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291.
CE Beyer Q Lin B Platt J Malberg G Hornby KM Sullivan DL Smith T Lock PJ Mitchell NT Hatzenbuhler DA Evrard BL Harrison R Magolda MN Pangalos LE Schechter S Rosenzweig-Lipson TH Andree 《British journal of pharmacology》2009,157(2):307-319
Background and purpose
As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT1A receptor antagonist activities, was evaluated in preclinical models.Experimental approach
Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.Key results
WAY-211612 inhibited 5-HT reuptake (Ki = 1.5 nmol·L−1; KB = 17.7 nmol·L−1) and exhibited full 5-HT1A receptor antagonist activity (Ki = 1.2 nmol·L−1; KB = 6.3 nmol·L−1; Imax 100% in adenyl cyclase assays; KB = 19.8 nmol·L−1; Imax 100% in GTPγS). WAY-211612 (3 and 30 mg·kg−1, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg−1, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg−1, s.c.) and a 5-HT1A antagonist (WAY-100635; 0.3 mg·kg−1, s.c). WAY-211612 (3.3–30 mg·kg−1, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg−1, i.p. and 10–56 mg·kg−1, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg−1, i.p.) in the rat scheduled-induced polydipsia model.Conclusions and implications
These findings suggest that WAY-211612 may represent a novel antidepressant. 相似文献292.
E Jaakkola A Mustonen P Olsen S Miettinen T Savuoja A Raams NGJ Jaspers H Shao BL Wu J Ignatius 《Clinical genetics》2010,78(6):541-547
Jaakkola E, Mustonen A, Olsen P, Miettinen S, Savuoja T, Raams A, Jaspers NGJ, Shao H, Wu BL, Ignatius J. ERCC6 founder mutation identified in Finnish patients with COFS syndrome. Cerebro‐oculo‐facio‐skeletal (COFS) syndrome is an autosomal recessive disorder characterized by microcephaly, congenital cataracts, facial dysmorphism, neurogenic arthrogryposis, growth failure and severe psychomotor retardation. We report a large consanguineous pedigree from northern Finland with six individuals belonging into four different sibships and affected with typical COFS syndrome phenotype. Two deceased patients have been published previously in 1982 as the first cases exhibiting cerebral calcifications typical for this disorder. Two living and one of the deceased patients were all shown to possess a novel homozygous mutation in the ERCC6 [Cockayne syndrome B (CSB)] gene, thereby confirming the diagnosis on molecular genetic level even for the earlier published cases. Genealogical investigation showed a common ancestor living in a northeastern village in Finland in the 18th century for all six patients implying a founder effect. 相似文献
293.
Bressler SL; Gray MD; Sopher BL; Hu Q; Hearn MG; Pham DG; Dinulos MB; Fukuchi K; Sisodia SS; Miller MA; Disteche CM; Martin GM 《Human molecular genetics》1996,5(10):1589-1598
Using the yeast two hybrid system, a mouse embryo cDNA library was screened
for proteins that interact with the C-terminus of the human beta-amyloid
precursor protein (beta PP). A fusion protein was identified that interacts
specifically with the cytoplasmic domain of beta PP and does not interact
with the beta-amyloid region. The protein encoded by this partial mouse
cDNA is identical to the C-terminus of the rat Fe65 protein. This mouse
protein also interacts with the homologous C-terminal domains of the mouse
amyloid precursor-like proteins, APLP1 and APLP2. These conserved
cytoplasmic regions contain a common amino acid motif, Asn-Pro-Thr-Tyr,
which has previously been shown to influence both the secretion and
internalization of beta PP. Fe65 has been implicated in regulatory and cell
signaling mechanisms because it contains two different motifs involved in
protein binding, a WW domain (a variant of Src homology 3 domains) and a
phosphotyrosine interaction domain (PID). Interestingly, the PID domain
binds to the same motif present in the conserved cytoplasmic domains of the
beta PP and beta PP-like proteins. RNA analyses reveal that Fe65 is
predominantly expressed in brain and in the regions most affected by
Alzheimer's disease (AD)-associated neuropathology. The human Fe65 mRNA was
cloned from a fetal brain cDNA library. The message encodes a protein of
735 amino acids that is 95% identical to the rat Fe65 protein. The human
Fe65 gene was mapped on human metaphase chromosomes to band 11p15 using
fluorescence in situ hybridization.
相似文献
294.
Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX 总被引:6,自引:0,他引:6 下载免费PDF全文
Barbara Triggs-Raine Timothy J. Salo Hong Zhang Brandy A. Wicklow Marvin R. Natowicz 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(11):6296-6300
Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular matrix, is important in cell migration during embryonic development, cellular proliferation, and differentiation and has a structural role in connective tissues. The turnover of HA requires endoglycosidic breakdown by lysosomal hyaluronidase, and a congenital deficiency of hyaluronidase has been thought to be incompatible with life. However, a patient with a deficiency of serum hyaluronidase, now designated as mucopolysaccharidosis IX, was recently described. This patient had a surprisingly mild clinical phenotype, including notable periarticular soft tissue masses, mild short stature, an absence of neurological or visceral involvement, and histological and ultrastructural evidence of a lysosomal storage disease. To determine the molecular basis of mucopolysaccharidosis IX, we analyzed two candidate genes tandemly distributed on human chromosome 3p21.3 and encoding proteins with homology to a sperm protein with hyaluronidase activity. These genes, HYAL1 and HYAL2, encode two distinct lysosomal hyaluronidases with different substrate specificities. We identified two mutations in the HYAL1 alleles of the patient, a 1412G --> A mutation that introduces a nonconservative amino acid substitution (Glu268Lys) in a putative active site residue and a complex intragenic rearrangement, 1361del37ins14, that results in a premature termination codon. We further show that these two hyaluronidase genes, as well as a third recently discovered adjacent hyaluronidase gene, HYAL3, have markedly different tissue expression patterns, consistent with differing roles in HA metabolism. These data provide an explanation for the unexpectedly mild phenotype in mucopolysaccharidosis IX and predict the existence of other hyaluronidase deficiency disorders. 相似文献
295.
296.
297.
Effects of lipid A and liposomes containing lipid A on platelet and fibrinogen production in rabbits 总被引:3,自引:0,他引:3
The effect of the lipid A moiety of endotoxin on platelet and fibrinogen production was studied in rabbits. Lipid A was infused intravenously in doses ranging from 1 to 100 micrograms/kg body mass; 18 hr later, selenomethionine-75Se was injected intravenously and its incorporation into fibrinogen and platelets determined. Lipid A in saline stimulated fibrinogen and platelet production, but the dose required was 50--100 times that required for an intact endotoxin. Although lipid A solubilized in triethylamine (TEA) was at least 60 times more active in the Limulus amebocyte lysate assay than was lipid A suspended in saline, the sensitivity of platelet and fibrinogen production to solubilized lipid A was increased only twofold. Incorporation of lipid A into liposomes had no effect on its Limulus activity. Lipid A in liposomes continued to stimulate platelet, but not fibrinogen, production. Leukopenia that was induced by lipid A in TEA did not occur when rabbits received the same dose of lipid A in liposomes. Lipid A, like intact endotoxin, can stimulate platelet and fibrinogen production and induce leukopenia but the doses required are high. The low solubility of lipid A in aqueous solutions may be only one factor that determines its biologic activity. 相似文献
298.
299.
Emmanuel Petroulakis Zhimin Cao Joe T. R. Clarke Don J. Mahuran Gregory Lee Barbara Triggs-Raine 《Human mutation》1998,11(6):432-442
Mutations in the HEXA gene, encoding the α-subunit of β-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of GM2 gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G→C (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of GM2 gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing α-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal α-subunit was not detected. When the W474C-containing α-subunit was transiently co-expressed with the β-subunit to produce Hex A (αβ) in COS-7 cells, the mature α-subunit was present, but its level was much lower than that from normal α-subunit transfections, although higher than in those cells transfected with an α-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C α-subunit was found to accumulate in comparison to the normal α-subunit precursor levels. We conclude that the 1422 G→C mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with α-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband. Hum Mutat 11:432–442, 1998. © 1998 Wiley-Liss, Inc. 相似文献
300.
Erratum:Hirakura Y, Lin M‐C, Kagan BL. 1999. Alzheimer amyloid Aβ1–42 channels: Effects of solvent, pH, and Congo Red. J Neurosci Res 57:458–466. In the article referenced above, incorrect figures were substituted for figures 1 and 4. The correct figures appear below. The publisher regrets this error. 相似文献