PubMed Health⌕ Search

Biomedical subjects

D Dewar

Publications and source records attributed to D Dewar.

At least 55 records · Page 3Linked to original sources
PubMed1995

Galanin receptor binding sites in the temporal and occipital cortex are minimally affected in Alzheimer's disease.

Galanin receptor binding sites were examined in the inferior temporal and medial occipital gyri of patients with Alzheimer's disease (AD) and matched control subjects using quantitative autoradiography. In the inferior temporal gyrus, galanin binding was reduced selectively in layers V-VI of the AD cases compared to controls, the magnitude of the reduction (45%) being similar to that of choline acetyltransferase activity (40%) in this region. In the medial occipital gyrus, galanin binding in the AD cases was not different from controls in any cortical layer despite a reduction in choline acetyltransferase activity. Galanin binding did not correlate with the densities of neuritic plaques in either temporal or occipital gyri. Thus, despite a significant cortical cholinergic deficit in AD, there is an anatomically selective reduction of cortical galanin receptor binding sites suggesting that the majority of galanin receptors are not located on cholinergic terminals in the human cerebral cortex.

Aged↗
PubMed1994

kappa-1 Opioid receptors of the temporal cortex are preserved in Alzheimer's disease.

The binding of [3H]-U-69593 and [3H]-CI-977 to kappa-1 opioid receptors has been examined in the temporal cortex of postmortem brains from patients with Alzheimer's disease and age-matched controls using quantitative autoradiography. There was no significant difference between Alzheimer and control subjects in the level of [3H]-U-69593 and [3H]-CI-977 binding, but ChAT activity was markedly reduced (by 73% compared to controls). These results are not consistent with a presynaptic localisation of kappa-1 receptors on cholinergic terminals in human temporal cortex.

Aged↗
PubMed1993

Differential alterations of ion channel binding sites in temporal and occipital regions of the cerebral cortex in Alzheimer's disease.

Three ion channel binding sites were examined by means of quantitative ligand binding autoradiography in temporal and occipital cortex from 9 patients with neuropathologically confirmed Alzheimer's disease (AD) and 7 matched control subjects. The following ligands were used: 125I-apamin to label a population of Ca(2+)-sensitive K+ channels; [3H]PN200-110 to label L-type voltage-sensitive Ca2+ channels and [3H]glibenclamide to label ATP-sensitive K+ channels. Ion channel binding sites were compared to: choline acetyltransferase (ChAT) activity and plaque densities measured in the same tissue. In the temporal cortex in AD 125I-apamin binding was increased compared to controls (e.g. superficial layers: control = 0.71 +/- 0.07; AD = 1.02 +/- 0.07, mean +/- S.E.M. pmol/g tissue). In contrast, in adjacent sections [3H]glibenclamide binding was reduced in AD compared to controls (e.g. superficial layers: control = 25.3 +/- 1.7; AD = 17.9 +/- 1.4 pmol/g tissue). [3H]PN200-110 binding in temporal cortex was not altered in AD compared to controls. In the occipital cortex 125I-apamin binding was increased in AD while both [3H]glibenclamide and [3H]PN-200-110 binding sites in this cortical area were not different from controls. Plaque density (per mm2) was higher in temporal (e.g. layers I-III, 43 +/- 6) than in occipital cortex (layers I-III, 27 +/- 4) in the AD patients while ChAT activity was reduced by 40% in temporal cortex and by 50% in occipital cortex compared to controls. The results suggest that the three ion channel binding sites are located on structural elements in the brain which are differentially affected by the pathophysiology of AD.

Alzheimer Disease↗
PubMed1993

Effects of post-mortem delay on high affinity forskolin binding sites and adenylate cyclase activity in rat and human striatum and cerebral cortex.

High affinity [3H]forskolin binding was measured using quantitative autoradiography in the striatum and frontal cortex of rat and human brain. Forskolin binding in rat striatum (310.8 +/- 26.0 pmol/g mean +/- S.E.M.) was approximately 4 times that in the frontal cortex (75.5 +/- 8.4 pmol/g), whereas in post-mortem human brain each region exhibited similar levels of forskolin binding (striatum 51.3 +/- 1.2 and cortex 53.2 +/- 2.1 pmol/g). Basal adenylate cyclase activity was assayed in membranes prepared from striatum and frontal cortex of rat and human; enzyme activity in the rat striatum was approximately 2-fold that in rat frontal cortex whereas enzyme activity in the human striatum was similar to that in the human frontal cortex. To investigate the effect of the interval between death and freezing of the brain, rats were killed by decapitation, then maintained at 37 degrees C for up to 4 hours before freezing and subsequent assay of forskolin binding and adenylate cyclase activity. Striatal forskolin binding declined markedly post-mortem such that 4 h post-mortem it was only 13% of the level in control animals while levels of cortical forskolin binding declined minimally during the immediate post-mortem period. Striatal and cortical adenylate cyclase activity (basal) was minimally influenced by post-mortem delay although in both regions there was a rapid loss of the ability of fluoroaluminate to stimulate adenylate cyclase. The data suggest that the striatum contains a population of high affinity forskolin binding sites which is extremely sensitive to post-mortem delay.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

Differential alterations in adenosine A1 and kappa 1 opioid receptors in the striatum in Alzheimer's disease.

The alterations in Alzheimer's disease (AD) of two binding sites in the striatum suggested to have a presynaptic localisation have been investigated by quantitative ligand binding autoradiography. Adenosine A1 binding sites labelled with [3H]cyclohexyladenosine (CHA) and kappa 1 opioid binding sites labelled with [3H]U-69593 were studied in adjacent sections of the striatum obtained postmortem from 10 patients with AD and 9 matched controls. In AD, there was a significant reduction of [3H]CHA binding sites in the caudate nucleus (control = 88 +/- 4; AD = 56 +/- 6 pmol/g tissue; mean +/- S.E.M.) and putamen (control = 83 +/- 4; AD = 58 +/- 7 pmol/g). In control subjects, highest levels of [3H]U-69593 binding were localised to patches within the caudate nucleus (9.66 +/- 0.58 pmol/g) with lower levels in the matrix (5.54 +/- 0.48 pmol/g). There was no alteration in [3H]U-69593 binding sites in either the caudate nucleus (patches and matrix) or putamen of AD patients. The activity of choline acetyltransferase (ChAT), determined in the same tissue samples used for autoradiographic analysis, was significantly reduced in AD (control = 124 +/- 11; AD = 64 +/- 14 nmol/h/mg protein). There was a positive correlation between ChAT activity and [3H]CHA binding (r = 0.769), but not [3H]U-69593 binding (r = 0.197). The results indicate that a marked loss of adenosine A1 receptors occurs in the striatum of AD with no loss of kappa 1 opioid receptors, and that the loss of A1 receptors parallels the loss of choline acetyltransferase activity.

Adenosine↗
PubMed1993

Alz-50 and ubiquitin immunoreactivity is induced by permanent focal cerebral ischaemia in the cat.

The effects of permanent focal cerebral ischaemia on Alz-50 and ubiquitin antibody immunohistochemical staining were investigated in vivo in the cat. Alz-50 and ubiquitin antibody staining was compared to the distribution of ischaemic cell damage. Six hours following permanent occlusion of one middle cerebral artery, Alz-50 immunoreactivity was present in neurones in the ipsilateral ischaemic cerebral cortex and caudate nucleus but not in any region of the contralateral hemisphere or in sham-operated cats. Only a proportion of neurones were stained with Alz-50 and these did not have the shrunken, pyknotic appearance characteristic of irreversible ischaemic cell damage. Ubiquitin immunoreactivity was also increased in the ischaemic hemisphere, again only a proportion of neurones were stained. The Alz-50 antibody recognises the microtubule-associated protein tau and stains neurofibrillary tangles as well as neurones vulnerable to neurofibrillary change in tissue sections of Alzheimer brain. The results indicate that there are changes in tau protein in response to an ischaemic insult, but only in some neurones, which may reflect an early stage of the degenerative process. Increased ubiquitin immunoreactivity may be a response to the presence of abnormal proteins, including tau, which are induced by an ischaemic challenge.

Animals↗
PubMed1993

High affinity hippocampal [3H]-glibenclamide binding sites are preserved in Alzheimer's disease.

ATP-sensitive K+ channels were examined in sections of the hippocampus from patients with Alzheimer's disease and age-matched control subjects by means of quantitative autoradiography. ATP-sensitive K+ channels were labelled with the sulfonylurea, [3H]-glibenclamide, which is a potent blocker of these channels. The density of cells in the subiculum and the activity of choline acetyltransferase were determined in the same hippocampal tissue samples. In the hippocampal formation of control subjects, the density of high affinity [3H]-glibenclamide binding sites ranged from 17.6 +/- 0.9 pmoles/g in the presubiculum to 11.6 +/- 0.6 pmoles/g in the parvo-pyramidal layer of the presubiculum. There was no difference between Alzheimer patients and controls in the level of high affinity [3H]-glibenclamide binding in any hippocampal region although there was a marked loss of subicular cells (reduced by 29% compared to controls) and a reduction in choline acetyltransferase activity (reduced by 60% compared to controls). The results suggest that ATP-sensitive K+ channels are associated with elements in the hippocampus which are preserved in Alzheimer's disease.

Adenosine Triphosphate↗
PubMed1993

Early changes in second messenger but not receptor binding sites after acute subdural hematoma: an in vitro autoradiographic study.

Neurotransmitter receptor-coupled mechanisms have been recently recognized as important determinants of cell damage after central nervous system (CNS) trauma and ischemia. Many of these receptors exert their intracellular effects via second messenger systems. This study used in vitro autoradiographic radioligand binding to measure beta-adrenergic and muscarinic cholinergic receptors and adenylate cyclase and protein kinase C (PKC) binding sites two h after acute subdural hematoma in rats. Both beta-adrenergic and cholinergic receptor binding sites were unchanged in comparison to controls, while adenylate cyclase binding significantly decreased in the ischemic cortex under the hematoma. These changes may constitute a major limiting factor on receptor-linked therapeutic strategies in trauma and ischemia. Protein kinase C activation significantly increased in the ischemic area under the hematoma in these studies. This appears to be a response to calcium flux, which may be in part glutamate mediated.

Adenylyl Cyclases↗
PubMed1992

A correlative study of calcium channel antagonist binding and local neuropathological features in the hippocampus in Alzheimer's disease.

[3H]PN200-110 binding sites were studied by means of quantitative autoradiography in hippocampal sections of patients with Alzheimer's disease and age-matched control subjects. Choline acetyltransferase activity, plaque, tangle and cell densities were also determined in the same tissue samples used for autoradiographic studies. Quantitative autoradiographic analysis of [3H]PN200-110 binding in control hippocampus revealed a heterogeneous pattern similar to that described in rodents, being particularly high in the dentate gyrus. In Alzheimer's disease, [3H]PN200-110 binding was markedly reduced in the subiculum (control = 9.85 +/- 1.41 pmol/g; Alzheimer = 3.41 +/- 0.54 pmol/g, mean +/- S.E.M., P less than 0.001). In the subiculum there was a disproportionate reduction of [3H]PN200-110 binding in comparison to cell loss in Alzheimer's disease. The activity of choline acetyltransferase in the hippocampus was markedly reduced in Alzheimer's disease (controls 6.9 +/- 1.0; Alzheimer 2.7 +/- 0.9 nmol/h/mg protein, mean +/- S.E.M., P less than 0.01). There was a strong correlation between choline acetyltransferase activity and [3H]PN200-110 binding in the subiculum. [3H]PN200-110 binding did not correlate with plaque density in the subiculum. The discrete reduction and preservation of [3H]PN200-110 binding in the present study is consistent with the pattern of selective cellular vulnerability in the hippocampal region in Alzheimer's disease.

Aged↗
PubMed1991

Preservation of [125I]galanin binding sites despite loss of cholinergic neurones to the hippocampus in Alzheimer's disease.

[125I]Galanin binding sites were examined in the hippocampal region of patients with Alzheimer's disease (AD) and age-matched control subjects using quantitative autoradiography. In control subjects, [125I]galanin binding sites were highly concentrated in the presubicular parvopyramidal layer (5.60 +/- 0.74 pmol/g), while other hippocampal regions had considerably lower levels of binding (0.56-1.73 pmol/g). In the majority of hippocampal regions, [125I]galanin binding was similar in AD patients to that in controls with a significant reduction being observed only in the deep layers of the parahippocampal gyrus. The activity of choline acetyltransferase, determined in the same tissue samples used for autoradiographic studies, was markedly reduced in AD (controls 6.8 +/- 0.6; AD 2.7 +/- 0.6 nmol/h/mg protein, mean +/- S.E.M.). These data are not consistent with a presynaptic location on cholinergic terminals of galanin binding sites in the human hippocampus unless upregulation has occurred.

Aged↗
PubMed1991

Selective reduction of [125I]apamin binding sites in Alzheimer hippocampus: a quantitative autoradiographic study.

[125I]Apamin binding sites were examined using quantitative autoradiography in the hippocampus of 9 patients with Alzheimer's disease and 8 age-matched controls. Within the hippocampal formation from control subjects, [125I]apamin binding sites were highly concentrated in the subiculum and CA1. In Alzheimer's disease there was a marked and discrete loss of [125I]apamin binding sites in the subiculum (control = 1.10 +/- 0.10 pmol/g; Alzheimer = 0.71 +/- 0.09 pmol/g) and CA1 (control = 1.41 +/- 0.09 pmol/g; Alzheimer = 0.85 +/- 0.11 pmol/g; values are mean +/- S.E.M.). This reduction of [125I]apamin binding sites in the subiculum correlated with cell density but not neuritic plaque density. These results indicate that an anatomically discrete loss of Ca(2+)-dependent K+ channels within the hippocampal formation occurs in Alzheimer's disease.

Aged↗
PubMed1991

Effects of chronic administration of MK-801 upon local cerebral glucose utilisation and ligand binding to the NMDA receptor complex.

Although clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists will involve prolonged drug administration, knowledge of the functional consequences of chronic NMDA receptor blockade is limited. Local cerebral glucose utilisation was measured in conscious rats in 74 discrete brain regions after chronic administration of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine (MK-801) (0.5 mg/kg i.p.). Chronic treatment with MK-801 caused small, significant changes in glucose use in 4 of the 74 brain areas; parietal cortex (-13%), frontal cortex (-10%), subthalamic nucleus (-14%) and nucleus accumbens (-17%). These focal alterations in glucose use were not associated with changes in ligand binding to various sites within the NMDA receptor complex (i.e. agonist recognition site, glycine site, ion channel site) which were assessed autoradiographically. The acute effects of MK-801 on glucose utilisation were significantly enhanced after chronic MK-801 in 7 brain regions (e.g. frontal and parietal cortices) and attenuated in 6 brain regions (e.g. nucleus accumbens, hippocampus, posterior cingulate cortex). Neither local enhancement nor attenuation of the acute response to MK-801 was due to alterations in ligand binding to sites within the NMDA receptor complex. The data clearly indicate that the functional consequences of NMDA blockade are altered after chronic MK-801 treatment in an anatomically organised, though complex manner. These adaptive functional changes after chronic MK-801 treatment cannot be attributed readily to alterations in the NMDA receptor complex in affected regions.

Animals↗
PubMed1991

Glutamate metabotropic and AMPA binding sites are reduced in Alzheimer's disease: an autoradiographic study of the hippocampus.

The distribution and levels of glutamate metabotropic binding sites were investigated in the hippocampal region of the human brain using quantitative autoradiography in normal subjects and patients with Alzheimer's disease. The topography of glutamate metabotropic binding sites was contrasted with those for kainate and 2-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) in adjacent sections from the same subjects. The regional distribution of glutamate metabotropic binding and AMPA binding were similar, being most abundant in the subiculum and CA1 region and lower in the CA3 region. The distribution of kainate binding differed from that of metabotropic binding being greatest in the deep layers of the parahippocampal gyrus and CA3 and lower in the subiculum and CA1. There were regionally distinct reductions in these non-N-methyl-D-aspartate (non-NMDA) binding sites in patients with Alzheimer's disease. Glutamate metabotropic. AMPA and kainate binding were each markedly reduced in the subiculum and the magnitude of the change correlated with neuronal loss within the subiculum. Glutamate metabotropic binding and AMPA binding were reduced significantly in CA1 in subjects with Alzheimer's disease whereas kainate binding was minimally altered in this region. Kainate and AMPA binding were reduced significantly in the parahippocampal gyrus in Alzheimer's disease while glutamate metabotropic binding was not. In a number of hippocampal areas (e.g. dentate gyrus, CA3), the binding of all ligands was minimally altered in Alzheimer's disease. These differences may reflect the localisation of the three types of glutamate binding sites on neuronal elements which are differentially susceptible to the neurodegenerative process of Alzheimer's disease.

Aged↗
PubMed1991

Autoradiographic imaging of [3H]phorbol 12,13-dibutyrate binding to protein kinase C in Alzheimer's disease.

Quantitative autoradiography was used to examine the distribution of [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding to protein kinase C in the middle frontal and temporal cortices and the hippocampal region of nine control and nine elderly subjects with Alzheimer's disease (AD). AD patients had a clinical diagnosis of the disease that was confirmed neuropathologically by the presence of numerous plaques in the hippocampus and cerebral cortex. Choline acetyltransferase (ChAT) activity was significantly reduced in the middle frontal and temporal cortex and in the hippocampus of AD subjects, with the deficit being greater than 60% of control values. Quantitative autoradiographic analysis of [3H]PDBu binding to protein kinase C revealed a heterogeneous pattern in control brain, being particularly high in superficial layers of the cortex and CA1 of the hippocampus. There were no significant differences between control and AD sections in all areas examined within the middle frontal cortex; e.g., layers I-II control, 491 +/- 46 versus AD, 537 +/- 39 pmol/g of tissue; middle temporal cortex, e.g., layers I-II control, 565 +/- 68 versus AD, 465 +/- 72 pmol/g of tissue; and hippocampal formation, e.g., CA1 control, 511 +/- 28 versus AD, 498 +/- 25 pmol/g of tissue. In a parallel study, [3H]PDBu binding to homogenate preparations of control and AD brain confirmed that there was no significant difference in [3H]PDBu binding in either the particulate or the cytosolic fraction. We have demonstrated in a well-defined population of AD patients that [3H]PDBu binding to protein kinase C remains preserved in brain regions that are severely affected by the neuropathological and neurochemical correlates of AD.

Alzheimer Disease↗
PubMed1990

Specific alterations in cardiovascular function and in glucose utilisation within lower brainstem nuclei following intracisternal neuropeptide Y in the conscious rat.

In the conscious normotensive rat, intracisternal neuropeptide Y (NPY) (1.25 nmol i.c.) gave rise to alterations in peripheral haemodynamic variables and glucose use within discrete areas of the CNS as measured by [14C]2-deoxyglucose autoradiography. The haemodynamic response to i.c. NPY comprised a transient hypertension followed by a prolonged hypotension and bradycardia. These cardiovascular responses to NPY were accompanied by a significant reduction in function related glucose use in the area postrema (-29% from vehicle-injected controls), nucleus tractus solitarius (caudal portion -24%, rostral portion -19%), Kolliker-Fuse nucleus (-14%), inferior colliculus (-18%) and subfornical organ (-19%). It is proposed that the area postrema, nucleus tractus solitarius and Kolliker-Fuse nucleus in the brainstem are involved functionally in the haemodynamic response to i.c. NPY.

Animals↗
PubMed1990

Selective alterations of high affinity [3H]forskolin binding sites in Alzheimer's disease: a quantitative autoradiographic study.

Quantitative autoradiographic analysis of high affinity [3H]forskolin binding sites was carried out in postmortem brains from normal controls and patients dying with Alzheimer's disease. Choline acetyltransferase (ChAT) activity and senile plaque formation were also quantified. [3H]Forskolin binding was markedly reduced in all layers of middle frontal gyrus in the Alzheimer brains and the deficit correlated with the deficit in ChAT activity in this area. In the hippocampal region [3H]forskolin binding was no different in the Alzheimer brains compared to controls, although ChAT activity was significantly reduced. There was an inconsistent reduction in [3H]forskolin binding in all layers of middle temporal gyrus which did not correlate with the cholinergic deficit. Significant senile plaque formation was observed in all 3 brain regions examined and [3H]forskolin binding did not correlate with plaque formation in any brain region. Thus, while all 3 brain regions were affected by the pathological correlates of Alzheimer's disease, [3H]forskolin binding was consistently reduced only in frontal cortex.

Adenylyl Cyclases↗
PubMed1990

Selective reduction of quisqualate (AMPA) receptors in Alzheimer cerebellum.

Multiple sites involved in glutamatergic neurotransmission were examined in the cerebellar cortex of 6 patients with Alzheimer's disease and 6 age-matched control patients by using quantitative ligand-binding autoradiography. Quisqualate (AMPA) receptor binding was markedly reduced in the molecular layer of the cerebellum from patients with Alzheimer's disease (167 +/- 13 pmoles/gm) compared with control patients (280 +/- 13 pmoles/gm). In adjacent sections from the same patients and controls, there was preservation of kainate and N-methyl-D-aspartate receptor binding in the cerebellum from patients with Alzheimer's disease compared with control patients. Neuropathological examination of the cerebellar cortex revealed the presence of plaques and preservation of Purkinje cells in the patients with Alzheimer's disease.

Aged↗