical plasma concentrations of these drugs. Thus, inhibition of the hPMAT by these CNS drugs may not (or only marginally) contribute to their therapeutic effects.
Archiv für Experimentelle Pathologie und Pharmakologie 12/2009; 381(1):33-9. · 2.65 Impact Factor
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ABSTRACT: Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, nerve growth factor, and neurotrophin-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NET knock out (NETKO) mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants.
Journal of Neurochemistry 09/2009; 111(2):403-16. · 4.06 Impact Factor
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Britta Haenisch,
Karoline Linsel,
Michael Brüss,
Ralf Gilsbach,
Peter Propping,
Markus M Nöthen,
Marcella Rietschel,
Rolf Fimmers,
Wolfgang Maier,
Astrid Zobel,
Susanne Höfels,
Vera Guttenthaler,
Manfred Göthert,
Heinz Bönisch
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ABSTRACT: Dysregulations of central noradrenergic and serotonergic neurotransmission have been suggested to contribute to the pathogenesis of neuropsychiatric disorders such as depression. The norepinephrine transporter (NET; SLC6A2) and the serotonin (5-HT)(1A) receptor (5-HT(1A) receptor; HTR1A) play an important role in central nervous monoaminergic homeostasis. As shown previously, variations in the human NET and 5-HT(1A) receptor genes can alter noradrenergic and serotonergic signaling in the brain: a single nucleotide polymorphism (SNP) in the coding region of the NET gene resulting in a F528C substitution increased plasma membrane expression of this NET variant, and a SNP in the human 5-HT(1A) receptor gene leading to the R219L receptor variant almost abolished cellular signal transduction subsequent to receptor activation. The present study aimed at investigating whether these NET and 5-HT(1A) receptor variants are associated with major depression (MD). The sample comprised 426 patients suffering from unipolar MD as well as 643 healthy control subjects for the variants of the 5-HT(1A) receptor and the NET. Both SNPs were shown to be associated with MD. In conclusion, our results favor the hypothesis that monoaminergic neurotransmission in general and the F528C NET and R219L 5-HT(1A) receptor variants in particular are involved in the pathogenesis of depression.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2009; 150B(7):1013-6. · 3.70 Impact Factor
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ABSTRACT: Regulation of agmatine homeostasis has so far only been poorly defined. In the present study, three mechanisms regulating human agmatine homeostasis were investigated. 1) Enzymatic regulation: expression of arginine decarboxylase, diamine oxidase, and ornithine decarboxylase in human colon neoplastic tissue was, at the mRNA level, about 75% and 50% lower and 150% higher, respectively, than in the adjacent normal tissue; expression of agmatinase was unchanged. 2) Bacteria-derived agmatine: ten representative bacteria strains of the human intestinal microbiota considerably differed in agmatine production and its efflux into their surrounding fluid, suggesting that the composition of the intestinal microbiota influences the agmatine availability in the gut lumen for absorption. 3) Regulation of blood plasma agmatine concentration by the human liver: at low concentrations in portal venous blood plasma, agmatine either slightly increased or further decreased in blood plasma through liver passage. Above a threshold of 14 ng/ml agmatine in the portal venous blood plasma, substantial hepatic agmatine removal from blood occurred. Taken together, a perturbation of agmatine homeostasis has been proven to be involved in the regulation of malignant cell proliferation. The amount of agmatine available for absorption, which is an important physiological source of agmatine in the human organism, should differ considerably depending on the composition of the bacterial flora in the chyme since the various species of intestinal bacteria largely differ in their ability to form agmatine. Finally, evidence has been presented that the liver plays a crucial physiological role in the maintenance of agmatine homeostasis in the human organism.
AJP Gastrointestinal and Liver Physiology 11/2008; 295(5):G1104-10. · 3.43 Impact Factor
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Kirsten Alfter,
Ivar von Kügelgen, Britta Haenisch,
Thomas Frieling,
Alexandra Hülsdonk,
Ulrike Haars,
Arndt Rolfs,
Gerhard Noe,
Ulrich W Kolck,
Jürgen Homann,
Gerhard J Molderings
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ABSTRACT: This study was aimed at investigating the form and prevalence of liver involvement in patients with systemic mast cell activation syndrome, a possibly common subvariant of systemic mastocytosis. An attempt was made to shed light on potential mechanisms responsible for mast cell mediator-related liver abnormalities.
The methods used were clinical investigation, biochemical determination of cholesterol, transaminases and bilirubin in blood, determination of chitotriosidase by enzyme-linked immunosorbent assay technique, and quantitative reverse transcribed-polymerase chain reaction to determine chitotriosidase expression.
An elevation of plasma cholesterol was detected in 75% of the patients; elevations of transaminases and bilirubin were determined in 40 and 36% of the patients respectively; hepatomegaly or morphological hepatic alterations were observed in 34%. Chitotriosidase level in blood as a surrogate parameter for Kupffer cell activation in the liver was unchanged. However, chitotriosidase expression in isolated mast cells was downregulated at the mRNA level.
Hypercholesterolaemia and liver abnormalities are frequently found in patients with the mast cell activation syndrome. Hence, the mast cell activation syndrome should be considered at an early stage as a possible cause of hypercholesterolaemia and of hepatic abnormalities of unknown reason. Mast cell activation may be indicated by a reduced expression of the enzyme chitotriosidase in blood-derived mast cells as well as by an increased plasma cholesterol level.
Liver international: official journal of the International Association for the Study of the Liver 08/2008; 29(2):181-6. · 3.82 Impact Factor
