Insertion of lysosomal targeting sequences to the amyloid precursor protein reduces secretion of beta A4.

The processing of the amyloid precursor protein (APP) was investigated in cells stably expressing different APP hybrid proteins. The cytoplasmic domain of APP was either deleted or replaced by the corresponding domain of the membrane protein TGN38, lamp-1, or LIMPII. The cytosolic domain of TGN38 in the APP molecule did not alter the secretion of beta A4 when compared with the wild-type APP; however, APP associated with the cell surface and the nonamyloidogenic processing of APP were reduced.

A single administration of d-amphetamine prior to stimulus pre-exposure and conditioning attenuates latent inhibition.

The effect of a single administration of d-amphetamine (0.32 mg/kg, s.c.

Extracts from rhizomes of Cyperus articulatus (Cyperaceae) displace [3H]CGP39653 and [3H]glycine binding from cortical membranes and selectively inhibit NMDA receptor-mediated neurotransmission.

The marshland plant Cyperus articulatus (Cyperaceae) is commonly used in traditional medicine in Africa and Latin America to treat a wide variety of human diseases ranging from headache to epilepsy. We tested the hypothesis that the purported anti-epileptic effect of this plant might be due to a functional inhibition of excitatory amino acid receptors. One or several component(s) contained in the extracts inhibited the binding of [3H]CGP39653 to the NMDA recognition site and of [3H]glycine to the strychnine-insensitive glycine site of the NMDA receptor complex from rat neocortex.

Amyloid precursor protein truncated at any of the gamma-secretase sites is not cleaved to beta-amyloid.

beta A4 secretion occurs upon processing of amyloid protein precursor (APP) by beta-secretase (N-terminus of beta A4) and gamma-secretase (C-terminus). To determine the sequence of these activities and the processing intermediate of beta A4, we expressed several truncated APP molecules in human HEK-293 cells. Immunofluorescence and biotinylation studies indicated that full-length APP or APP lacking the cytosolic domain both were located intracellularly, associated with the cell surface and secreted.

The competitive NMDA receptor antagonist SDZ 220-581 reverses haloperidol-induced catalepsy in rats.

The present studies investigated whether SDZ 220-581 ((S)-alpha-amino 2'chloro-5-(phosphonomethyl)[1,1'-biphenyl]-3-propanoic acid), a potent, competitive antagonist at the NMDA glutamate receptor subtype, reversed haloperidol-induced catalepsy in rats, a widely used model of Parkinson's disease. SDZ 220-581 (0.32-3.

Biphenyl-derivatives of 2-amino-7-phosphono-heptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonists--II. Pharmacological characterization in vivo.

A selection of biphenyl-analogues of 2-amino-7-phosphonoheptanoic acid (AP7), N-methyl-D-aspartate (NMDA) receptor antagonists with high affinity in vivo efficacy. The lead compound SDZ EAB 515 was found to inhibit L-phenylalanine uptake by the large neutral amino acid carrier in vitro and in vivo; active transport may thus confer a good bioavailability to this class of compounds. CNS effects were demonstrated by significant changes in 2-deoxyglucose-uptake in various brain regions at doses from 1 to 10 mg/kg i.

Biphenyl-derivatives of 2-amino-7-phosphonoheptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonist--I. Pharmacological characterization in vitro.

Omega-Phosphono-substituted alpha-amino acids have long been known to be antagonists at the N-methyl-D-aspartate (NMDA) receptor. D-2-Amino-5-phosphonopentanoic (D-AP5) and D-2-amino-7-phosphonoheptanoic (D-AP7) acids are the "prototype" compounds of this kind. Insertion of a biphenyl-moiety in the middle of the AP7 chain results in increased affinity and reverses the enantioselectivity from a D- to an L-form preference (Müller et al.

Effect of alkalizing agents on the processing of the beta-amyloid precursor protein.

We investigated the processing pathway of the amyloid precursor protein (APP) to the secretion of beta A4 under the treatment of ammonium chloride (NH4Cl), bafilomycin A1 (bafA1), or chloroquine, all three agents thought to raise the pH in acidic compartments. HEK-293 cells expressing wild-type APP (APPwt) and APP carrying the Swedish double mutation (APPswe) were affected in a different manner: while cells expressing APPswe decreased the secretion of beta A4 after treatment with bafA1 and NH4Cl, cells expressing APPwt compensated the drug-induced decrease in beta A4 by an increased generation of alternative beta A4-related peptides. Within cells APP accumulated, while the formation of a C-terminal fragment of APP generated by beta-secretase was completely inhibited.

Conformations of synthetic beta peptides in solid state and in aqueous solution: relation to toxicity in PC12 cells.

The secondary structures of peptides beta 25-35 (the active toxic fragment) and beta 35-25 (reverse sequence and non-toxic fragment), as well as of the amidated beta (25-35)-NH2 peptide were investigated in aqueous solution and in the solid state by means of Fourier-transformed infrared spectroscopy and circular dichroism spectroscopy. The conformations of the beta 25-35 and beta 35-25 in solid state were identical and contained mostly beta-sheet structures. In solid state the amidated beta (25-35)-NH2 peptide also contained mostly beta-sheet structures.

Reduction of inflammation and pyrexia in the rat by oral administration of SDZ 224-015, an inhibitor of the interleukin-1 beta converting enzyme.

1. The aim of this study was to determine whether a synthetic inhibitor of the interleukin-1 beta converting enzyme (ICE) displays oral activity in models of inflammation. 2.

D-cycloserine enhances social behaviour in individually-housed mice in the resident-intruder test.

D-Cycloserine (DCS) has been reported to affect the central nervous system in man. To investigate whether the compound produces specific behavioural effects, DCS was administered to male mice in a resident-intruder situation and the behaviour of the interacting mice assessed using ethological analysis. Resident mice given DCS (32.

Isolation, biochemical characterization and N-terminal sequence of rolipram-sensitive cAMP phosphodiesterase from human mononuclear leukocytes.

A cyclic AMP specific phosphodiesterase (type IV) was purified 450,000-fold from human peripheral blood mononuclear cells through a sequence of chromatographic steps involving anion exchange, affinity chromatography on a matrix coupled to a derivative of the type IV inhibitor rolipram, and gel filtration. The enzyme showed apparent molecular masses of 70 kDa on gel filtration and 35 kDa on denaturing or native PAGE, indicating a possible dimerization or cleavage under certain conditions. The isoelectric point was 4.

Clozapine promotes approach-oriented behavior in male mice.

Clozapine, an atypical antipsychotic agent, exerts ameliorative effects upon negative symptoms, but to date, its mechanism of action is poorly understood. We employed ethological methods to study the effects of clozapine, given 1 hour beforehand, on the social responses of (1) an individually housed male mouse exposed to an equally "matched" aggressive male opponent and (2) a group-housed "intruder" mouse exposed to an isolated, aggressive male. Encounters lasted 6 minutes.

Somatostatin (SRIH) messenger ribonucleic acid expression in human neuroendocrine and brain tumors using in situ hybridization histochemistry: comparison with SRIH receptor content.

Somatostatin (SRIH) receptors are expressed in a large number of neuroendocrine and brain tumors. To evaluate the potential of these tumors locally to produce the SRIH required to bind to SRIH receptors, we have investigated in 158 human tumors whether they express mRNA for SRIH, using in situ hybridization. Among 78 neuroendocrine tumors tested, 13 of 13 medullary thyroid carcinomas, 19 of 34 pheochromocytomas, 3 of 11 paragangliomas, 0 of 4 small cell lung cancers, 4 of 9 adrenal neuroblastomas, and 4 of 7 gastroenteropancreatic tumors contained SRIH mRNA.

Antagonism of non-NMDA receptors inhibits handling-induced, strychnine-potentiated convulsions.

The effects of blockade of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA) and kainate subtypes of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) and compared to the effects of N-methyl-D-aspartate (NMDA) receptor blockade with D-CPPene (D-(E)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylic acid), a competitive NMDA antagonist. Both compounds exerted peak blocking activity 30 min after intraperitoneal administration. Using this pretreatment interval, a dose-response relationship for blocking handling-induced, strychnine-potentiated convulsions was generated for each compound.

Modulation of secretory processes of phagocytes by IX 207-887.

In chronic inflammation, the mediators released by phagocytes are in part responsible for the initiation and perpetuation of the disease. IX 207-887, which is a novel antiarthritic drug, inhibits the release of cytokines from mononuclear cells at concentrations which are achieved therapeutically in human rheumatoid arthritis and in animal models of arthritis. Furthermore, the production of superoxide and release of azurophil and specific granules by N-formyl-Met-Leu-Phe-stimulated neutrophils are significantly reduced.

Somatostatin receptors in human renal cell carcinomas.

The presence of somatostatin receptors was evaluated in samples of 39 surgically removed human renal cell carcinomas with receptor autoradiography on tumor sections by using iodinated [Tyr3]octreotide as the radioligand. All types, grades and stages of tumors were represented. Twenty-eight of 39 renal cell carcinomas (72%) were shown to be somatostatin receptor positive.

Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications.

Somatostatin receptors (SS-R) have been identified in membrane homogenates or tissue sections from several hundred tumors. SS-R were found in most neuroendocrine tumors, i.e.

Prevention of adjuvant arthritis by cyclosporine in rats.

The effect of cyclosporine A during the development phase of adjuvant arthritis was studied in 40 female rats. Five groups of eight animals each received oral cyclosporine, 2.5, 5, 10, 20, or 30 mg/kg daily for 30 days.

Biochemical and thermodynamic aspects of the binding of [3H]glycine to its strychnine-insensitive recognition site associated with the N-methyl-D-aspartate receptor complex.

The molecular mechanism of interaction between glycine and its strychnine-insensitive binding site linked to the N-methyl-D-aspartate receptor was investigated by examining on the one hand the thermodynamic properties of glycine binding, and, on the other hand, the effects of various functional group modifying agents on ligand binding. Raising the incubation temperature from 0 degrees to 37 degrees resulted in a consistent decrease of glycine binding affinity. Calculation of thermodynamic parameters from the corresponding Van't Hoff plot showed that the binding of glycine was mainly entropy-driven, the change in enthalpy contributing only little (25-30%) to the change in Gibbs free energy.

N-methyl-D-aspartate receptor antagonists and channel blockers have different effects upon a spinal seizure model in mice.

Spinal seizures in mice induced by handling following pretreatment with a subconvulsive dose of strychnine could be blocked by competitive N-methyl-D-aspartate (NMDA) receptor antagonists (D-, L-, DL-CPPene (CPPene = (E)-4-(3-phophonoprop-2-enyl)-piperazine-2-carboxylic acid), D-AP5 (D-2-amino-5-phophonovalerate)) and compounds acting at receptor-coupled modulatory sites (R-HA 966, ifenprodil). NMDA cation channel antagonists (MK-801, phencyclidine) however, resulted in ataxia, tremor and loss of righting. There are differences between NMDA antagonists acting via the receptor and the cation channel in this model of spinal seizure.

Spectrophotometric method to quantify and discriminate urokinase and tissue-type plasminogen activators.

Plasminogen activator and urokinase are often used as biological markers of cell activation. However, the methods currently used are cumbersome, make no discrimination between tissue-type plasminogen activator and urokinase, and do not allow expression of the results of the overall reaction in International Units. The one-step method described in this paper lacks these drawbacks.

Induction of neutrophil-mediated cartilage degradation by interleukin-8.

Neutrophil influx into the inflamed joint is a characteristic feature of disease flares in patients with rheumatoid arthritis. Recently, a protein produced by monocytes and fibroblasts that has chemoattractive/activating properties for neutrophils has been identified and characterized. This protein has been called interleukin-8 (IL-8).

Contrasting modulation by transforming growth factor-beta-1 of insulin-like growth factor-I production in osteoblasts and chondrocytes.

The importance of locally produced insulin-like growth factor-I (IGF-I) in connective tissues has recently been recognized. It has been postulated that the action of anabolic hormones on bone may be mediated through local IGF-I release. However, whether IGF-I can also be modulated by other locally acting cytokines has not been addressed.