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Biomedical subjects

J McCulloch

Publications and source records attributed to J McCulloch.

At least 127 records · Page 7Linked to original sources
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

Differential alterations of second messenger systems and cerebral glucose use following excitotoxic lesion of rat cerebral cortex.

Quantitative autoradiography of [3H]forskolin and [3H]phorbol 12,13 dibutyrate (PDBu) binding was examined 21 days after unilateral lesioning of the rat visual cortex using ibotenic acid. In the same animals, the functional deficit was assessed using quantitative [14C]-2-deoxyglucose autoradiography. [3H]Forskolin binding was significantly reduced in each layer of the lesioned visual cortex by at least 40% compared to the contralateral hemisphere. Significant reductions in [3H]forskolin binding were observed in the superior colliculus (-15%) and dorsal lateral geniculate body (-12%) ipsilateral to the lesioned cortex. [3H]PDBu binding was significantly reduced in the lesioned visual cortex (layers V-VI) by 34%, compared with the control hemisphere. There were no significant alterations in [3H]DPBu binding in any other brain regions. Following ibotenate-induced lesioning of the visual cortex, glucose use was significantly reduced throughout the lesioned cortex by at least 25% with minor alterations in glucose use in the ipsilateral dorsal lateral geniculate body and superior colliculus. The present study highlights the relative robustness of [3H]PDBu binding compared to [3H]forskolin binding after excitotoxic damage to the cerebral cortex and suggests that [3H]forskolin binding sites are present on cortical efferent fibres.

Animals↗
PubMed1991

Effects of intracisternal endothelin-1 injection on blood flow to the lower brain stem.

The central effects of endothelin-1 (Et-1, 10-30 pmol in 2.5 microliters injected intracisternally) have been investigated in the conscious rat. With 10 and 20 pmol Et-1, no significant change in blood pressure was observed. With 30 pmol Et-1, mean arterial blood pressure rose by 40 +/- 10 mm Hg with an accompanying modest, short-lived bradycardia at 2 min post-injection. Cerebral blood flow [( 14C]iodoantipyrine autoradiography), measured simultaneously with the hypertensive response, was markedly reduced throughout the caudal medulla and cerebellum (by up to 85%), while significant hyperaemia was evident in a number of forebrain structures (e.g. an increase of 78% in sensorimotor cortex). These observations have relevance to two distinct scientific areas. Concerning the significant effect of Et-1 in central cardiovascular control, these results caution against drawing conclusions from ventricular application with knowledge only of cardiovascular parameters. These results also illustrate the profound effects of Et-1 which is uniquely capable of overriding cerebral autoregulatory mechanisms.

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

Alterations of functional glucose use and ligand binding to second messenger systems following unilateral orbital enucleation.

Quantitative autoradiography was used to examine the effect of lesioning a well-defined glutamatergic system (retinofugal fibres) on [3H]forskolin binding to Gs-adenylate cyclase and [3H]PDBu (phorbol-12,13-dibutyrate) binding to protein kinase C (PKC) in the rat visual system at 1, 5, 10 and 20 days after unilateral orbital enucleation. Local cerebral glucose utilisation was determined in the same animals using quantitative [14C]2-deoxyglucose autoradiography. At 5 days post-lesion, [3H]forskolin binding sites were significantly reduced in the visually-deprived superior colliculus (-14 +/- 1%) and dorsal lateral geniculate body (-8 +/- 2%), and these reductions persisted until 20 days post-lesion. There were no significant alterations in the amount of [3H]PDBu binding in any region in the visually-deprived hemisphere following enucleation. Function-related glucose use was significantly reduced throughout the visual pathway after enucleation. In this study, there was no conclusive evidence of plastic modifications of second messenger systems in the rat visual system despite a general depression of visual function following lesion of retinofugal fibres.

Adenylyl Cyclases↗
PubMed1991

Alterations in neurotransmitter receptors and glucose use after unilateral orbital enucleation.

Serotonin (5-hydroxytryptamine; 5-HT), acetylcholine and gamma-aminobutyric acid (GABA) are neurotransmitters in the rat visual system. Using quantitative autoradiography, the effect of unilateral orbital enucleation on [3H]5-HT, [3H]ketanserin, [3H]quinuclidinyl benilate (QNB) and [3H]muscimol binding to 5-HT1, 5-HT2, muscarinic and GABAA receptors has been examined within anatomical components of the visual pathway at 4 time points up to 20 days after the lesion. The functional deficit was assessed in the same animals using quantitative [14C]2-deoxyglucose autoradiography. At 1 day after unilateral orbital enucleation, there were no significant alterations in ligand binding although local cerebral glucose use was reduced in primary visual structures in the visually deprived hemisphere. At 5 days post-enucleation, however, [3H]5-HT binding was significantly reduced in both the visually deprived superior colliculus (by 17%) and dorsal lateral geniculate body (DLG) (by 33%). There were similar alterations in the binding of this ligand in these primary retinal projection areas at 10 and 20 days after orbital enucleation, but there were no changes in secondary areas (e.g. visual cortex) at any time point. [3H]Muscimol binding was significantly reduced in the visually deprived DLG (30%) and visual cortex (21%) only at 20 days post-lesion, whilst [3H]ketanserin and [3H]QNB were not altered in any region in the visually deprived hemisphere at any time point post-enucleation. At 10 and 20 days post-enucleation, the degree of [3H]5-HT, and [3H]muscimol binding deficits in visually deprived structures correlated significantly with the level of reduced metabolic activity in these areas (r = 0.700 and r = 0.543 respectively). The specificity and regional and temporal heterogeneity of neurotransmitter receptor binding alterations provides evidence of selective adjustments within visual system components in response to orbital enucleation.

Animals↗
PubMed1991

Selective alterations in glutamate receptor subtypes after unilateral orbital enucleation.

Glutamate is the major excitatory neurotransmitter in the rat visual system. Using quantitative autoradiography the effect of unilateral orbital enucleation on [3H]kainate, [3H]alpha-amino-3-hydroxy-5-methyl- isoxazole-4-propionic acid [( 3H]AMPA) and [3H]glutamate binding to kainate, quisqualate and NMDA receptors respectively has been examined within anatomical components of the visual pathway at 4 time points up to 20 days post-lesion. The time course for the degeneration of retinal projection fibres was assessed in a separate group of animals by quantifying [3H]cyclohexyladenosine [( 3H]CHA) binding to presynaptic adenosine A1 receptors. Over the first 5 days after orbital enucleation, there were no significant alterations in glutamate or adenosine A1 receptor binding in visual structures of the visually deprived hemisphere. However, at 10 days post-lesion [3H]AMPA binding was significantly reduced (30%) in the visually deprived superior colliculus but unaltered in other visual structures. At this time point there was also a significant reduction (50%) in [3H]CHA binding in the visually deprived superior colliculus but not in other retino-recipient nuclei. There were similar changes in [3H]AMPA and [3H]CHA binding at 20 days post-enucleation. [3H]Kainate binding was significantly increased in the visually deprived superior colliculus only at 20 days post-enucleation. Saturation analysis of [3H]kainate and [3H]AMPA binding at this time point indicated a selective increase in the Bmax value for the high affinity [3H]kainate binding site and a concomitant decrease in the Bmax value for the high affinity [3H]AMPA binding site in the visually deprived superior colliculus. There were, however, no significant alterations in [3H]AMPA or [3H]kainate binding in other primary projection areas or in secondary visual areas (e.g. visual cortex) at any time point. NMDA sensitive [3H]glutamate binding was unaltered in the visually deprived hemisphere up to 20 days post-enucleation. These results suggest an upregulation of kainate receptors in the visually deprived superior colliculus after orbital enucleation and a loss of presynaptic quisqualate receptors on degenerating retinal fibres. The plastic alterations in kainate receptors in the superior colliculus are supportive of electrophysiological data suggesting a physiological role for these sites in mediating excitatory postsynaptic potentials in tectal neurons.

Animals↗
PubMed1991

Reduced levels of calcitonin gene-related peptide-like immunoreactivity in human brain vessels after subarachnoid haemorrhage.

Human cerebral vessels were found to contain calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI) which in the reversed phase HPLC co-eluted with authentic human alpha-CGRP. The level was significantly lower in arteries removed from patients who had died from a subarachnoid haemorrhage (SAH) as compared to patients who died of a coronary infarction. On a molar basis human alpha-CGRP was more potent than human beta-CGRP to dilate human brain vessels and to dilate vasoconstriction elicited by whole blood. It is suggested that the trigemino-cerebrovascular system storing CGRP-LI may be involved in the pathophysiology of SAH in man.

Adult↗
PubMed1991

Evaluation of a competitive NMDA antagonist (D-CPPene) in feline focal cerebral ischemia.

The effects of a competitive, N-methyl-D-aspartate (NMDA) receptor antagonist, D(-)E-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylic acid (D-CPPene), on the volume of ischemic brain damage was assessed by quantitative histological study in 35 chloralose-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery and the animals were killed by transcardiac perfusion fixation 6 hours later. Pretreatment with D-CPPene (1.5, 4.5, or 15 mg/kg, administered intravenously 15 minutes prior to occlusion, with subsequent drug infusions to maintain a plateau in the plasma drug concentrations) effected dose-dependent reductions in the volume of ischemic brain damage. At the highest dose studied (15 mg/kg, plus an infusion of 170 micrograms/kg/min), D-CPPene reduced the volume of ischemic damage in the cerebral cortex by more than 75% compared to vehicle-treated control animals. The plasma concentration of D-CPPene, which is associated with a half maximal reduction in the volume of ischemic damage, was estimated to be 24 micrograms/ml during the initial 120 minutes after the middle cerebral artery occlusion. Treatment with D-CPPene (15 mg/kg, plus an infusion of 170 micrograms/kg/min) initiated 1 hour after occlusion reduced the volume of ischemic brain damage in the cerebral cortex by 30%, but this response did not achieve statistical significance. Precise definition of dose dependency for the anti-ischemic effects of NMDA antagonists and the therapeutic time window are influenced greatly by brain pharmacokinetics of the agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Tachykinins (substance P, neurokinin A, neuropeptide K, and neurokinin B) in the cerebral circulation: vasomotor responses in vitro and in situ.

The vasomotor responses of tachykinins have been studied in the cerebral vasculature of human, pig, cat, and guinea pig. Substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and neuropeptide K (NPK) induced concentration-dependent relaxations of precontracted cerebral arteries in all species when examined by a sensitive in vitro technique. In addition, the relaxant responses to SP, NKA, and NKB were studied in cat pial arterioles by peptide microapplication in situ. In human pial vessels, the order of relaxant potency was SP greater than NKB greater than NKA greater than NPK; in the pig middle cerebral artery, there was no difference in potency between the tachykinins; in the cat middle cerebral artery, SP = NKB greater than NKA = NPK; and in the guinea pig basilar artery, SP much greater than NPK = NKA greater than NKB. Responses induced by SP, NKA, and NKB in the cat were comparable in vitro and in situ. Removal of the endothelium abolished relaxation induced by all four tachykinins. The relaxant responses of guinea pig basilar arteries to SP, NKA, and NPK were competitively antagonized by the SP antagonist Spantide. However, Spantide lowered the Imax of the NKB concentration-response curve without any rightward shift, suggesting action at a different site than the other tachykinins. In the guinea pig basilar artery, the relaxation seems to be exerted via a NK-1 receptor subtype while the receptor subtype is more unclear in cerebral arteries from human, cat, and pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Reduction in local cerebral blood flow induced by endothelin-1 applied topically to the middle cerebral artery in the rat.

The role of endothelin-1 (ET-1) in cerebral ischemic injury remains the subject of much debate. Vasoconstriction in large conduit vessels may not be associated with reductions in flow at the tissue level. We present two studies examining the effects on local cerebral blood flow of topical application of ET-1 to the surgically exposed middle cerebral artery (MCA) in adult male Sprague-Dawley rats. In the first series using 14C-iodoantipyrine autoradiography, 10 min following application of ET-1 (1 nmol) to the MCA, up to 80% reduction in blood flow in the territory of distribution of the MCA is seen (e.g., dorsolateral caudate nucleus--flow reduced from 131 +/- 3 ml/100 g/min to 29 +/- 25 ml/100 g/min). These levels of flow are comparable with those seen with permanent bipolar diathermy occlusion and division of the proximal MCA--a standard rat model of focal cerebral ischemia. In a second series using hydrogen clearance technique for measurement of local cerebral blood flow in the caudate nucleus, we have shown that flow ipsilateral to application of ET-1 (0.25 nmol) is significantly reduced compared with saline controls for 80 min. Such reduction of flow, at the tissue level, sustained over this duration is consistent with the induction of ischemic cell damage by ET-1.

Administration, Topical↗
PubMed1991

Robustness of G proteins in Alzheimer's disease: an immunoblot study.

Many of the neurotransmitter systems that are altered in senile dementia of the Alzheimer type are known to mediate their effects via G proteins, yet the integrity of guanine nucleotide-binding proteins (G proteins) in Alzheimer's diseased brains has received minimal investigation. The aim of this study was to establish whether the level of G alpha subunits of five G proteins was altered in Alzheimer's disease. We used immunoblotting (Western blotting) to compare the amounts of Gi1, Gi2, GsH (heavy molecular weight), GsL (light molecular weight), and Go in the frontal cortex and hippocampus, two regions severely affected by the disease, and the cerebellum, which is less severely affected. The number of senile plaques was also quantified. We report that there was no significant difference in the level of these G alpha subunits between Alzheimer's diseased and age-matched postmortem brains. These results suggest that alterations in the amount of G protein alpha subunits are not a feature of Alzheimer's disease.

Alzheimer Disease↗
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↗
PubMed1991

Correlation of the extracellular glutamate concentration with extent of blood flow reduction after subdural hematoma in the rat.

The excitatory neurotransmitters glutamate and aspartate are an important factor in the causation of ischemic brain damage. The concentration of glutamate and aspartate was serially measured in extracellular fluid using in vivo microdialysis after induction of a subdural hematoma or after a sham operation in the rat. Measurements were made in the cortex underlying the hematoma and in the ipsilateral hippocampus, and these findings were correlated with regional cerebral blood flow (CBF), measured autoradiographically 2 hours after hematoma induction. In the severely ischemic cortex underlying the hematoma (mean CBF less than 25 ml/100 gm/min), glutamate and aspartate content increased more than 750% over basal levels. In individual animals the magnitude of glutamate release correlated with the extent of the focal ischemic zone under the hematoma (r = 0.907). Hippocampal glutamate levels rose 339%, yet regional CBF was preserved (114 ml/100 gm/min). This accords with focal hypermetabolism in this model, and may imply a glutamate-mediated "excitotoxic" process after subdural hematoma.

Amino Acids↗
PubMed1991

Ischemic neuronal damage after acute subdural hematoma in the rat: effects of pretreatment with a glutamate antagonist.

The ability of a competitive N-methyl-D-aspartate (NMDA) receptor antagonist (D-CPP-ene) to reduce irreversible brain damage has been examined in a rodent model of acute subdural hematoma. Acute subdural hematoma was produced by the slow injection of 400 microliters homologous blood into the subdural space overlying the parietal cortex in halothane-anesthetized rats. Brain damage was assessed histologically in sections at multiple coronal planes in animals sacrificed 4 hours after induction of the subdural hematoma. Pretreatment with D-CPP-ene (15 mg/kg) significantly reduced the volume of ischemic brain damage produced by the subdural hematoma from 62 +/- 8 cu mm (mean +/- standard error of the mean) in vehicle-treated control rats to 29 +/- 7 cu mm in drug-treated animals. These data demonstrate the anti-ischemic efficacy of NMDA antagonists in an animal model of intracranial hemorrhage in which intracranial pressure is elevated, and suggest that excitotoxic mechanisms (which are susceptible to antagonism by D-CPP-ene) may play a role in the ischemic brain damage which is observed in patients who die after acute subdural hematoma.

Animals↗
PubMed1991

Endothelin-1-induced hypertension: a consequence of medullary ischemia?

The central hemodynamic effects of the peptide endothelin-1 (ET-1) have been investigated in the conscious, normotensive rat. Intracisternal administration of ET-1 (0.01-0.03 nmol) gave rise to an increase in mean arterial pressure with minimal effects on heart rate and was accompanied in some cases by barrel rolling activity. Intracisternal administration of 0.03 nmol ET-1 gave rise to a significant elevation in plasma noradrenaline and adrenaline levels. This elevation in plasma catecholamines was present only in those animals that also exhibited marked behavioral changes. Autoradiographic measurement of cerebral blood flow carried out during the maximum response to 0.03 nmol of intracisternal ET-1 revealed a widespread and profound ischemia throughout the caudal brainstem. Cerebral ischemia is known to activate compensatory circulatory reflexes in the medulla oblongata that result in increased sympathetic and vagal outflow. This is the most likely cause of intracisternal ET-1-induced hypertension. ET-1 is unique in its ability to override the brain's autoregulatory mechanisms and induce ischemia of pathological magnitude.

Animals↗