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Biomedical subjects

D M Bowen

Publications and source records attributed to D M Bowen.

At least 19 recordsLinked to original sources
PubMed1992

NMDA receptors assessed by autoradiography with [3H]L-689,560 are present but not enriched on corticofugal-projecting pyramidal neurones.

Experimental lesions followed by binding of [3H]4-trans-2-carboxy-5,7-dichloro-4-phenylamino-carbonylamino-1,2 ,3,4- tetrahydroquinoline ([3H]L-689,560, a novel ligand that binds to the glycine modulatory site), [3H]glycine and [3H]glutamate (N-methyl-D-aspartate (NMDA) sensitive) to cryostat sections and quantitative autoradiography were used to investigate the cellular localization of the NMDA receptor complex in the neocortex of the rat. The lesions were produced by intrastriatal injections of either volkensin (2 and 6 ng) or ricin (10 ng): both are suicide transport agents but only the former is retrogradely transported in the CNS. The binding of [3H]L-689,560 was significantly reduced in rats receiving 2 or 6 ng volkensin in deep cortical layers of Fr1/Fr2 ipsilateral to the striatal lesion. Similar reductions were also seen in [3H]glycine and [3H]glutamate binding, but only in rats receiving 6 ng volkensin. Quantitative histological analysis had previously revealed a loss of large infragranular pyramidal neurones with sparing of both interneurones and supragranular pyramidal neurones. There were no significant reductions in binding of any ligand in the superficial layers. In cortical areas Par1/Par2, [3H]L-689,560 was also significantly reduced in deep layers but only in rats receiving 6 ng volkensin. Binding was also reduced in the superficial layers by contrast to Fr1/Fr2. [3H]Glycine and [3H]glutamate binding were unaffected in this area. Binding of [3H]L-689,560 was unaffected in any area following intrastriatal ricin injection. The present study indicates that the NMDA receptor complex is present on pyramidal cells forming the corticofugal pathways. This is discussed in terms of the 5-HT1A receptor which is enriched on these cells.

Aminoquinolines↗
PubMed1992

Protease 'Clipsin' extract activity reflects demographic characteristics of human brain.

'Clipsin' and other peptide bond hydrolase activities that appear to be integral membrane proteins, including two implicated in the formation of the histological hallmarks of Alzheimer's disease, were assayed in the frontal and parietal cortex from a large (n = 45) series of postmortem human brains. Tissues were extracted sequentially with detergent-containing and low ionic strength buffers. The final extracts obtained with detergent-high ionic strength buffer were assayed for peptide-bond hydrolase activity using radiolabelled casein and four chromophore-linked peptide substrates. Hydrolysis of N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide and alpha-casein showed evidence of sensitivity to the presence of Alzheimer's disease (n = 22) and some of the seven other demographic features (postmortem delay; mode of death in the case of one substrate) of the brain samples considered. By contrast, activity towards carbobenzoxy(Z)-Leu-Leu-Glu-2-naphthylamide, Z-Val-Lys-Met-4-methyl-coumaryl-7-amide and Z-Val-Lys-Lys-Arg-4-methoxy-2-naphthylamide were independent of all factors. The results are discussed in terms of damage to a sub-population of protease-containing membranes.

Aged↗
PubMed1992

Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms.

Behavioural symptoms of Alzheimer's disease, such as aggression, may determine the care patients required. Most postmortem neurochemical studies have been of institutionalized patients and conclusions drawn from these may not be valid for all patients. We have shown that serotonin 2 receptors are not lost from 12 of the 13 areas of cerebral cortex examined in the patients assessed to be free of aggressive symptoms. This has been interpreted as representing the relative preservation of cortical interneurones. In contrast choline acetyltransferase activity was reduced in all areas whereas serotonin content was reduced in only 2 of the 4 areas examined.

Aged↗
PubMed1992

Effect of psychotropic drugs on excitatory amino acids in patients undergoing psychosurgery for depression.

Samples of ventricular CSF were taken from 52 consecutive patients admitted for psychosurgery for intractable depression. Concentrations of asparagine, aspartate, glutamine, glutamic acid, and serine were determined. Glutamate and aspartate concentrations, implicated in excitotoxic brain damage, were not affected by various types of psychotropic drug treatment. Serine, a modulator of glutamate responses, was significantly elevated in samples from subjects receiving antidepressants. These subjects responded poorly to the operation. Psychotropic drugs are unlikely to be neurotoxic. Nevertheless, antidepressants may influence excitatory neurotransmission.

Adult↗
PubMed1992

5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched on neocortical pyramidal neurones destroyed by intrastriatal volkensin.

Experimental lesions followed by binding of [3H]8-hydroxy-2-(n-dipropylamino)tetralin (8-OH-DPAT) and [3H]ketanserin to cryostat sections and quantitative autoradiography were used to investigate the cellular localization of 5-hydroxytryptamine1A (5-HT1A) and 5-hydroxytryptamine2 (5-HT2) receptors in the neocortex of the rat. The lesions were produced by intrastriatal injections of either volkensin (2 and 6 ng) or ricin (10 ng): both are suicide transport agents, but only the former is retrogradely transported in the central nervous system. Only animals treated with volkensin showed cortical receptor changes and these were almost exclusively confined to the 5-HT1A site. The binding of [3H]8-OH-DPAT was significantly reduced in rats receiving 2 or 6 ng volkensin in the deeper cortical layers of areas Fr1/Fr2 of neocortex ipsilateral to the striatal lesion. Quantitative histological analysis of adjacent sections had previously revealed a significant loss of large infragranular pyramidal neurones with sparing of both interneurones and supragranular pyramidal neurones. There was no significant reduction in [3H]8-OH-DPAT binding in superficial layers. In cortical areas, Par1/Par2 [3H]8-OH-DPAT binding was significantly reduced (2 and 6 ng animals) in both superficial and deeper cortical layers, but quantitative histological analysis has not been performed. The binding of [3H] ketanserin was unaffected except for the most superficial layers of Par1/Par2, where binding was significantly reduced in only the 2 ng animals. There was no reduction in [3H]8-OH-DPAT binding after intrastriatal ricin injection, which caused as much cell loss in the striatum as 2 ng of volkensin, but did not destroy cortical pyramidal neurones.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

D-cycloserine, a putative cognitive enhancer, facilitates activation of the N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain.

The action of D-Cycloserine (DCS) at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex has been studied with membranes from inferior parietal cortex of patients with Alzheimer's disease. The maximal response of the site, measured using [3H]MK-801 binding, was 64% of that observed with glycine. Stimulation of binding induced by DCS in the presence of fixed concentrations of glycine resulted in a family of dose-response curves, consistent with the antibiotic having the property of a partial agonist at this glycine site. It is proposed that because of circumscribed glutamatergic pyramidal cell pathology DCS will have benefit for Alzheimer's patients over and above all other types of cognitive impairment.

Aged↗
PubMed1991

Destruction of a sub-population of cortical neurones by suicide transport of volkensin, a lectin from Adenia volkensii.

A method for the destruction of a sub-population of neocortical pyramidal neurones is described. The technique uses unilateral striatal injections of volkensin, a toxic lectin from Adenia volkensii, which undergoes retrograde axonal transport from the site of injection to destroy subcortically projecting pyramidal cells within the neocortex. Striatal volkensin injections produce a significant reduction in the number of large pyramidal neurones of the infragranular layer. The selectivity of the lesion was demonstrated by the preservation of glutamic acid decarboxylase mRNA positive cells, considered to be cortical interneurones within ipsilateral cortex. The binding of the serotonin 1A receptor agonist [3H]-8-hydroxy-2-(n-dipropylamino)tetralin, visualised by autoradiography, was reduced in areas showing loss of large cells, indicating that these receptors may be present on subcortically projecting pyramidal cells. Ricin, another toxin lectin, but effective as a suicide transport agent in only the peripheral nervous system, produced local striatal damage but no cortical cell loss. The selective destruction by volkensin of neocortical pyramidal neurones with subcortical projection targets should aid the neurobiological investigation of such cells. Additionally, data obtained using this technique may provide insights into the interpretation of biochemical findings in neurodegenerative disease in which pyramidal cell loss is a significant feature.

Animals↗
PubMed1991

Terminal coma affects messenger RNA detection in post mortem human temporal cortex.

In situ hybridization histochemistry has been used to study the amount of M1 muscarinic receptor mRNA in temporal cortex from subjects with Alzheimer's disease and other neurodegenerative disorders, where the duration of terminal coma was known. Total polyadenylated mRNA and glutamate decarboxylase activity were also measured. Both muscarinic receptor mRNA and enzyme activity showed a significant decline with increasing duration of terminal coma, but were not related to diagnosis. Polyadenylated mRNA signal did not show an association with coma. These data indicate the need to consider the nature of the terminal illness in post mortem studies of mRNA as well as for neurochemical research.

Alzheimer Disease↗
PubMed1991

Characterisation of the glycine modulatory site of the N-methyl-D-aspartate receptor-ionophore complex in human brain.

[3H]Glycine binding and glycine modulation of [3H]MK-801 binding have been used to study the glycine allosteric site associated with the N-methyl-D-aspartate receptor complex in postmortem human brain. The effect of glycine on [3H]MK-801 binding appeared sensitive to duration of terminal coma, and possibly postmortem delay. Thirty percent of the binding occurred in a subfraction of brain tissue and did not show enhancement by glycine and glutamic acid. [3H]Glycine binding to a subfraction free from this component was studied and showed high specific binding. KD and Bmax values showed considerable intersubject variability which did not appear to be due to demographic features or to tissue content of amino acids with an affinity for this site. The pharmacological characteristics of binding in this subfraction and a correlation between Bmax values and the maximal enhancement of [3H]MK-801 binding by glycine are consistent with [3H]glycine binding occurring to an N-methyl-D-aspartate receptor complex associated site. Further support for this is provided by a significantly lower Bmax value for [3H]glycine binding in subjects with Alzheimer's disease and reduced glycine enhancement of [3H]MK-801 binding. However, the effect of perimortem factors makes it difficult to confidently attribute this solely to a disease-related change in the receptor. The possible role of the glycine allosteric site in the treatment of neuropsychiatric disorders is discussed.

Aged↗
PubMed1991

A comparison of [3H]MK-801 and N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine binding to the N-methyl-D-aspartate receptor complex in human brain.

The binding of (+)-[3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate ([3H]MK-801) and N-[1-(2-thienyl)cyclohexyl]-3,4-[3H]piperidine ([3H]TCP) to the N-methyl-D-aspartate (NMDA) receptor complex of human brain has been investigated. Significant differences were noted between the binding of the two ligands in the same tissue samples. Binding of both ligands was stimulated by addition of glutamic acid or glycine. However, addition of both compounds resulted in an additional effect with [3H]MK-801 but not [3H]TCP binding. Saturation analysis revealed approximately twice as many high-affinity sites for [3H]MK-801 (Bmax, 1,500 +/- 300 fmol/mg of protein) than for [3H]TCP (Bmax, 660 +/- 170 fmol/mg of protein). In addition, a low-affinity site was detected for [3H]MK-801 binding but not [3H]TCP binding. The pharmacology of the high-affinity [3H]MK-801 and [3H]TCP binding sites was similar with rank order of potency of inhibitors being MK801 greater than TCP greater than phencyclidine greater than N-allylnormetazocine (SKF 10047). 2-Amino-5-phosphonopentanoate inhibited binding of both ligands with comparable potency whereas both 7-chlorokynurenic acid and ZnCl2 were more potent inhibitors of [3H]MK-801 than of [3H]TCP binding. All compounds examined exhibited Hill coefficients of significantly less than unity. Saturation analysis performed in the striatum revealed that the number of binding sites was the same for both [3H]MK-801 (Bmax, 1,403 +/- 394 fmol/mg) and [3H]TCP (Bmax, 1,292 +/- 305 fmol/mg). Addition of glutamate or glycine stimulated striatal binding but there was no further increase on addition of both together.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Spermidine enhancement of [3H]MK-801 binding to the NMDA receptor complex in human cortical membranes.

The effects of spermidine on the binding of [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor complex was studied in human cerebral cortical membranes. [3H]MK-801 binding was increased from 56 +/- 5 fmol/mg protein (mean +/- S.E.M., n = 7) to 319 +/- 71 fmol/mg protein in the presence of 200 microM spermidine. The ED50 for spermidine stimulation of [3H]MK-801 binding was 89 +/- 22 microM (mean +/- S.E.M., n = 6). In the presence of glutamate (1 microM) plus glycine (1 microM) the ED50 was reduced to 5.5 +/- 0.7 microM. The increase in binding in the presence of spermidine was characterised by an increase in the rate of association of [3H]MK-801. In the presence of spermidine. [3H]MK-801 was inhibited by AP5. 7-chlorokynurenic acid and ifenprodil with IC50 values of 0.5 +/- 0.3 24 +/- 19 and 91 +/- 28 microM, respectively. None of these antagonists was a competitive inhibitor of the spermidine stimulation of [3H]MK-801 binding. Thus spermidine modulates the NMDA receptor complex in human brain, providing further evidence that the complex is similar in rat and human cortex.

Adrenergic alpha-Antagonists↗