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Biomedical subjects

A Bond

Publications and source records attributed to A Bond.

At least 37 records · Page 2Linked to original sources
PubMed1999

NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus.

Recent studies have shown that a brief 'pre-conditioning' ischaemic insult reduces the hippocampal cell death caused by a subsequent more severe test insult. In the present studies, we have examined the effects of the non-competitive NMDA receptor antagonist ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine, MK-801) a competitive NMDA receptor antagonist, LY202157, AMPA receptor antagonist ((3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroiso quinoline-3-carboxylic acid, LY293558), a non-competitive AMPA receptor antagonist ((-)-1-(4-amino-phenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-acetyl -2,3-benzodiazepine, LY300164), and a mixed NMDA/AMPA receptor antagonist, LY246492, in a gerbil model of ischaemic tolerance. Ischaemic tolerance was induced by subjecting gerbils to a 2-min 'pre-conditioning' ischaemia (bilateral carotid occlusion) 2 days prior to a 3-min test ischaemia. The effects of MK-801 (2 mg/kg i.p.), LY293558 (20 mg/kg i.p., followed by 4 x 10 mg/kg at 3 h intervals), LY300164 (4 x 10 mg/kg i.p. at 1 h intervals), LY246492 (40 mg/kg i.p., followed by 4 x 20 mg/kg i.p. at 3 h intervals) and LY202157 (30 mg/kg i.p., followed by 4 x 15 mg/kg i.p. at 2 h intervals) were then examined in this model. Initial dosing commenced 30 min prior to the 2-min 'pre-conditioning' ischaemia. Results indicated that a 2-min 'pre-conditioning' ischaemia produced ischaemic tolerance in all cases. The non-competitive NMDA receptor antagonist, MK-801, produced a significant (P < 0.01) reduction in the induced tolerance, while the competitive NMDA receptor antagonist, LY202157, also attenuated (P < 0.05) the induction of tolerance. In contrast, two AMPA receptor antagonists (LY293558 and LY300164) and a mixed NMDA/AMPA receptor antagonist (LY246492) had no effect on the induction of tolerance. These results suggest that NMDA receptor activation, but not AMPA receptor activation is involved in the phenomenon of ischaemic tolerance.

Animals↗
PubMed1999

Early-onset myasthenia gravis: a recurring T-cell epitope in the adult-specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a.

No immunodominant T-cell epitopes have yet been reported in the human acetylcholine receptor (AChR), the target of the pathogenic autoantibodies in myasthenia gravis (MG). We have selected and characterized T cells from MG patients by restimulation in culture with recombinant human AChR to alpha, gamma and epsilon subunits; the gamma and epsilon distinguish the fetal and adult AChR isoforms, respectively. We obtained clones specific for the epsilon, rather than the alpha or gamma, subunit in 3 of the first 4 early-onset MG cases tested. They all responded to peptide epsilon201-219 and to low concentrations of adult but not fetal AChR. Moreover, although using different T-cell receptor genes, they were all restricted to HLA-DR52a (DRB3*0101), a member of the strongly predisposing HLA-A1-B8-DR3 haplotype. This apparently immunodominant epsilon201-219 epitope (plus DR52a) was also recognized by clones from an elderly patient whose MG had recently been provoked by the drug D-penicillamine. In all 4 cases, however, the serum antibodies reacted better with fetal than adult AChR and may thus be end products of determinant spreading initiated by adult AChR-specific T cell responses. Furthermore, as these T cells had a pathogenic Th1 phenotype, with the potential to induce complement-activating antibodies, they should be important targets for selective immunotherapy.

Amino Acid Sequence↗
PubMed1999

Neuroprotective actions of novel and potent ligands of group I and group II metabotropic glutamate receptors.

The role of group I metabotropic glutamate (mGlu) receptors in neurodegeneration is controversial because of the contradictory effects of mGlu1/5 agonists in in vitro models of neuronal cell death. In this study, novel and selective antagonists of mGlu1 and mGlu5: LY367385 and LY367366 were found to show consistent neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced excitotoxicity in vitro and in vivo. Furthermore, intraventricular administration of LY367385 reduced hippocampal cell death in gerbils subjected to transient global ischemia. Previous studies have also shown that activation of group II mGlu receptors may contribute to neuroprotective mechanisms in vitro and in vivo. Three potent group II mGlu agonists--LY354740, LY379268 and LY389795--were found to attenuate both NMDA excitotoxicity and staurosporine-induced neuronal cell death. LY354740 and LY379268 were protective against transient global ischemia in gerbils when dosed intraperitoneally. These results support the view that antagonists of mGlu1 and mGlu5 and agonists of group II mGlu receptors may be useful agents in the therapeutic treatment of neurodegenerative disease.

Animals↗
PubMed1998

Neuroprotective effects of a systemically active group II metabotropic glutamate receptor agonist LY354740 in a gerbil model of global ischaemia.

The neuroprotective effects of a novel Group II metabotropic glutamate receptor (mGluR) agonist, LY354740, have been evaluated in a gerbil model of global ischaemia. When administered at 50 mg/kg, i.p., 30 min and 6 h after a 3 min period of bilateral carotid artery occlusion (BCAO), the compound reduced the damage to CA1 hippocampal neurones to a significant level. However, when the ischaemic insult was made more severe, by increasing the period of occlusion to 4 and 5 min, the neuroprotective effects of LY354740 were reduced. From these findings, it would appear that Group II mGluRs may play a role in ischaemic damage in the gerbil hippocampus and that agonists at these receptors are potential neuroprotective agents.

Animals↗
PubMed1998

Quantitation of the oligosaccharides of human serum IgG from patients with rheumatoid arthritis: a critical evaluation of different methods.

Several different chromatographic methods and a lectin-based assay have been compared for the quantitation of oligosaccharides released from immunoglobulin G (IgG). The analysis of a series of IgG samples purified from the serum of rheumatoid arthritis patients was carried out by these methods to evaluate the percentage of the glycoforms having 0, 1 or 2 galactose residues (G0, G1 and G2) in order to (a) identify the method that can be most widely used for quantitation, (b) accurately define the range of G0 values found in patients with rheumatoid arthritis, and (c) make available a series of characterised standards for distribution to clinical chemistry laboratories. The chromatographic methods involved: release of oligosaccharides by glycoamidase A after protease digestion followed by HPLC analysis of aminopyridine derivatives on reverse phase and normal phase columns; hydrazinolysis treatment with exoglycosidases (G0 mix) and Biogel P4 chromatography of 2-aminobenzamide (2-AB) derivatives; hydrazinolysis and weak anion exchange or normal phase HPLC of 2-AB derivatives; release of oligosaccharides by PNGase F and either Biogel P4 chromatography of 2-AB derivatives or HPAEC-PAD analysis of native oligosaccharides. The G0 values given by these methods compared favourably with each other and a dot blot assay of denatured IgG interaction with Ricinus communis agglutinin and Bandeiraea simplicifolialectin II. The HPLC and HPAEC methods give additional information that may be important in less routine assays.

Arthritis, Rheumatoid↗
PubMed1997

A novel orally active group 2 metabotropic glutamate receptor agonist: LY354740.

Non-specific metabotropic glutamate receptor (mGluR) agonists have previously been shown to potentiate responses of spinal neurones to ionotropic glutamate receptor agonists. In this study we show that LY354740, which is a highly selective Group 2 mGluR agonist with nanomolar potency in vitro, also mimics the above effects following local ejection on spinal neurones in vivo, an action which is blocked by a Group 2 antagonist. Despite its polar nature, LY354740 is also active given either by the i.v. or the oral route (2.5-20 mg/kg) and thus will be a useful agent for investigating the role of Group 2 mGluRs both physiologically and clinically.

Administration, Oral↗
PubMed1997

A detailed lectin analysis of IgG glycosylation, demonstrating disease specific changes in terminal galactose and N-acetylglucosamine.

Serum IgG from rheumatoid arthritis patients contains a decreased number of oligosaccharide structures ending in galactose and thus there is an increase in N-acetylglucosamine as the terminal sugar, compared with healthy individuals. The relationship between these two sugars varies depending on the disease examined: IgG from patients with rheumatoid arthritis, juvenile onset chronic arthritis and Crohn's disease are at one extreme, and exhibit a reciprocal galactose:N-acetylglucosamine relationship, while Sjögren's syndrome and osteoarthritis IgG are at the other extreme, exhibiting a parallel increase in the expression of both galactose and N-acetylglucosamine. These results may occur as a consequence of more than one glycosylation site which is differentially glycosylated, but more likely by changes in the level of bisecting N-acetylglucosamine.

Acetylglucosamine↗
PubMed1997

L-selectin expression on the surface of peripheral blood leucocytes from rheumatoid arthritis patients is linked to disease activity.

Recruitment of mononuclear cells from the circulation to sites of inflammation relies on migration across vessel endothelium. T and B cells, macrophages and neutrophils infiltrate synovial tissue of rheumatoid arthritis (RA) patients. The authors have analysed the numbers of circulating CD3+, CD19+ lymphocytes, monocytes, and granulocytes expressing adhesion molecules (L-selectin, CD44 and CD11a), together with levels of expression in RA patients compared to healthy individuals. Numbers of leucocytes expressing the adhesion molecules detected were similar in RA and control groups. Lower levels of expression of L-selectin on all cells were found in RA patients compared to controls. Expression of L-selectin on T and B cells was found to correlate with disease activity in RA. The authors have observed a characteristic pattern of adhesion molecule expression in RA patients, particularly when analysing the relationships between cells. The close regulation of these molecules between RA patients and healthy individuals is discussed.

Adult↗
PubMed1997

Post-partum flare in MRL-lpr/lpr mice is associated with a parallel increase of N-acetylglucosamine on serum IgG.

Our objective was to investigate IgG glycosylation and disease activity post partum in the MRL-lpr/lpr mouse. Disease activity was monitored using bimalleolar ankle swelling. Levels of galactose and N-acetylglucosamine (GlcNAc) on IgG isolated from serum were measured using biotinylated lectins. Our results show that disease severity increased post partum. This post-partum flare correlated significantly with an increase in IgG GlcNAc expression. The disease severity increased post partum in the MRL-lpr/lpr mouse model similar to the changes seen in rheumatoid arthritis (RA).

Acetylglucosamine↗
PubMed1997

Trends in deliberate self-harm in Oxford, 1985-1995. Implications for clinical services and the prevention of suicide.

BACKGROUND: Deliberate self-harm (DSH) has been a major health problem in the UK for nearly three decades. Any changes in rates of DSH or the demographic characteristics of the patient population are likely to have important implications for clinical services and suicide prevention. METHOD: Data collected by the Oxford Monitoring System for Attempted Suicide were used to review trends in DSH between 1985-1995. RESULTS: There was a substantial increase in DSH rates during the 11-year study period, with a 62.1% increase in males and a 42.2% increase in females. The largest rise was in 15-24-year-old males (+ 194.1%). Changes in DSH rates correlated with changes in national suicide rates in both males and females in this age group. Rates of repetition of DSH increase in both genders during the study period. Paracetamol self-poisoning has continued to increase, half of all overdoses in 1995 involving paracetamol, and antidepressant overdoses have become more common. CONCLUSIONS: The increase in DSH, especially in young males, has important implications for general hospital DSH and medical services. It may herald a reversal of recent progress towards achievement of national suicide targets.

Adolescent↗
PubMed1996

Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase.

The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.

Adenylyl Cyclases↗
PubMed1996

Stereoselective effects-of 2,3-benzodiazepines in vivo: electrophysiology and neuroprotection studies.

The stereoselectivity and potency of 3N-substituted 2,3-benzodiazepines were examined in vivo against excitation of spinal neurones induced by electrophoretic ejection of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate in anaesthetised rats. AMPA receptor antagonist activity resided in the (-) isomers, LY300164 and LY303070, which were effective given electrophoretically, intravenously (2.5-5 mg/kg) or orally (10 mg/kg). The same stereoselectivity was observed in neuroprotection studies. Thus, systemic administration of the (-) isomer, but not the (+) isomer, of these 2,3-benzodiazepines before or immediately after bilateral carotid artery occlusion in the gerbil was neuroprotective. For example, 10 mg/kg of LY300164 intraperitoneally or orally provided survival of up to 25% of hippocampal CA1 neurones.

Animals↗
PubMed1996

The relationship between exposed galactose and N-acetylglucosamine residues on IgG in rheumatoid arthritis (RA), juvenile chronic arthritis (JCA) and Sjögren's syndrome (SS).

The relationship between exposed galactose and N-acetylglucosamine on IgG in RA, JCA and SS was investigated. This was achieved using IgG isolated from serum where the levels of galactose and N-acetylglucosamine (GlcNAc) were detected using biotinylated lectins. Galactose and GlcNAc on IgG from patients with RA and JCA are inversely related, but in contrast, in SS, galactose expression on IgG decreased while GlcNAc expression remained similar to normal levels. Alterations in IgG glycosylation are closely associated with the development of adult and juvenile chronic arthritis and SS, but the changes involved are different in RA compared with SS, suggesting that the precise pattern of exposed sugars is associated with different rheumatological diseases.

Acetylglucosamine↗
PubMed1995

Distinct oligosaccharide content of rheumatoid arthritis-derived immune complexes.

OBJECTIVE: To investigate the association between glycosylation and immune complex formation in various disease groups. METHODS: Immune complexes and IgG were isolated from serum and their carbohydrate content evaluated in a dot-blot assay using specifically binding lectins. RESULTS: Significantly more N-acetylglucosamine was detected in complexes from patients with rheumatoid arthritis (RA) than in those from patients with systemic lupus erythematosus, Crohn's disease, or infectious endocarditis, or from normal controls (P < 0.001). The immune complex concentration in the circulation was strongly associated with N-acetylglucosamine levels (P < 0.001 by chi-square analysis). CONCLUSION: The composition of immune complexes from RA patients is distinct in carbohydrate content from those found in other disease groups.

Acetylglucosamine↗