Biomedical subjects

J McCulloch

Publications and source records attributed to J McCulloch.

At least 145 records · Page 8Linked to original sources

PubMed1991

Ischaemic brain damage--prevention with competitive and non-competitive antagonists of N-methyl-D-aspartate receptors.

Excessive activation of glutamate receptors, most notably the N-methyl-D-aspartate (NMDA) subtype, appears to be a crucial factor in the sequence of cellular events which lead to irreversible ischaemic damage to neurones. The ability of newly developed antagonists of the NMDA receptor to reduce ischaemic brain damage has been assessed in cat and rodent models of focal cerebral ischemia. Non-competitive NMDA receptor antagonists such as dizocilpine (CAS 77086-21-6) which act at a site within the receptor operated ion channel markedly reduce (by more than 50%) ischaemic brain damage when administered prior to the ischaemic episode or 2 h after the onset of ischaemia. Competitive NMDA receptor antagonists, such as D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid, which act at the neurotransmitter recognition site are equally effective in reducing the ischaemic brain damage when administered prior to the onset of the ischaemic episode. The clinical utility of competitive and non-competitive NMDA receptor antagonists in man will, however, be determined not by their tremendous anti-ischaemic efficacy, but by their profile of adverse effects. Careful selection of the therapeutic target for NMDA antagonists will be necessary if beneficial effects are to be established in man.

Animals↗

PubMed1990

Second messenger systems: functional role in cerebrovascular smooth muscle regulation.

The role of two second messenger systems in alterations of cerebrovascular smooth muscle tone was examined in feline cerebral arteries using an in vitro preparation of vessel segments and cortical pial vessels in situ. Forskolin, which is known to activate adenylate cyclase, elicited a concentration-dependent relaxation of arteries preconstricted with prostaglandin F2 alpha (PGF2 alpha) (EC50 was approximately 300 nM). Microapplication of forskolin around individual cortical arteries and arterioles in situ elicited a dose-dependent dilatation. The maximum increase in arteriolar calibre was 54 +/- 4% from pre-injection calibre and EC50 was approximately 100 nM. Phorbol 12,13 dibutyrate (PDBu), which activates protein kinase C, elicited strong contractions of cerebral vessels. In vitro, PDBu contracted vessel segments in a concentration-dependent manner (EC50 was approximately 100 nM). Similarly, PDBu elicited potent dose-dependent constriction of pial arterioles in situ. The maximum response to PDBu was a 37 +/- 5% reduction in arteriolar calibre and the concentration eliciting EC50 was approximately 100 nM. These data provide an assessment to capacity of feline cerebral arteries to dilate and contract in response to adenylate cyclase and protein kinase C activation respectively.

Animals↗

PubMed1990

Effects of MK-801 upon local cerebral glucose utilisation in conscious rats following unilateral lesion of caudal entorhinal cortex.

Local cerebral glucose utilisation was examined in 62 discrete regions of conscious rats following unilateral ibotenic acid lesion of the caudal entorhinal cortex, and subsequent pharmacological challenge with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Fourteen days after unilateral lesion of the entorhinal cortex, there were no significant alterations in local cerebral glucose use except within the lesioned entorhinal cortex (reduced by 31% compared to sham-operated control animals). In sham-operated animals, systemic administration of MK-801 (0.5 mg/kg, i.v.) induced anatomically organised alterations in glucose use with increases in olfactory areas, subicular complex and some limbic areas (posterior cingulate cortex, mammillary body and anteroventral thalamic nucleus), and decreases in the inferior colliculus and neocortex (auditory, sensory-motor, somatosensory and frontal cortices). In animals with unilateral entorhinal cortex lesions, the metabolic response to MK-801 differed significantly from the response to the drug in sham-lesioned animals in a number of regions, viz. hippocampus, molecular layer (ipsilateral to lesion), entorhinal cortex (ipsilateral), dentate gyrus (ipsilateral), presubiculum (bilateral), parasubiculum (bilateral) and nucleus accumbens (bilateral). The ability of MK-801 to reduce glucose use in the neocortex was not altered by entorhinal cortex lesion. These data suggest that the functional consequences of non-competitive NMDA receptor blockade are dependent in some areas upon the integrity of the perforant pathway from the entorhinal cortex to the hippocampus.

Animals↗

PubMed1990

Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat.

Endothelin-1 (1 nmol) was applied to the exposed left middle cerebral artery (MCA) in anaesthetised adult male Sprague-Dawley rats. Local cerebral blood flow (1CBF), using [14C]iodoantipyrine and quantitative autoradiography, was measured in 27 anatomically defined structures, 10 min after topical application of endothelin-1. In those areas supplied by the MCA, 1CBF was markedly reduced beyond the threshold for ischaemic damage (e.g. dorsolateral caudate nucleus reduced from 131 +/- 3 to 29 +/- 25 ml.100 g-1.min-1, sensorimotor cortex from 109 +/- 5 to 31 +/- 21 ml.100 g-1.min-1). Distant areas were not affected.

Animals↗

PubMed1990

Effects of unilateral intrahippocampal injection of MK-801 upon local cerebral glucose utilisation in conscious rats.

The effects of unilateral intrahippocampal injections of the non-competitive NMDA receptor antagonist, MK-801, on local cerebral glucose utilisation have been examined in conscious rats using [14C]2-deoxyglucose autoradiography. The intrahippocampal injection of MK-801 (10 nmol) induced significant marked increases in glucose use in the ipsilateral hippocampus molecular layer and dentate gyrus (by 31 and 44%, respectively). Function-related glucose use in brain regions with known neuronal connections with the site of drug administration (e.g. entorhinal cortex, septal nucleus, mamillary body) was minimally altered after intrahippocampal MK-801 administration. Blockade of hippocampal NMDA receptors does not appear to modify activity, as reflected in local glucose utilisation, in hippocampal afferent and efferent circuits in conscious rats.

Animals↗

PubMed1990

Local cerebral blood flow following the intrastriatal administration of vasoactive intestinal peptide or peptide histidine isoleucine in the rat.

The effect of the intrastriatal microinjection of either vasoactive intestinal peptide (VIP) or a related peptide-peptide histidine isoleucine (PHI)-on local cerebral blood flow in the striatum was examined using iodo[14C]antipyrine quantitative autoradiography. In 37 rats, an injection needle was inserted into a chronically implanted guide cannula and 1 microliter of vehicle, VIP or PHI was injected into the striatum. Blood flow in sham controls was reduced by 15% in proximity to the injection site, when compared with blood flow in the contralateral uninjected control side (P less than 0.01). Similarly, following PHI administration (20 pmol), blood flow in the striatum was reduced by 14% when compared to that contralaterally (P less than 0.02). In contrast, following VIP administration (20 pmol), blood flow in proximity to the injection site was increased compared to flow in the contralateral striatum in 4/8 animals with the mean flow being elevated by 10% (n.s.) compared to blood flow contralaterally. VIP and PHI had similar effects on local cerebral glucose utilization in the caudate nucleus, their response being equivalent to that of sham animals. These experiments suggest that VIP and PHI have a differential influence on the microvasculature of the caudate nucleus, with VIP but not PHI mediating cerebrovascular dilation.

Animals↗

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

The effects of N-methyl-D-aspartate receptor blockade with MK-801 upon the relationship between cerebral blood flow and glucose utilisation.

The local cerebral circulatory and metabolic effects of MK-801, a selective non-competitive N-methyl-D-aspartate receptor antagonist have been examined in conscious rats with quantitative autoradiographic techniques using [14C]iodoantipyrine and [14C]2-deoxyglucose as tracers. Local cerebral blood flow (CBF) and local cerebral glucose utilisation (GU) were measured in 41 discrete neuroanatomical loci using identical criteria for region of interest localisation. Animals received either saline or MK-801 (0.5 mg/kg in saline) intravenously 10 min prior to the start of GU determination, or 15 min before the CBF measurement. MK-801 effects an immediate transient, elevation in mean arterial pressure (elevated by 30% from baseline) which returned rapidly to preinjection levels and a sustained moderate hypercapnia (arterial carbon dioxide tension increased by 16%) which persisted throughout the measurement periods. Statistically significant changes in GU were observed in 13 brain region structures after MK-801 administration. Glucose utilisation was significantly and markedly elevated with MK-801 in some limbic structures (particularly the hippocampus, posterior cingulate and entorhinal cortices), the inferior colliculus and most of the neocortex displayed moderate reductions in GU after MK-801 treatment. In the majority of brain regions (28 or the 41 studied), MK-801 minimally altered GU. There were widespread alterations in local CBF with MK-801 although in the majority of brain regions (24 of the 41 studied) there was no statistically significant alteration in CBF with MK-801. With one exception (the anterior thalamic nucleus), CBF was increased with MK-801 in all regions in which glucose use was elevated with the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

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↗

PubMed1990

Changes in extracellular glutamate concentration after acute subdural haematoma in the rat--evidence for an "excitotoxic" mechanism?

Using a rat model of subdural haematoma which is associated with ischaemic damage in the ipsilateral hemisphere, we have measured cerebral blood flow and release of excitatory amino acids after the haematoma. A more than sevenfold rise in glutamate and aspartate, persisting for forty minutes occurred in the severely ischaemic cortex (CBF less than 5 ml 100 gm-1 min-1) and a threefold, sustained rise was seen in hippocampus, although CBF was preserved (85 ml/100 g/-1 min-1). Excitotoxic mechanisms may, therefore, be involved in the ischaemic damage associated with subdural haematoma.

Acute Disease↗

PubMed1990

Ischaemic brain damage associated with tissue hypermetabolism in acute subdural haematoma: reduction by a glutamate antagonist.

Ischaemia results in elevated extracellular glutamate concentrations, and drugs which act at the N-methyl-D-aspartate sub-type of glutamate receptor have been shown to decrease ischaemic brain damage. Because almost all patients who die after severe head injury demonstrate ischaemic brain damage, and acute subdural haematoma (ASDH) is one of the commonest complications of severe head injury, we have studied this condition in a rat model. Using double-label autoradiography, we have measured the effects of ASDH on cerebral glucose utilization and cerebral blood flow (RCBF). Following ASDH, increased glucose utilisation was observed in some cortical and hippocampal structures, without concomitant increases in blood flow. Directly below the ASDH, blood flow and glucose utilization were profoundly reduced. Pre-treatment with D-CPP-ene, a competitive NMDA antagonist, resulted in amelioration of hypermetabolism induced by the ASDH. The results suggest that NMDA antagonists may prevent ischaemic brain damage after ASDH by reducing hypermetabolism, induced by glutamatergic mechanisms.

Acute Disease↗

PubMed1990

5 HT2 receptors in dementia of Alzheimer type: a quantitative autoradiographic study of frontal cortex and hippocampus.

Using both quantitative autoradiography in sections and a homogenate preparation assay, the distribution and density of 3H-ketanserin binding to 5 HT2 receptors was examined in frontal cortex and the hippocampal region from six control subjects and seven subjects who had dementia of the Alzheimer type (DAT). There was no difference between control and DAT subjects in the levels of ketanserin binding in any region of the frontal cortex or hippocampus determined by quantitative autoradiography or in parallel experiments using homogenate preparations (e.g. left frontal cortex, layer III; controls, 34.4 +/- 1.6 pmol/g, DAT, 37.1 +/- 4.6 pmol/g). In all of the DAT brains there were abundant neuritic plaques (e.g. superficial layers of left frontal cortex; 35 +/- 7 plaques/mm2), and a marked reduction of choline acetyltransferase activity, (by 30-60% relative to controls), in both frontal cortex and the hippocampus. Thus, despite the presence of morphological abnormalities and a loss of cholinergic function, two classic features of DAT, 5 HT2 receptor binding was unaltered in this group of DAT brains compared to controls.

Alzheimer Disease↗

PubMed1990

Neuropeptide Y and the cerebral circulation.

The significance of neuropeptide Y (NPY) in the cerebral circulation has been examined in the rat using immunocytochemistry, isolated cerebral artery preparations, and quantitative autoradiographic techniques for determining local CBF and glucose utilisation. In the rat the middle cerebral artery and the lenticulostriate artery from which blood is supplied to the caudate nucleus were found to be invested with numerous perivascular NPY immunoreactive nerve fibres. NPY (3-300 nM) contracted rat middle cerebral artery segments in a concentration-dependent manner. Intracerebral microinjections of NPY (200 pmol) or vehicle (1 microliter) were performed in rats after full recovery from anaesthesia via previously implanted guide cannulae. Following injection of NPY into the striatum, local blood flow was markedly decreased by 36% throughout the ipsilateral caudate nucleus (e.g., from 104 +/- 25 to 67 +/- 15 ml 100 g-1 min-1; mean +/- SD), whereas glucose use in this region was not altered significantly (e.g., 73 +/- 8 and 74 +/- 10 mumol 100 g-1 min-1 with vehicle and NPY, respectively). Intrastriatal NPY did not alter CBF or glucose use in the majority of other brain areas, including all of the 40 contralateral regions examined and almost all regions within the ipsilateral hemisphere. In a small number of highly discrete brain areas remote from the injection site (e.g., amygdala), there were significant reductions in blood flow with minimal changes in glucose use. Since NPY is present around rat cerebral blood vessels, is capable of evoking their contraction, and has the ability to produce reductions in blood flow independently of oxidative metabolism, this neuropeptide may be of major importance in cerebrovascular regulation.

Animals↗

PubMed1990

Focal cerebral ischemia in the cat: pretreatment with a competitive NMDA receptor antagonist, D-CPP-ene.

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPP-ene; SDZ EAA 494) upon ischemic brain damage have been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) and the animals were killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotaxic planes. Pretreatment with D-CPP-ene (15 mg/kg i.v. followed by continuous infusion at 0.17 mg/kg/min until death), 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 20.6 +/- 9.9% of the cerebral hemisphere in vehicle-treated cats to 7.2 +/- 4.4% in drug-treated cats; p less than 0.01). The competitive NMDA receptor antagonist D-CPP-ene is as effective as noncompetitive NMDA antagonists in reducing the amount of ischemic brain damage in this model of focal cerebral ischemia in a gyrencephalic species.

Animals↗

PubMed1990

Contractile responses to endothelin in feline cortical vessels in situ.

In this study in chloralose-anaesthetised cats, the vasomotor responses of individual pial vessels on the cortical surface to perivascular subarachnoid microapplication of endothelin were examined. Endothelin (3 x 10(-10) -3 x 10(-6) M) induced marked vasoconstriction of pial arterioles (-33.5 +/- 3.8% at 3 x 10(-6) M) and pial veins (-35.1 +/- 2.7% at 3 x 10(-6) M). The concentration of endothelin inducing half-maximal response was in the nanomolar range, with pial veins being slightly more sensitive to the peptide than pial arterioles. Vasoconstrictions induced by endothelin were extremely prolonged, persisting for approximately 90 min after a single microapplication. Arterioles constricted by endothelin remained responsive to perivascular microapplication of K+ (10 mM) or alkalotic CSF (pH 7.48).

Animals↗

PubMed1990

Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type.

Involvement of cortical glutamatergic mechanisms in senile dementia of the Alzheimer type (SDAT) has been investigated with quantitative ligand-binding autoradiography. The distribution and density of Na(+)-dependent glutamate uptake sites and glutamate receptor subtypes--kainate, quisqualate, and N-methyl-D-aspartate--were measured in adjacent sections of frontal cortex obtained postmortem from six patients with SDAT and six age-matched controls. The number of senile plaques was determined in the same brain region. Binding of D-[3H]aspartate to Na(+)-dependent uptake sites was reduced by approximately 40% throughout SDAT frontal cortex relative to controls, indicating a general loss of glutamatergic presynaptic terminals. [3H]Kainate receptor binding was significantly increased by approximately 70% in deep layers of SDAT frontal cortex compared with controls, whereas this binding was unaltered in superficial laminae. There was a positive correlation (r = 0.914) between kainate binding and senile plaque number in deep cortical layers. Quisqualate receptors, as assessed by 2-amino-3-hydroxy-5-[3H]methylisoxazole-4-propionic acid binding, were unaltered in SDAT frontal cortex compared with controls. There was a small reduction (25%) in N-methyl-D-aspartate-sensitive [3H]glutamate binding only in superficial cortical layers of SDAT brains relative to control subjects. [3H]Glutamate binding in SDAT subjects was unrelated to senile plaque number in superficial cortical layers (r = 0.104). These results indicate that in the presence of cortical glutamatergic terminal loss in SDAT plastic alterations occur in some glutamate receptor subtypes but not in others.

Aged↗

PubMed1990

Cerebrovascular responses to capsaicin in vitro and in situ.

1. The cerebrovascular effects of capsaicin have been examined in vitro, in feline isolated cerebral arteries (circular segments, 2-3 mm long, 300-400 microns extended diameter) and, in situ, in pial arterioles (diameter 40-200 microns) on the cortical surface of chloralose-anaesthetized cats. 2. In isolated middle cerebral arteries, low concentrations of capsaicin (10(-14)-10(-10) M) effected a concentration-dependent relaxation of vessels precontracted with prostaglandin F2 alpha. This relaxant response was markedly attenuated by repeated administration of capsaicin but was minimally affected by the presence of atropine, propranolol, cimetidine or spantide in the tissue bath. 3. In isolated middle cerebral arteries, higher concentrations of capsaicin effected a marked concentration-dependent contraction. This contraction was not modified by 10(-6) M phentolamine or 10(-6) M ketanserin. A markedly reduced contraction by capsaicin was found upon the removal of calcium ions from the buffer solution. Also the calcium entry blocker nimodipine reversed the capsaicin-induced contraction. 4. Subarachnoid perivascular microapplication of capsaicin around individual pial arterioles in situ elicited a biphasic response (an immediate vasoconstriction followed by a sustained vasodilatation). The maximum vasoconstriction was a 60 +/- 6% reduction in diameter from base line and the maximum vasodilatation a 38 +/- 7% increase in diameter. Vasodilatation occurred at lower concentrations of capsaicin (EC50, approximately 5 x 10(-8) M) than those required for vasoconstriction (EC50 3 x 10(-7) M). 5. Trigeminal ganglionectomy 10-16 days before the microapplication abolished the in situ vasodilator effects of capsaicin (10(-6) M) applied perivascularly, but was without effect on the vasoconstrictor actions of this agent. 6. Repeated administration of capsaicin (10-6M) around the same arteriole resulted in a progressive attenuation of the vasodilator phase of the response, with no modification of the vasoconstrictor phase. 7. The present study suggests that capsaicin-induced cerebral vasodilatation is due to the release of vasoactive agents from cerebrovascular trigeminal nerve fibres, whereas the vasoconstrictor effect 6f capsaicin is due to a direct effect on the cerebral vasculature which is mediated via the transmembrane passage of extracellular calcium.

Animals↗