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At least 667 records · Page 37Linked to original sources
PubMed1997

Induction of heat-shock protein (HSP72) in the cingulate and retrosplenial cortex by drugs that antagonize the effects of excitatory amino acids.

To address the issue of the cytotoxicity of glutamate antagonists, we administered representative agents to rats and used HSP72 immunocytochemistry as a measure of neuronal injury in the brain. The doses studied spanned the reported neuroprotective range for each compound. Some, but not all, glutamate antagonists induce neuronal injury in the brain. The non-competitive NMDA antagonists (MK801 and dextrorphan) demonstrate maximum toxicity. Competitive NMDA antagonists (CGS 19755 and MDL 100,453) may or may not induce neuronal injury depending on the particular compound. The polyamine site (SL 82.0715-10) antagonist does not result in neuronal injury. Cingulate and retrosplenial cortex neurotoxicity is not a ubiquitous feature of neuroprotective agents that block excitotoxcity, but is limited to NMDA antagonists and may depend upon the duration and completeness of the blockade of the NMDA receptor.

Animals↗
PubMed1995

Comparative studies on the anticoagulant and protease generation inhibitory actions of newly developed site-directed thrombin inhibitory drugs. Efegatran, argatroban, hirulog, and hirudin.

Site-directed thrombin inhibitors are being currently assessed clinically for their antithrombotic efficacy. Although these agents are claimed to be specific and direct thrombin inhibitors, their mechanism of inhibition varies. The objective of these studies was to compare four such agents in in vitro systems and to assess their relative anticoagulant efficacy. The four agents utilized in these studies were argatroban, Efegatran, hirulog, and hirudin. While hirulog and hirudin are specific irreversible inhibitors of thrombin, argatroban and Efegatran are reversible. All four agents were found to have a concentration-dependent anticoagulant effect when supplemented into normal human plasma, as assessed in the global clotting tests (PT, APTT, and Heptest). The most potent anticoagulant on a molar basis was hirudin in all three tests. The other three agents had similar anticoagulant actions. All four agents were also capable of inhibiting the generation of thrombin and factor Xa as determined by an amidolytic method after intrinsic or extrinsic activation of fibrinogen-deficient human plasma. Except for hirulog, all agents inhibited the extrinsic generation of thrombin, with hirudin being the most potent agent. The intrinsic generation of thrombin was blocked by the reversible thrombin inhibitors (argatroban and Efegatran) but not by the irreversible inhibitors (hirulog and hirudin). While all agents were capable of inhibiting the intrinsic generation of factor Xa at very low concentrations, only Efegatran was capable of blocking the extrinsic generation of the same factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1986

Presence of the peroxisomal 22-kDa integral membrane protein in the liver of a person lacking recognizable peroxisomes (Zellweger syndrome).

Peroxisomes have not been detected in liver and kidney of patients with Zellweger syndrome. Some peroxisome proteins are missing; others are present in normal amounts but are located in the cytosol. We have prepared an antiserum against the 22-kDa integral membrane protein characteristic of rat liver peroxisomes. The antiserum crossreacts with the human liver counterpart, which likewise has a mass of 22 kDa. By immunoblot analysis, we demonstrate that the 22-kDa protein is present in normal amount in Zellweger liver and is integral to a membrane. The result suggests that peroxisome membranes are assembled in Zellweger syndrome but may be defective for the import of matrix proteins. As a result, newly synthesized proteins are left in the cytosol, where some persist and others are degraded. Lacking their usual content, such aberrant peroxisomal membranes would be unrecognizable morphologically. Immunoblot analyses also showed that the peroxisomal hydratase-dehydrogenase is deficient in Zellweger kidney as well as liver, but catalase is present in both organs.

Catalase↗
PubMed1996

Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia.

Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion throughout cortex. N-methyl-D-aspartate (NMDA) receptors play a crucial role in the initiation of long-term memory. Neurochemical mechanisms underlying the transient memory storage required for working memory, however, remain obscure. Auditory sensory memory, which refers to the ability of the brain to retain transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, represents one of the simplest components of the brain working memory system. Functioning of the auditory sensory memory system is indexed by the generation of a well-defined event-related potential, termed mismatch negativity (MMN). MMN can thus be used as an objective index of auditory sensory memory functioning and a probe for investigating underlying neurochemical mechanisms. Monkeys generate cortical activity in response to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological micromanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in primary auditory cortex. These findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Furthermore, they suggest a crucial role of cortical NMDA receptors in the assessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance.

Animals↗
PubMed1983

Pharmacological differentiation between responses of rat medullary dorsal horn neurons to noxious mechanical and noxious thermal cutaneous stimuli.

Response of lamina V medullary dorsal horn neurons to noxious thermal and noxious mechanical facial stimuli were challenged with iontophoretically applied cis-2,3-piperidine dicarboxylic acid, a broad spectrum excitatory amino acid antagonist. This antagonist reduced neuronal responses to noxious mechanical stimuli but not responses to noxious thermal stimuli. These results suggest that different neural mechanisms underlie the responses of lamina V neurons to different noxious stimuli, and that responses to noxious mechanical stimuli appear to involve excitatory amino acid receptors.

Animals↗
PubMed1991

[Thrombin.antithrombin III complex].

Increase of TAT is reflected by the generation of thrombin in hypercoagulable state. TAT might increase in DIC characterized by the formation of disseminated micro-thrombosis. DIC was classified into three groups according to the results of screening tests (FDP, platelet count, fibrinogen, prothrombin time). TAT values significantly increased in the stage of pre-DIC compared with the control group consisting of DIC prone underlying disease. Pre-DIC was easily detected by an increase of TAT during the clinical course. Management of high TAT began with the use of an anticoagulant such as heparin under the condition of sufficient ATIII level. The lowering effect of TAT was easily obtained by the anticoagulant. In ATIII-deficient DIC, the high TAT reduced with the substitution of ATIII concentrate, though a transient increase of TAT was found during the administration of ATIII. To reduce the high TAT under the deficient state of ATIII, MD805, a synthetic thrombin inhibitor, was introduced to avoid further consumption of ATIII. The TAT was decreased by the use of MD805 without administration of ATIII. MD805 could be used as an effective anticoagulant in high TAT due to DIC under an ATIII-deficient state. Although the TAT improved with an adequate anticoagulation in DIC, spontaneous bleeding sometimes appeared as a complication associated with the high level of alpha 2 plasmin inhibitor plasmin complex. In this case, the combined use of tranexamic acid relieved the bleeding.

Antithrombin III↗
PubMed1996

Functionality map analysis of the active site cleft of human thrombin.

The Multiple Copy Simultaneous Search methodology has been used to construct functionality maps for an extended region of human thrombin, including the active site. This method allows the determination of energetically favorable positions and orientations for functional groups defined by the user on the three-dimensional surface of a protein. The positions of 10 functional group sites are compared with those of corresponding groups of four thrombin-inhibitor complexes. Many, but not all features, of known thrombin inhibitors are reproduced by the method. The results indicate that certain aspects of the binding modes of these inhibitors are not optimal. In addition, suggestions are made for improving binding by interaction with functional group sites on the thrombin surface that are not used by the thrombin inhibitors.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Use of thrombin inhibitors ex vivo allows critical care clinical chemistry and hematology testing on common specimens.

OBJECTIVE: To evaluate the suitability of the thrombin inhibitors PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethylketone) or Argatroban for anticoagulation of blood prior to critical care testing of whole blood or plasma. DESIGN AND METHODS: Initially we evaluated the effect of PPACK (0-200 microM) or Argatroban (0-590 microM) on serum glucose, urea, creatinine, calcium and electrolyte tests on two chemistry analyzers (Hitachi 717 and Ektachem 700XR). Subsequently plasma and serum from whole blood samples containing either heparin 15,000 IU/L or PPACK 75 microM or Argatroban 245 microM or no anticoagulant were tested and compared. We analysed and compared whole blood containing either PPACK 75 microM or Argatroban 245 microM or ethylenediaminetetraacetic acid (EDTA) using a Coulter STK-R hematology analyzer at intervals for 90 minutes. RESULTS: The measurement of electrolytes, urea, creatinine, calcium or glucose was unaffected by either Argatroban or PPACK in either serum or anticoagulant-specific plasmas (p > 0.05). For specimens from individual donors, serum potassium was higher than plasma potassium, irrespective of anticoagulant used. Clinically equivalent complete blood counts were achieved for 60 minutes using EDTA-whole blood, or whole blood containing 245 microM Argatroban or 75 microM PPACK. However automated differential white cell counting was not reliable with either form of thrombin inhibitor-whole blood. Argatroban-anticoagulated blood demonstrated concentration and time dependent changes in platelet counts, whereas platelet counts were stable in blood containing 75 microM PPACK for up to 90 minutes. CONCLUSION: Specimens of blood anticoagulated with either 75 microM PPACK or 245 microM Argatroban can be used for either critical care chemistry or hematology testing.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Presynaptic origin of paired-pulse depression at climbing fibre-Purkinje cell synapses in the rat cerebellum.

1. Climbing fibre-mediated excitatory postsynaptic potentials (CF-EPSPs) or currents (CF-EPSCs) were recorded from Purkinje cells in rat cerebellar slices using the whole-cell recording technique. 2. Climbing fibre responses displayed prominent paired-pulse depression (PPD). In the current-clamp recording mode, PPD resulted in a decreased number of spikelets in the second complex spike of the pair, and depression of the after-depolarization and after-hyperpolarization. 3. The mechanism of PPD was examined under voltage clamp. Manipulations that reduce transmitter release significantly affected PPD. These included lowering extracellular Ca2+ concentration and bath application of baclofen or adenosine. 4. Changing the number of stimulated climbing fibres, equivalent to changing the number of release sites, had no effect on PPD. 5. Selective manipulations of postsynaptic responsiveness had no effect on PPD. These included partial blockade of CF-EPSCs by a non-NMDA receptor antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and changing the holding potential. 6. A rapidly dissociating AMPA receptor antagonist, 2,3-cis-piperidine dicarboxylic acid, inhibited the second CF-EPSC of the pair proportionately more than the first, suggesting that presynaptic release by the second pulse is decreased. 7. PPD at interstimulus intervals of 50 ms or longer (up to 3000 ms) was not significantly affected by manipulations that change postsynaptic glutamate receptor desensitization. 8. Blockade of metabotropic glutamate, GABAB and adenosine receptors had no effect on PPD, suggesting that presynaptic autoreceptors do not contribute to PPD. 9. These results indicate that decreased transmitter release is a major cause of PPD at cerebellar climbing fibre-Purkinje cell synapses.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Study of the pharmacological effect of the bile salt, sodium scymnol sulfate, from Rhizoprionodon acutus. IV. Effects of naturally occurring bile alcohols, bile acids and their conjugates on lesion development and vascular endothelial cell injury in a rat peripheral arterial occlusion model.

A series of naturally occurring bile alcohols, bile acids and their conjugates has been investigated as part of our studies to develop unique anticoagulants with a potent prophylactic effect against vascular endothelial cell injury induced by lactic acidosis in vivo and in vitro. In an in vivo rat peripheral arterial occlusion model induced by lactic acid injection, oral administration of a single dose of 3 mg/kg scymnol significantly inhibited edematous swelling and development of lower limb lesions, including gangrene, and reduced changes in clotting system functions and serum lactate dehydrogenase activity. It had no effect on clotting system functions in sham-operated rats. The structure-activity relationship suggests that the [24R-(+)-5beta-cholestane-3alpha,7alpha,24,26-pento l] or [3alpha,7alpha-dihydroxy-5beta-cholanic acid] structure is important for a potent prophylactic effect following oral administration. Intravenous administration of a single dose of 0.3 mg/kg sodium (25S)-scymnol sulfate or scymnol prevented lesion progression as effectively as oral administration of scymnol. Sodium (25S)-scymnol sulfate and ursodeoxycholic acid showed clear protective effects against cultured vascular endothelial cell damage due to lactic acidosis which were dose-dependent. The above results suggest that bile steroids such as scymnol, sodium (25S)-scymnol sulfate, ursodeoxycholic acid, and chenodeoxycholic acid may play a role in protecting endothelial cells against injury caused by lactic acidosis. These compounds are candidates for novel anti-ischemic drugs that act by specifically protecting vascular endothelial cells.

Animals↗
PubMed1989

Behavioral pharmacological profile of CGS 19755, a competitive antagonist at N-methyl-D-aspartate receptors.

CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylic acid), a competitive antagonist at N-methyl-D-aspartate (NMDA)-preferring receptors, blocked both NMDA-induced convulsions in normal CF1 mice and sound-induced wild running in seizure-prone DBA/2 mice. The ED50 values for CGS 19755 to produce these effects (in the range of 2 mg/kg i.p.) were at least 3-fold lower than those which impaired the traction reflex, an index of motor coordination. When administered p.o. by gavage, CGS 19755 had little or no effect in these test procedures. In an experimental model of anxiety in rats, CGS 19755 significantly increased conflict responding within a relatively narrow dose range (minimum effective dose, 1.73 mg/kg i.p.). At higher doses of CGS 19755, this effect appeared to be obscured by drug-induced reductions in overall responding. Potential muscle relaxant effects were also suggested by the generalization of CGS 19755 to diazepam discriminative stimuli (ED50 = 9.0 mg/kg i.p.) and by impaired rotorod performance (ED50 = 6.2 mg/kg i.p.) in rats. Although some resemblances were apparent between the behavioral effects of CGS 19755 and those of phencyclidine-type drugs, the phencyclidine-like behaviors appeared only at considerably higher doses of CGS 19755 than those associated with anticonflict activity, and only partial generalization of CGS 19755 to dexoxadrol was observed at high doses. CGS 19755 promises to be an important new research tool for investigating the function of brain NMDA receptors.

Animals↗
PubMed1993

The antithrombotic effect of low molecular weight synthetic thrombin inhibitors, argatroban and PPACK, on He-Ne laser-induced thrombosis in rat mesenteric microvessels.

The antithrombotic effect of low molecular weight synthetic thrombin inhibitors, argatroban ((2R, 4R)-4-methyl-1-[N2-[(3-methyl-1, 2, 3, 4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarbox ylic acid monohydrate]) and PPACK (D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone) on He-Ne laser-induced thrombosis in rat mesenteric microvessels was studied. Both inhibitors showed a significant antithrombotic effect at 0.5 mg/kg which lasted for 50 min and 50-60 min using argatroban and PPACK, respectively. A dose-dependent effect was observed in arterioles and venules. The results suggest that thrombin plays an important role in the formation of a platelet thrombus in vivo.

Amino Acid Chloromethyl Ketones↗
PubMed1987

Characterization of motor activity patterns induced by N-methyl-D-aspartate antagonists in gerbils.

A computerized motor activity data collection and analysis system is described. An example of the utilization of the Digiscan system is provided, in which motor activity patterns induced by three N-methyl-D-aspartate (NMDA) antagonists and the dissociative anesthetic, ketamine, are compared. All of these compounds produce a distinct pattern of motor activity characterized by an increase in distance traveled, movement time, speed and perimeter walking, with a decrease in vertical activity. Recently described links between NMDA and phencyclidine (PCP) binding sites may account for these findings. The utility of computerized motor activity apparatus is clearly demonstrated.

2-Amino-5-phosphonovalerate↗
PubMed1992

Isolation and structural characterization of a new crosslinking amino acid, cyclopentenosine, from the acid hydrolysate of elastin.

A novel polyfunctional crosslinking amino acid, which was developed slower than lysinonorleucine and faster than desmosine on thin layer chromatography, was isolated from the hydrolysate of bovine aorta elastin. Its proposed structure was verified by ultraviolet spectroscopy, fast atom bombardment mass spectroscopy, and nuclear magnetic resonance spectroscopy. The data indicated it to be a trifunctional amino acid with a cyclopentene structure. The mass spectral analysis indicated a parent compound with a mass of 381 (C18H27N3O6). The proposed structure is one derived from the condensation of three allysine residues. Based on the names of other crosslinking amino acids found in elastin, the trivial name of cyclopentenosine is given to this compound.

Amino Acids↗
PubMed1999

Study of the pharmacological effect of the bile salt, sodium scymnol sulfate, from Rhizoprionodon acutus. III. Protective effect of scymnol against vascular endothelial cell damage in a rat peripheral arterial occlusion model.

The prophylactic action of scymnol in a rat peripheral arterial occlusion model, involving injection of 5% lactic acid into the femoral artery, was investigated. Increases in serum lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities and in plasma levels of thrombin and antithrombin III complex (TAT) were observed in this model 3 h after injection of lactic acid. Changes in LDH activity were characterized by increases in isozymes LDH4 and LDH5 and an elevated LDH4/LDH5 ratio. The ratio of the LDH4 to LDH5 increments was similar to that seen in a rat endothelial cell culture. Oral preadministration of scymnol had a preventive effect on the development of lesions in this model. It significantly reduced the LDH4 and LDH5 activity, the LDH4/LDH5 ratio and the TAT levels dose-dependently over the range 1, 3 or 10 mg/kg, compared with the values in control rats. However, its administration after lactic acid injection, or to sham-operated rats was ineffective, even at a dose of 10 mg/kg. The effects of scymnol were also compared with those of ticlopidine and argatroban. The findings show that scymnol may be useful in preventing thrombotic peripheral arterial occlusive disorders and that it potently protects endothelial cells against lactic acidosis in this model.

Alanine Transaminase↗