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Results for “Enhancer mapping”

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At least 307 records · Page 17Linked to original sources

PubMed2003

Using matrix peaks to map topography: increased mass resolution and enhanced sensitivity in chemical imaging.

It is well known in secondary ion mass spectrometry (SIMS) that sample topography leads to decreased mass resolution. Specifically, the ion's time of flight is dependent on where it was generated. Here, using matrix-enhanced SIMS, it is demonstrated that, in addition to increasing the yield of intact pseudomolecular ions, the matrix allows the user to semiquantitatively record the topography of a sample. Through mapping the topography-related mass shifts of the matrix (which leads to decreased mass resolution), the analogous mass shifts of higher mass ions can be deconvoluted and higher resolution and greater sensitivity obtained. Furthermore, the semiquantitative topographical map obtained can be compared with any chemical images obtained, allowing the user to quickly ascertain whether local intensity maximums are due to topological features or represent genuine features of interest.

Journal Article↗

PubMed2000

Regulation of nitric oxide production in cultured human T84 intestinal epithelial cells by nuclear factor-kappa B-dependent induction of inducible nitric oxide synthase after exposure to bacterial endotoxin.

BACKGROUND: Intestinal epithelium is consistently in contact with lipopolysaccharide (LPS) produced by intraluminal microbes. LPS induces nitric oxide production in many rodent cells, but in human cells it is very differently regulated. AIM: To test the hypothesis that exposure to LPS up-regulates nitric oxide synthesis in human intestinal epithelium. METHODS AND RESULTS: LPS induced nitric oxide synthesis in T84 cells in a time- and dose-dependent manner whereas detectable amounts of peroxynitrite were not produced. A novel selective inducible nitric oxide synthase (iNOS) inhibitor 1400 W potently inhibited LPS-induced nitric oxide synthesis in T84 cells while dexamethasone was relatively ineffective. Nitric oxide production was sensitive to cycloheximide, indicating that it was dependent on de novo protein synthesis. Nuclear factor-kappa B (NF-kappa B) inhibitor pyrrolidinedithiocarbamate abolished iNOS and nitric oxide production. Nitric oxide synthesis was also suppressed by genistein (tyrosine kinase inhibitor) and PD 98059 (p44/42 MAP kinase inhibitor) but enhanced by SB 203580 (p38 MAP kinase inhibitor). CONCLUSIONS: Intestinal epithelial cells express iNOS and produce nitric oxide in a nuclear factor-kappa B-dependent manner when exposed to LPS. The process is regulated by tyrosine kinases, and p44/42 and p38 MAP kinases. Because nitric oxide acts as an antimicrobial agent and immune modulator, these findings are implicated in the regulation of gut mucosal immunity.

Amidines↗

PubMed1995

The Wnt-1 proto-oncogene regulates MAP kinase activation by multiple growth factors in PC12 cells.

PC12/Wnt-1 cells display morphological changes in response to stimulation by select growth factors but do not respond to NGF. Furthermore, stimulation by EGF can induce neuronal differentiation in these cells but not in wild type cells. We have found that in these cells, compared to wild type PC12 cells, FGF and EGF stimulation of MAP kinase activity is enhanced, while NGF stimulation of MAP kinase in diminished. Finally, in cells expressing Wnt-1, the effect of cyclic adenosine monophosphate (cAMP) on MAP kinase activation is reversed; cAMP stimulates MAP kinase in wild type PC12 cells but inhibits MAP kinase in PC12/Wnt-1 cells. These data suggest that Wnt-1 expression alters the specificity of growth factor signaling in neuronal cells.

Animals↗

PubMed2002

Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways.

Hepatocyte growth factor (HGF) regulates various physiological and developmental processes in concert with other growth factors, cytokines and hormones. We examined interactions between cell signaling events elicited by HGF and the cytokine interleukin (IL)-4, in the IL-3-dependent murine myeloid cell line 32D transfected with the human HGF receptor, c-Met. HGF was a potent mitogen in these cells, and prevented apoptosis in response to IL-3 withdrawal. IL-4 showed modest anti-apoptotic activity, but no significant mitogenic activity. IL-4 synergistically enhanced HGF-stimulated DNA synthesis, whereas only additive prevention of apoptosis was observed. IL-4 did not enhance HGF-dependent tyrosine phosphorylation of c-Met or Shc. In contrast, HGF-stimulated activation of MAP kinases was enhanced by IL-4, suggesting that the IL-4 and HGF signaling pathways converge upstream of these events. Although phosphatidylinositol 3-kinase (PI3K) inhibitors diminished HGF-induced mitogenesis, anti-apoptosis, and MAP kinase activation, IL-4 enhanced HGF signaling persisted even in the presence of these inhibitors. IL-4 enhancement of HGF signaling was partially blocked in 32D/c-Met cells treated with inhibitors of MEK1 or c-Src kinases, completely blocked by expression of a catalytically inactive mutant of Janus kinase 3 (Jak3), and increased in 32D/c-Met cells overexpressing STAT6. Our results suggest that the IL-4 and HGF pathways converge at multiple levels, and that IL-4-dependent Jak3 and STAT6 activities modulate signaling events independent of PI3K to enhance HGF-dependent mitogenesis in myeloid cells, and possibly other common cellular targets.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Cloning of a human homolog of the Drosophila enhancer of zeste gene (EZH2) that maps to chromosome 21q22.2.

To identify genes that map on human chromosome 21 (HC21) and that may contribute to the phenotype of Down syndrome (DS), exon trapping was applied to cosmid DNA from an HC21-specific library LL21NCO2-Q. More than 550 potential exons were cloned and partially characterized. One of these, hmc23b04 (GenBank X88270) showed strong homology to the Drosophila Enhancer of zeste protein (GenBank U00180) from amino acid 665 to 694 (p = 7.6 x 10(-11). We have cloned the full-length cDNA for this human homolog of the Drosophila E(z) gene (termed EZH2) and mapped it to within YACs 64f11 and 809b11 between markers D21S65 and ERG on human chromosome 21q22.2. Sequence analysis indicates that EZH2 encodes a 746-amino-acid polypeptide that shows 60.5% identity to the Drosophila E(z) protein and contains a trithorax-like domain and a DNA-binding motif. Northern blot analysis revealed that EZH2 is expressed in several tissues. Alternatively spliced mRNA species have been observed. The Drosophila E(z) protein is a member of the polycomb group genes that maintain homeotic gene repression and are thought to control gene expression by regulating chromatin. The strong sequence conservation suggests a possible function of EZH2 in regulation of gene transcription and chromatin structure; it may therefore contribute to certain phenotypes of Down syndrome by altered regulation of its target genes.

Alternative Splicing↗

PubMed1989

Cerebral blood flow determination within the first 8 hours of cerebral infarction using stable xenon-enhanced computed tomography.

Cerebral blood flow mapping with stable xenon-enhanced computed tomography (Xe/CT) was performed in conjunction with conventional computed tomography (CT) within the first 8 hours after the onset of symptoms in seven patients with cerebral infarction. Six patients had hemispheric infarctions, and one had a progressive brainstem infarction. Three patients with very low (less than 10 ml/100 g/min) blood flow in an anatomic area appropriate for the neurologic deficit had no clinical improvement by the time of discharge from the hospital; follow-up CT scans of these three patients confirmed infarction in the area of very low blood flow. Three patients with moderate blood flow reductions (15-45 ml/100 g/min) in the appropriate anatomic area had significant clinical improvement from their initial deficits and had normal follow-up CT scans. One patient studied 8 hours after stroke had increased blood flow (hyperemia) in the appropriate anatomic area and made no clinical recovery.

Aged↗

PubMed2003

A molecular marker map in 'Kanota' x 'Ogle' hexaploid oat (Avena spp.) enhanced by additional markers and a robust framework.

Molecular mapping of cultivated oats was conducted to update the previous reference map constructed using a recombinant inbred (RI) population derived from Avena byzantina C. Koch cv. Kanota x Avena sativa L. cv. Ogle. In the current work, 607 new markers were scored, many on a larger set of RI lines (133 vs. 71) than previously reported. A robust, updated framework map was developed to resolve linkage associations among 286 markers. The remaining 880 markers were placed individually within the most likely framework interval using chi2 tests. This molecular framework incorporates and builds on previous studies, including physical mapping and linkage mapping in additional oat populations. The resulting map provides a common tool for use by oat researchers concerned with structural genomics, functional genomics, and molecular breeding.

Avena↗

PubMed1995

Epitope mapping and analysis of a growth-enhancing monoclonal antibody by limited tryptic digestion of porcine GH.

In this study, the epitope of a murine PS-7.6 monoclonal antibody (mAb) which was raised against the recombinant porcine GH (pGH) and subsequently shown to enhance the growth-promoting activity of pGH in a hypophysectomized rat model, was mapped by the limited tryptic digestion of pGH. A pGH fragment corresponding to amino acid residues 70-95 was separated by reverse-phase HPLC and also immunoprecipitated by PS-7.6 mAb. This fragment was found in an RIA to compete with radiolabelled pGH for the binding of PS-7.6 mAb in a dose-dependent fashion. Several peptides covering this potential epitope region of pGH(70-95) were synthesized and assayed by competitive RIA. The results suggested that pGH(75-90) was the optimal sequence recognized by PS-7.6 mAb. Sequential alanine substitution of each residue of pGH(75-90) revealed that the side chains of Leu76, Ile83 and Leu87 were critical for binding to PS-7.6 mAb. Other residues could be replaced by alanine without substantially altering the binding affinity. The region of amino acids 75-95 comprises the C-terminal end of the second helix of pGH and the repeating pattern of i and i + 3 (i + 7) of the critical amino acids appears consistent with PS-7.6 mAb binding to the hydrophobic side of the helix. The sequence and the helical structure of the epitope of PS-7.6 mAb provide the basis for designing the effective peptide vaccines to enhance the growth performance of animals.

Amino Acids↗

PubMed1995

Signaling functions of L-selectin. Enhancement of tyrosine phosphorylation and activation of MAP kinase.

L-selectin is a leukocyte cell surface glycoprotein involved in carbohydrate-specific ligand binding which mediates rolling of leukocytes along endothelial surfaces. In addition to its role in adhesion, an intracellular signaling role for L-selectin has recently been recognized. In particular, cross-linking L-selectin leads to increased cytosolic Ca2+ levels and potentiation of the oxidative burst. As several cell surface glycoproteins have been shown to be linked to tyrosine kinases, we examined the hypothesis that L-selectin may be linked to pathways involving tyrosine phosphorylation in human neutrophils. Ligation of L-selectin by three different antibodies recognizing separate epitopes led to increased tyrosine phosphorylation of several cellular proteins as judged by anti-phosphotyrosine immunoblots of whole cell lysates with prominent bands at 40-42, 55-60, 70-72, and 105-120 kDa. The 42-kDa band comigrated with mitogen-activated protein (MAP) kinase as determined by immunoblotting with anti-MAP kinase antibody. This effect was specific for L-selectin, because antibodies against CD18, CD45, and CD10 did not increase tyrosine phosphorylation. Phosphorylation was not due to Fc binding, since F(ab')2 fragments of the anti-L-selectin antibodies were similarly effective, and the response was unaffected by Fc receptor blockade. Cross-linking of L-selectin was not required for enhanced tyrosine phosphorylation, because monovalent Fab fragments also increased tyrosine phosphorylation. The response to L-selectin antibodies was not inhibited by cytochalasin, suggesting that reorganization of the actin cytoskeleton was not required for this response. Sulfatides, sulfated glycolipids which may be natural ligands for L-selectin, also induced a rapid, dose-dependent increase in tyrosine phosphorylation. In addition, sulfatides, but not control glycolipids, resulted in enhanced tyrosine phosphorylation of MAP kinase. Both sulfatides and anti-L-selectin antibodies increased kinase activity of MAP kinase as determined by gel renaturation assay. The tyrosine kinase inhibitor, genistein, blocked the transient increase in intracellular Ca2+ and the oxidative burst induced by sulfatides, suggesting that this tyrosine phosphorylation is functionally important. We conclude that L-selectin is able to transmit intracellular signals, including increased tyrosine phosphorylation and activation of MAP kinase in neutrophils. We speculate that these events may contribute to the activation of neutrophils during adhesion.

Animals↗

PubMed2002

Pressor and pulmonary responses to ET-1(1-31) in guinea-pigs.

1. Endothelin-1(1-31) (ET-1(1-31); 0.25 to 4 nmol kg(-1); i.v.) induced, in the guinea-pig, graded increases in MAP and an indomethacin-sensitive enhancement of pulmonary insufflation pressure (PIP). At all doses, ET-1(1-31) induced a monophasic pressor response, except at 4 nmol kg(-1), which caused a rapid and transient response (first phase: over first 10 min after injection) followed by a more slowly-developing and sustained (second phase: between 10 and 45 min after injection) increase in MAP. ET-1(1-31) was 4 to 10 fold less potent than ET-1 on PIP responses. 2. Phosphoramidon (5 and 10 mg kg(-1)) reduced both pressor and PIP effects of ET-1(1-31). Thiorphan (0.25 and 2.5 mg kg(-1)) did not affect the pressor responses to ET-1(1-31) although its PIP effects were markedly reduced by the NEP inhibitor. A selective endothelin-converting enzyme (ECE) inhibitor, CGS 35066 (1 mg kg(-1)), significantly reduced the second phase pressor response and increase in PIP triggered by ET-1(1-31). 3. The second (but not the first) pressor phase of ET-1(1-31) (4 nmol kg(-1)) was markedly reduced by BQ-123 (selective ET(A) antagonist), whereas the increase of PIP was significantly reduced by BQ-788 (selective ET(B) antagonist). Co-administration of BQ-123 plus BQ-788 abolished ET-1(1-31)-induced increase in PIP, but blockade of the second pressor phase afforded by BQ-123 was now reversed. 4. In guinea-pig isolated perfused lungs, ET-1(1-31) (50 nM) induced the release of prostacyclin and thromboxane A(2), which was inhibited by BQ-788 (5 nM) or thiorphan (25 microM), but not BQ-123 (1 microM). 5. These results suggest that ET-1(1-31) enhances MAP. Its sustained, but not transient, pressor effects are mediated via ET(A) receptor activation. Furthermore, ET-1(1-31) increases airway resistance in vivo and triggers prostacyclin and thromboxane A(2) release from perfused lungs predominantly via ET(B) receptor activation. ET-1(1-31) failed to display any selectivity of action towards either ET(A) or ET(B) receptors in these models. 6. We suggest that, in order to raise MAP, ET-1(1-31) requires conversion to ET-1, predominantly by ECE and to a lesser extent neutral endopeptidase 24.11, whereas the reverse holds true regarding its pharmacological effects in airways.

Analysis of Variance↗

PubMed2000

Different activation of vascular mitogen-activated protein kinases in spontaneously and DOCA-salt hypertensive rats.

Regulation mechanisms of the activity of vascular mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, may be altered in hypertension. To examine whether vascular MAP kinase activation mechanisms are altered in hypertension, we measured the activity of MAP kinases in rat aorta strips from spontaneously hypertensive rats (SHR) and from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, and examined whether vascular angiotensin and endothelin systems are responsible for the alteration of MAP kinase activation in these hypertensive models. Endothelium-denuded aorta strips were incubated at 37 degrees C in medium. MAP kinase activity after incubation was increased in rat aorta strips. The MAP kinase activation was greater in 9- and 15-week-old SHR aorta strips than in age-matched Wistar Kyoto rats (WKY) aorta strips. Similarly, MAP kinase activation was enhanced in aorta strips from DOCA-salt hypertensive rats. In aorta strips from these kinds of rats, the angiotensin receptor antagonist, losartan, and the endothelin receptor antagonist, cyclo (D-alpha-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl) (BQ123), inhibited the MAP kinase activation. The losartan-induced, but not BQ123-induced, inhibition of MAP kinase activation was enhanced in 15-week-old SHR aorta strips, whereas the BQ123-induced, but not losartan-induced, inhibition of MAP kinase activation was enhanced in DOCA-salt hypertensive rat aorta strips. Angiotensin II-induced MAP kinase activation was enhanced in 15-week-old SHR aorta strips, whereas it was depressed in DOCA-salt hypertensive rat aorta strips. These results indicate that MAP kinase activation function is enhanced in aorta strips from both kinds of hypertensive rats. It appears that the enhancement of MAP kinase activation results partly from enhanced vascular angiotensin system in SHR and from enhanced vascular endothelin system in DOCA-salt hypertensive rats.

Angiotensin II↗

PubMed1999

Hoxa5 gene regulation: A gradient of binding activity to a brachial spinal cord element.

The Hox genes cooperate in providing positional information needed for spatial and temporal patterning of the vertebrate body axis. However, the biological mechanisms behind spatial Hox expression are largely unknown. In transgenic mice, gene fusions between Hoxa5 (previously called Hox-1.3) 5' flanking regions and the lacZ reporter gene show tissue- and time-specific expression in the brachial spinal cord in day 11-13 embryos. A 604-bp regulatory region with enhancer properties directs this spatially specific expression. Fine-detail mapping of the enhancer has identified several elements involved in region-specific expression, including an element required for expression in the brachial spinal cord. Factors in embryonic day 12.5 nuclear extracts bind this element in electrophoretic mobility shift assays (EMSA) and protect three regions from DNase digestion. All three sites contain an AAATAA sequence and mutations at these sites reduce or abolish binding. Furthermore, this element binds specific individual embryonic proteins on a protein blot. The binding activity appears as a gradient along the anterior-posterior axis with two- to threefold higher levels observed in extracts from anterior regions than from posterior regions. In parallel with the EMSA, the proteins on the protein blot also show reduced binding to probes with mutations at the AAATAA sites. Most importantly, transgenic mice carrying Hoxa5/lacZ fusions with the three AAATAA sites mutated either do not express the transgene or have altered transgene expression. The brachial spinal cord element and its binding proteins are likely to be involved in spatial expression of Hoxa5 during development.

Animals↗

PubMed2001

Map Manager QTX, cross-platform software for genetic mapping.

Map Manager QTX (QTX) is software for analysis of genetic mapping experiments in experimental plants and animals. It includes functions for mapping both Mendelian and quantitative trait loci. QTX is an enhanced version of Map Manager QT, rewritten with the aid of cross-platform libraries (XVT, Boulder Software Foundry, Inc.), which allow it to be compiled for multiple computer platforms. It currently is distributed for Microsoft Windows and Mac OS and is available at http://mapmgr.roswellpark.org/mmQTX.html.

Animal Population Groups↗

PubMed1995

Development of a genetic map of the chicken with markers of high utility.

Microsatellites are tandem duplications with a simple motif of one to six bases as the repeat unit. Microsatellites provide an excellent opportunity for developing genetic markers of high utility because the number of repeats is highly polymorphic, and the assay to score microsatellite polymorphisms is quick and reliable because the procedure is based on the polymerase chain reaction (PCR). We have identified 404 microsatellite-containing clones of which 219 were suitable as microsatellite markers. Primers for 151 of these microsatellites were developed and used to detect polymorphisms in DNA samples extracted from the parents of two reference populations and three resource populations. Sixty, 39, 46, 49, and 61% of the microsatellites exhibited length polymorphisms in the East Lansing reference population, the Compton reference population, resource population No. 1 (developed to identify resistance genes to Marek's disease), resource population No. 2 (developed to identify genes involved in abdominal fat), and resource population No. 3 (developed to identify genes involved in production traits), respectively. The 91 microsatellites that were polymorphic in the East Lansing reference population were genotyped and 86 genetic markers were eventually mapped. In addition, 11 new random amplified polymorphic DNA (RAPD) markers and 24 new markers based on the chicken CR1 element were mapped. The addition of these markers increases the total number of markers on the East Lansing genetic map to 273, of which 243 markers are resolved into 32 linkage groups. The map coverage within linkage groups is 1,402 cM with an average spacing of 6.7 cM between loci. The utility of the genetic map is greatly enhanced by adding 86 microsatellite markers. Based on our current map, approximately 2,550 cM of the chicken genome is within 20 cM of at least one microsatellite marker.

Animals↗

PubMedDate not supplied

Segmental enhancement of the cochlea on contrast-enhanced MR: correlation with the frequency of hearing loss and possible sign of perilymphatic fistula and autoimmune labyrinthitis.

PURPOSE: To relate the finding of selective enhancement of different turns of the cochlea to the frequency range of the hearing loss measured by audiogram. METHODS: Six patients aged 23 to 53 years, four men and two women, who presented with sudden hearing loss and had segmental enhancement of different turns of the cochlea on contrast-enhanced MR imaging were included in this retrospective study. The patients were imaged on a 1.5 T MR imaging system using pre- and postcontrast axial T1-weighted images and postcontrast coronal T1-weighted images through the temporal bone. RESULTS: The basal turn of the cochlea enhanced selectively in five of the six patients and the apical turn enhanced in the sixth patient. All patients had sensorineural hearing loss. Three of the patients with basal turn enhancement had predominantly high-frequency hearing loss, whereas the patient with apical turn enhancement had predominantly low-frequency hearing loss. The two other patients with basal turn enhancement had complete hearing loss. Three patients had presumed autoimmune labyrinthitis. The other three patients had strong clinical and surgical evidence of a perilymphatic fistula. CONCLUSION: Contrast-enhanced MR imaging may demonstrate selective enhancement of different turns of the cochlea. In certain patients, the areas of enhancement may correlate with specific hearing loss in the frequencies mapped by the enhancing segment. Enhancement of the cochlea may represent radiologic evidence of cochlear inflammation secondary to a perilymphatic fistula.

Adult↗

PubMed2003

Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-beta-dependent responses in human mesangial cells.

Transforming growth factor beta (TGF-beta) stimulates renal cell fibrogenesis by a poorly understood mechanism. Previously, we suggested a synergy between TGF-beta1 activated extracellular signal-regulated kinase (ERK) and Smad signaling in collagen production by human glomerular mesangial cells. In a heterologous DNA binding transcription assay, biochemical or dominant-negative ERK blockade reduced TGF-beta1 induced Smad3 activity. Total serine phosphorylation of Smad2/3, but not phosphorylation of the C-terminal SS(P)XS(P) motif, was decreased by pretreatment with the MEK/ERK inhibitors, PD98059 (10 microM) or U0126 (25 microM). This effect was not seen in the mouse mammary epithelial NMuMG cell line, indicating that ERK-dependent activation of Smad2/3 occurs only in certain cell types. TGF-beta stimulated phosphorylation of an expressed Smad3A construct, with a mutated C-terminal SS(P)XS(P) motif, was reduced by a MEK/ERK inhibitor. In contrast, MEK/ERK inhibition did not affect phosphorylation of a Smad3 construct mutated at consensus phosphorylation sites in the linker region (Smad3EPSM). Constitutively active MEK (caMEK) induced alpha2(I) collagen promoter activity, an effect blocked by co-transfected Smad3EPSM, but not Smad3A. The effects of caMEK and TGF-beta1 on collagen promoter activity were additive. These results indicate that ERK-dependent R-Smad linker region phosphorylation enhances collagen I synthesis and imply positive cross talk between the ERK and Smad pathways in human mesangial cells.

Animals↗

PubMed1997

ET-1 cooperates with EGF to induce mitogenesis via a PTX-sensitive pathway in airway smooth muscle cells.

We have examined the mitogenic effect of endothelin-1 (ET-1) alone or in combination with epidermal growth factor (EGF) in cultured airway smooth muscle cells (ASM) from guinea pig. ET-1 showed a weak mitogenic activity compared with the effect of EGF. However, when ET-1 and EGF were applied simultaneously, ET-1 synergistically enhanced the mitogenic activity of EGF. Neither inhibition of phospholipase C-beta nor depletion of protein kinase C affected this synergism. On the other hand, pertussis toxin (PTX), a Gi protein inhibitor, abolished the synergistic effect of ET-1 on EGF-induced mitogenesis. ET-1 induced a transient mitogen-activated protein (MAP) kinase activation peaking at 5 min. In contrast, EGF induced a stronger signal that was maintained for up to 20 min. However, concomitant stimulation of ASM with ET-1 and EGF caused an enhanced MAP kinase activation compared with EGF alone. Moreover, PTX abolished the enhanced MAP kinase activation observed in this condition. These results indicate that ET-1 can interact with an EGF-induced mitogenic axis through the Gi protein-dependent pathway, which is distinct from its direct mitogenic pathway.

Animals↗

PubMed1996

Comparative pharmacodynamic studies with the novel serotonin uptake-enhancing tianeptine and -inhibiting fluvoxamine utilizing EEG mapping and psychometry.

In a double-blind, placebo-controlled study, the encephalotropic and psychotropic effects of tianeptine (TIA)--a new tricyclic antidepressant, enhancing serotonin reuptake--were investigated as compared with the serotonin reuptake inhibiting antidepressant, fluvoxamine (FLU), utilizing EEG mapping, psychometric and psychophysiological measures. 16 healthy volunteers (8 males, 8 females) aged 21-35 (man 27) years received randomized and at weekly intervals single oral doses of placebo, 12.5 and 25 mg TIA and 50 mg FLU. EEG recordings, psychometric and psychophysiological tests and evaluation of pulse, blood pressure and side effects were carried out at 0, 2, 4, 6 and 8 hours; blood sampling, in addition, at hour 1. TIA plasma levels rose fast to peaks at 1-2 hours and declined rapidly as well, while the MC5 metabolite peaked in the 4th hour and declined more slowly. EEG mapping demonstrated that both TIA and FLU induced significant changes in brain function between the 1st and 8th hour, which, however, differed in their time course. 12.5 mg TIA exhibited, as compared with placebo, slight activating properties in the EEG (decrease of delta and theta, increase of alpha and beta, acceleration of the centroid), parallelled by thymopsychic improvement (mood elevation). 25 mg TIA showed EEG activation up to the 4th hour, later EEG sedation, accompanied by an initial thymopsychic improvement and differential changes thereafter (improved mood, decreased vigility), with the noopsyche improving at all times (attention, Pauli test). 50 mg FLU induced initially sedation and thereafter activation, accompanied by thymopsychic deterioration and subsequent improvement, the latter also being observed in the noopsyche (attention, memory). In pupillary and skin conductance measures, generally a slight activation occurred after placebo, which was attenuated by 25 mg TIA. Correlation maps between plasma levels and EEG changes demonstrated: the higher the TIA plasma levels, the more absolute and relative beta power, the less alpha power and the faster the centroid of the total power spectrum, reflecting CNS-activation. Topographically, the correlations were mostly seen over both fronto-temporal regions. In the latter, dominant frequency signalled desactivation in the right and activation in the left hemiphere after both antidepressants which, thereby induced changes in brain function opposite to those observed in depression. Both drugs were well tolerated.

Adult↗