Biomedical subjects

J McCulloch

Publications and source records attributed to J McCulloch.

At least 55 records · Page 3Linked to original sources

PubMed1997

Intracortical glutamate perfusion in vivo induces cellular alterations in specific protein kinase C isoforms and amyloid precursor protein.

This study investigated the immunostaining of protein kinase C (PKC) isoforms and amyloid precursor protein (APP) in rat brain cortex and determined alterations following an excitotoxic challenge in vivo. Cellular alterations in APP and PKC isoforms (alpha, beta, gamma, delta, epsilon, and zeta) following glutamate perfusion in the rat parietal cortex were compared with NaCl perfusion. In all animals, two histological zones could be defined consistently, a necrotic core and a boundary zone immediately adjacent to the core. Following glutamate and NaCl perfusion, cellular immunoreactivity to PKC isoforms and amino-terminal APP was significantly reduced within the necrotic core. Striking carboxy-terminal APP immunoreactivity was observed in some neurons remaining within the necrotic core. In the boundary of the glutamate lesion, the perikarya of most neurons were intensely immunoreactive to PKC alpha and beta. Furthermore, within the boundary zone, enhanced immunoreactivity within neuronal perikarya was observed to amino-terminal APP and, to a lesser extent, carboxy-terminal APP. Increased immunostaining of PKC alpha and beta and APP at the boundary zone was a consistent feature of intracortical glutamate perfusion and was not observed following NaCl perfusion. There were minimal alterations in PKC isoforms gamma, delta, epsilon, and zeta, in the boundary region following intracortical glutamate or NaCl perfusion. There was no astrocytic response, as detected by GFAP immunoreactivity, at the boundary zone. These findings indicate that there is a topographical relationship between cellular alterations of specific PKC isoforms and APP following an excitotoxic challenge in vivo.

Amyloid beta-Protein Precursor↗

PubMed1997

The effect of postmortem delay on the distribution of microtubule-associated proteins tau, MAP2, and MAP5 in the rat.

Breakdown or disruption of the cytoskeleton has been implicated in the neurodegenerative processes of a variety of diseases, including Alzheimer disease (AD) and stroke. Studies of such diseases in the human involve the use of postmortem brain tissue. Postmortem delay may vary considerably from a few hours to a few days, and within this period, a degree of cytoskeletal breakdown may occur. It is therefore crucial to examine alterations occurring in the cytoskeleton as a result of postmortem delay and subtract these from those caused by the disease. In this study, the distribution of tau, MAP2, and MAP5 immunohistochemistry was examined following postmortem intervals of 0-72 h in the rat cerebral cortex, corpus callosum, caudate nucleus, and hippocampus. Each microtubule-associated protein (MAP) underwent unique changes that were dependent both on postmortem interval and the brain region examined. Following long postmortem delays, some of the changes in these proteins were similar to those seen in rodent models of cerebral ischemia. These results demonstrate that MAPs are not stable during postmortem delay in the rat. Therefore, caution must be exercised when interpreting changes in MAPs in human postmortem tissue, especially in cases where ischemic injury may be involved. Examination of control tissue carefully matched for postmortem delay is therefore essential to allow meaningful interpretation of cytoskeletal abnormalities in human neurodegenerative disease.

Animals↗

PubMed1997

Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid.

Human transthyretin (TTR) can be transformed into amyloid fibrils by partial acid denaturation to yield a monomeric amyloidogenic intermediate that self-associates into amyloid through quaternary structural intermediates, which are identified by sedimentation velocity methods. The monomeric amyloidogenic intermediate has substantial beta-sheet structure with a nonnative but intact tertiary structure as discerned from spectroscopic methods. Proteolysis sensitivity studies suggest that the C-strand-loop-D-strand portion of TTR becomes disordered and moves away from the core of the beta-sandwich fold upon formation of the monomeric amyloidogenic intermediate over the pH range 5.1-3.9. The single site mutations that are associated with early onset amyloid disease [familial amyloid polyneuropathy (FAP)] function by destabilizing tetrameric TTR. Under mild denaturing conditions, the FAP variants populate the monomeric amyloidogenic intermediate conformation, which assembles into amyloid, whereas wild-type TTR remains tetrameric and nonamyloidogenic. The FAP mutations do not significantly alter the native folded structure; instead, they appear to act by making the thermodynamics and perhaps the kinetics more favorable for formation of the amyloidogenic intermediate. Suppressor mutations have also been characterized that strongly stabilize tetrameric TTR and disfavor the formation of the monomeric amyloidogenic intermediate, thus inhibiting amyloid formation. The mechanistic details characterizing transthyretin amyloid fibril formation available from the biophysical studies outlined within have been utilized to develop a new therapeutic strategy for intervention in human amyloid disease. This approach features small molecules that bind with high affinity to the normal fold of transthyretin, inhibiting the quaternary and tertiary structural changes associated with the formation of the monomeric amyloidogenic intermediate that self-assembles into amyloid. Ligand binding to TTR stabilizes the native tetrameric fold, which is nonamyloidogenic.

Amyloid↗

PubMed1997

Rapid alteration of tau in oligodendrocytes after focal ischemic injury in the rat: involvement of free radicals.

Glial inclusions containing the microtubule-associated protein tau are present in a variety of chronic neurodegenerative conditions. We now report a rapid and time-dependent increase of tau immunoreactivity within oligodendrocytes after focal cerebral ischemia in the rat. The number of tau positive oligodendrocytes in the ipsilateral subcortical white matter increased six- to eightfold by 40 minutes after permanent middle cerebral artery occlusion (MCAO). Tau was detected using antibodies that label both the N- and C-terminal of the protein, suggesting accumulation of full-length protein within these cells. Pretreatment with the spin trap agent alpha-phenyl-tert-butyl-nitrone (PBN)(100mg/kg) reduced the number of tau-positive oligodendrocytes by 55% in the subcortical white matter of the ischemic hemisphere compared with untreated animals at 40 minutes after MCAO. In contrast, pretreatment with glutamate receptor antagonists MK-801 (0.5 mg/kg) or 2,3-dihydroxy-6-nitro-7-sulpfamoyl-benzo(f)quinoxaline (NBQX) (2 x 30 mg/kg), failed to reduce the number of tau-positive oligodendrocytes after 40 minutes of ischemia. The results indicate that oligodendrocytes respond rapidly to an ischemic challenge and that free radical-mediated mechanisms are involved in the cascade leading to increased tau immunoreactivity.

Animals↗

PubMed1997

Endothelin-B receptors in cerebral resistance arterioles and their functional significance after focal cerebral ischemia in cats.

In the cerebral circulation, endothelin-A receptor activation mediates marked prolonged vasoconstriction whereas endothelin-B (ETB) receptor activation effects dilation. In contrast to some peripheral vascular beds, ET(B) receptor-induced vasoconstriction has not yet been demonstrated in brain vessels. In this study in chloralose-anesthetized cats, with perivascular microapplications of ET(B) selective agonist (BQ-3020) and antagonist (BQ-788), we investigated whether ET(B) receptor-mediated constriction could be uncovered in cortical arterioles in vivo. In addition, we examined whether normal dilator response to ET(B) receptor activation is preserved in postischemic cerebral arterioles. The first microapplication of the selective ET(B) receptor agonist BQ-3020 (1 micromol/L) onto a pial cortical arteriole elicited marked dilation (caliber increased by 26.3 +/- 15.1% from preinjection baseline). A second application of BQ-3020 (10-minute interval) onto the same vessel failed to evoke any significant vasomotor response. Subsequent (third and fourth) adventitial microapplication of the ET(B) receptor agonist on the same arteriolar site effected a significant constriction of cerebral arterioles (-15.3 +/- 12.7% and -9.7 +/- 6.3% from preinjection baseline, respectively, at 20 and 30 minutes after the first application). The pial arterioles did not display tachyphylaxis to repeated applications of potassium (10 mmol/L). The perivascular application of the ET(B) receptor antagonist BQ-788 (0.001 to 1 micromol/L) had no effect on arteriolar caliber per se but blocked both BQ-3020-induced dilation (inhibitory concentration approximately 5 nmol/L) and vasoconstriction elicited by repeated activation of ET(B) receptors. After middle cerebral artery occlusion, most of the arterioles examined displayed a sustained dilation. The microapplication of BQ-3020 into the perivascular space surrounding postischemic dilated arterioles elicited a constriction of a similar magnitude to that induced by application of CSF (-17 +/- 7% and -17 +/- 7% from preinjection baseline, respectively). The adventitial microapplication of the ET(B) receptor antagonist (BQ-788, 0.1 micromol/L) on postocclusion dilated pial arterioles effected no change in the arteriolar caliber when compared with preinjection baseline. This BQ-788-induced response was significantly different from that induced by perivascular microinjection of CSF (P < 0.001, analysis of variance). These investigations indicate that (1) repeated activation of ET(B) receptors displays tachyphylaxis of the vasodilator response but also uncovers significant constriction of cerebral arterioles in vivo; (2) the ability of BQ-3020 to elicit dilation is lost within 30 minutes of induced focal ischemia; and (3) ET(B)-mediated contractile tone contributes in a small but significant manner in limiting postischemia dilation of cortical pial arterioles.

Animals↗

PubMed1997

First SPET images of glutamate (NMDA) receptor activation in vivo in cerebral ischaemia.

This report describes the initial clinical assessment of (+)-3-[123I]Iodo-MK-801 and its potential to provide single photon emission tomographic (SPET) images in vivo of NMDA receptor activation during cerebral ischaemia. Multiple SPET images were obtained in the 120 min after the administration of 150 MBq of (+)-3-[123I]Iodo-MK-801 to five patients with cerebral ischaemia (due to cerebral haemorrhages) and to five normal volunteers. In normal subjects, (+)-3-[123I]Iodo-MK-801 has a rapid uptake into the brain. The tracer has a high non-specific retention in the central nervous system due to its lipophilicity, which was made evident by the retention of tracer in the cerebellum and white matter (brain areas with few NMDA receptors). In all patients with cerebral haemorrhages, the initial uptake of (+)-3-[123I]Iodo-MK-801 into the ipsilateral hemisphere was markedly reduced, consistent with a reduced level of cerebral blood flow. In two of five patients, relatively increased tracer retention at later time points (60-120 min after tracer administration) could be seen in cortical areas adjacent to the site of the haemorrhage, consistent with activated NMDA receptors. In three of the patients, no relatively enhanced tracer retention could be identified. Using (+)-3-[123I]Iodo-MK-801, it may be possible to image excessive glutamate (NMDA) receptor activation during an ischaemic episode in living human patients. The utility of (+)-3-[123I]Iodo-MK-801 as a SPET ligand for assessing modest alterations in NMDA receptor activity may ultimately be limited by its lipophilicity and consequent high non-specific binding.

Aged↗

PubMed1996

The effects of bosentan on cerebral blood flow and histopathology following middle cerebral artery occlusion in the rat.

The involvement of endothelins in the cerebrovascular events which follow a focal ischemic insult in the rat was explored in the present study. Intravenous (i.v.) administration of bosentan (3, 15 and 30 mg/kg), an endothelin ETA and ETB receptor antagonist, prior to middle cerebral artery occlusion in the rat did not significantly alter cortical perfusion in these rats. A 62 +/- 3% reduction in laser doppler flow was observed 10 min after middle cerebral artery occlusion in the vehicle-treated group compared to a 49 +/- 5% reduction in laser doppler flow in the group receiving 15 mg/kg bosentan. Pre-treatment with intravenous bosentan (15 mg/kg) prior to middle cerebral artery occlusion in the rat also failed to elicit significant alterations in the reduction in regional cerebral blood flow (frontal cortex; 81 +/- 13 ml/100 g/min) and subsequent hemispheric volume of ischemic damage observed (94 +/- 9 mm3) compared to the vehicle treated animals (68 +/- 9 ml/100 g/min, 113 +/- 5 mm3, respectively). Minimal changes were also observed in these endpoints, when a 15 mg/kg dose of bosentan was administered following middle cerebral artery occlusion. In conclusion bosentan failed to expose a major role for endothelins in focal ischemic pathology in the rat.

Animals↗

PubMed1996

Endothelin receptor mediated constriction and dilatation in feline cerebral resistance arterioles in vivo.

The receptors mediating the cerebrovascular actions of endothelins have been examined in feline cerebral resistance arterioles in vivo. The adventitial microapplication of the endothelin ETA receptor antagonist BQ-123 (cyclo D-aspartate-D-tryptophan-L-leucine-D-valine-L-proline) (0.1-10 microM) per se had minimal effect on cerebral resistance arterioles examined. The adventitial microapplication of endothelin-1 (10 nM) elicited a marked vasoconstriction of cerebral resistance arterioles (-29.1 +/- 1.9% from pre-injection baseline). The endothelin-1 induced vasoconstriction was attenuated, in a dose dependent manner, by the adventitial co-application of BQ-123 and endothelin-1 (estimated IC50 0.7 microM). The adventitial microapplication of the endothelin ETB receptor agonist BQ-3020 N-acetyl[Ala11,Ala15]ET-1 (6-21)) (0.001-1 microM) effected a dose dependent vasodilatation (EC50 30 nM, maximum response 25 +/- 5% from pre-injection baseline). The magnitude of the vasodilatation elicited by BQ-3020 (100 nM and 1 microM) was dependent on the pre-injection calibre of the arterioles examined. The intracarotid infusion (via the lingual artery) of BQ-3020 (0.5-500 pmol/min) had no significant effect on the calibre of cerebral resistance arterioles. These results suggest that the peptide endothelin ETB receptor agonist fails to gain access to the cerebrovascular endothelin ETB receptors following its intraluminal administration. These investigations indicate that endothelin ETA receptors mediate vasoconstriction and endothelin ETB receptors mediate vasodilatation in feline cerebral resistance arterioles in vivo.

Animals↗

PubMed1996

The relationship between glutamate release and cerebral blood flow after focal cerebral ischaemia in the cat: effect of pretreatment with enadoline (a kappa receptor agonist).

The effect of the kappa-opioid agonist enadoline (CI-977) upon the relationship between cerebral blood flow and glutamate release was simultaneously assessed (using microdialysis and hydrogen clearance techniques respectively) at the same anatomical locus in the cerebral cortex (suprasylvian gyrus) after permanent middle cerebral artery (MCA) occlusion in halothane-anaesthetised cats. During controlled graded ischaemia, pretreatment with enadoline (0.3 mg/kg i.v. followed by continuous infusion at 0.15 mg/kg/h), initiated 30 min prior to MCA occlusion, significantly attenuated the marked increases in extracellular glutamate, aspartate and GABA observed in the focal ischaemic penumbra. The present data are consistent with the hypothesis that the neuroprotective efficacy of enadoline in focal cerebral ischaemia is due to inhibition of glutamate release in the ischaemic penumbra.

Animals↗

PubMed1996

Intracortical perfusion of glutamate in vivo induces alterations of tau and microtubule-associated protein 2 immunoreactivity in the rat.

Modifications of microtubule-associated proteins (MAP) have been reported in both acute and chronic degenerative conditions, such as cerebral ischaemia and Alzheimer's disease, and may be associated with cytoskeletal breakdown. Glutamate excitotoxicity has been implicated in the pathogenesis of both of these conditions and has been shown in some in vitro studies to induce changes in tau similar to those occurring in Alzheimer's disease. This study examines the effects of high extracellular glutamate concentrations on the distribution of tau and MAP2 in vivo in order to determine whether glutamate induces similar changes in tau to those previously reported in vitro in the intact, adult central nervous system. Monosodium glutamate was perfused into the rat parietal cortex for 90 min using in vivo microdialysis and at 4 h after the start of perfusion the distribution of tau and MAP2 was determined by immunohistochemistry. At the core of the glutamate-induced lesion tau immunostaining, as detected with the Tau 1 antibody, was decreased in axons and increased within perikarya compared to controls. Increased immunostaining was not apparent with polyclonal antibodies raised against full-length tau or towards the N or C termini of the protein. In contrast, increased tau immunoreactivity was detected, with all the antibodies used in this study, within oligodendrocytes following either glutamate or sodium chloride perfusion. MAP2 immunoreactivity was increased within perikarya at the core of the glutamate-induced lesion, while dendritic immunoreactivity was reduced. These results suggest that glutamate excitotoxicity in vivo may not be involved in neurofibrillary tangle formation but may be important in the progression of cytoskeletal pathology following cerebral ischaemia.

Animals↗

PubMed1996

Changes in local microvascular permeability and in the effect of intervention with 21-aminosteroid (Tirilazad) in a new experimental model of focal cortical injury in the rat.

In a new, reproducible model of rodent focal cortical injury, we have shown that in the absence of early traumatic disruption of the microvasculature and subsequent hemorrhage, delayed perivascular protein leakage and polymorphonuclear leukocyte infiltration of the injured cortex occur. In this study we employed a sensitive quantitative autoradiographic technique (using alpha-aminoisobutyric acid as a tracer) to investigate the focal changes in microvascular permeability with time and to determine the effects of administration of a 21-aminosteroid (Tirilazad) initiated 5 min after induction of the cortical injury. At all time points studied, there was a significant increase in perilesional blood-brain barrier permeability in lesioned animals treated with vehicle, compared to shamoperated animals, with the most marked increase in blood-brain barrier permeability at 4 h postinjury (mean Ki +/- SE = 19.2 +/- 2.4/1000 min with cortical injury, 1.5 +/- 0.3/1000 min in shams) (mean volume +/- SE = 15.48 +/- 0.7 mm3). In animals with cortical injury treated with Tirilazad (10 mg/kg), there was a significant reduction in microvascular permeability at the site of injury (Ki = 3.1 +/- 0.5, p < 0.001) and a significant reduction in volume of increased permeability (4.86 +/- 0.7 mm3, p < 0.01) at 4 h postinjury. In this model of cortical injury, a delayed increase in microvascular permeability occurs, which is significantly attenuated by postinjury treatment with Tirilazad.

Analysis of Variance↗

PubMed1996

Failure of an endothelin antagonist to modify hypoperfusion after transient global ischaemia in the rat.

The role of endogenous endothelins in mediating postischaemic hypoperfusion after transient global ischaemia was investigated in halothane-anaesthetised rats. Pretreatment with the broad-spectrum (ET (A) and ET (B)) endothelin antagonist. Bosentan (17 micromol/kg) had minimal effect on postischaemic hypoperfusion, measured by hydrogen clearance, in the caudate nucleus and the parietal cortex in the 3 h after bilateral common carotid artery occlusion with concomitant haemorrhagic hypotension (transient global ischaemia). In a separate series of rats with CBF measured by [14C]iodoantipyrine autoradiography at 90 min after carotid occlusion with concomitant haemorrhagic hypotension, Bosentan treatment failed to significantly alter CBF in any of the 35 brain regions examined. No significant alterations in CBF, measured by hydrogen clearance, were observed after transient bilateral common carotid artery occlusion. [14C]Iodoantipyrine autoradiography at 90 min after occlusion failed to demonstrate any significant increases in CBF after transient bilateral common carotid artery occlusion in any of the 35 brain regions examined in anaesthetised rats. The failure of the broad-spectrum endothelin antagonist Bosentan, at concentrations known to inhibit the cerebrovascular effects of exogenous ET-1, provide no support for the view that endothelins have a major role in mediating acute postischaemic hypoperfusion.

Animals↗

PubMed1996

Endothelin-mediated vascular tone following focal cerebral ischaemia in the cat.

The actions of Bosentan and PD155080, nonpeptide endothelin receptor antagonists, were examined in feline pial arterioles in situ following middle cerebral artery (MCA) occlusion to gain insight into the cerebrovascular influence of endogenous endothelins in focal cerebral ischaemia. Immediately following permanent MCA occlusion, all pial arterioles overlying the suprsylvian and ectosylvian gyri displayed marked dilatations, which were maintained in a population of vessel but differentiated into sustained constrictions in others. Perivascular subarachnoid microinjections of Bosentan (30 microM), PD155080 (30 microM), and artificial CSF (pH 7.2) were performed between 30 and 210 min following MCA occlusion. The perivascular microapplication of Bosentan (30 microM) and PD155080 (30 microM) around pial vessels overlying the suprasylvian and ectosylvian gyri, which are within the territory of the occluded MCA, elicited in increase in the calibre of postocclusion dilated and constricted pial arterioles. The perivascular microapplication of PD155080 (30 microM) around postocclusion constricted arterioles overlying the ectosylvian and suprasylvian gyri elicited an increase in the calibre of arterioles (69 +/- 49% from preinjection baseline; n = 8). The perivascular microapplication of Bosentan (30 microM) around postocclusion constricted arterioles overlying the ectosylvian and suprasylvian gyri also elicited an increase in the calibre of arterioles (68 +/- 60% from preinjection baseline; n = 13). In contrast, the microapplication of CSF (pH 7.2) elicited small reductions in pial arteriolar calibre of postocclusion constricted arterioles (-8 +/- 13% from preinjection baseline; n = 8). The perivascular microapplication of PD155080 (30 microM) around postocclusion dilated pial arterioles overlying the ectosylvian and suprasylvian gyri elicited an increase in the calibre of arterioles (11 +/- 10% from preinjection baseline; n = 38). The perivascular microapplication of Bosentan (30 microM) around postocclusion dilated arterioles elicited an increase in the calibre of arterioles (16 +/- 15% from preinjection baseline; n = 36). In contrast, the microapplication of CSF (pH 7.2) elicited small reductions in pial arteriolar calibre of postocclusion dilated arterioles (-9 +/- 6% from preinjection baseline; n = 44). Perivascular microapplication of Bosentan or PD155080 had minimal effect on the calibre of pial arterioles on the parasagittal gyrus (anterior cerebral artery territory), although these arterioles had also displayed sustained dilatation following MCA occlusion. These results indicate that contractile factors (whose effects can be reversed with endothelin receptor antagonists) constrict or impair dilatation of cortical resistance arterioles in an acute cerebral ischaemic episode.

Animals↗

PubMed1996

Endothelin receptor antagonist increases cerebral perfusion and reduces ischaemic damage in feline focal cerebral ischaemia.

These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor antagonist PD156707 in normal and ischaemic cat brain. A dose of PD156707 that inhibited the effects of exogenous endothelin-1 was established in nonischaemic cerebral resistance arterioles. Perivascular microapplication of the endothelin-receptor antagonist PD156707 (0.03-3 microM) had a minimal effect on nonischaemic pial resistance arterioles. The perivascular co-application of PD156707 and ET-1 (10 nM) effected a dose-dependent attenuation of the ET-1 vasoconstrictive response (IC50 = 0.1 microM). Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion) attenuated the vasoconstriction elicited by perivascular ET-1 (10 nM) in normal pial arterioles (ET-1 vasoconstriction: -37 +/- 13% from preinjection baseline; after intravenous PD156707: 6 +/- 10% from preinjection baseline). In the focal ischaemia studies, cerebral perfusion was measured in the suprasylvian and ectosylvian gyri (by laser Doppler flowmetry). Occlusion of the middle cerebral artery reduced cerebral perfusion in the suprasylvian and ectosylvian gyri by approximately 50%. Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion), initiated 30 min after middle cerebral artery occlusion, effected a progressive increase in cerebral perfusion up to preocclusion baseline levels, whereas cerebral perfusion in vehicle-treated animals did not vary from its postocclusion level. In these animals, the intravenous administration of PD156707 reduced the hemispheric volume of ischaemic damage by 45% (vehicle: 2,376 +/- 1,107 mm3; PD156707: 1,307 +/- 548 mm3; p < 0.05). Our investigations indicate that endothelin receptor antagonism may be a new therapeutic strategy for the amelioration of focal ischaemic damage.

Animals↗

PubMed1996

A new experimental model of contusion in the rat. Histopathological analysis and temporal patterns of cerebral blood flow disturbances.

The authors have devised a simple reproducible rodent model of focal cortical injury that uses a mechanical suction force applied through intact dura. The time course and pattern of changes in neurons, glia, and microvasculature were investigated using this model. Early traumatic disruption of the blood-brain barrier and hemorrhage do not occur in this model; however, many of the features of human contusion seen with light and electron microscopy are closely reproduced. At the site of injury, early swelling and lucency of neural dendritic processes have been shown to precede an astrocyte response. In the absence of perivascular hemorrhage, delayed perivascular protein leakage and polymorphonuclear infiltration of the damaged cortex occurs, which is suggestive of an acute inflammatory response. Cerebral blood flow (CBF) has been measured using 14C-iodoantipyrine autoradiography at 30 minutes, 4 hours, and 24 hours after induction of negative-pressure injury in rats anesthetized with halothane and in time-matched sham-operated controls. A significant reduction in blood flow in the sensorimotor cortex at the site of the injury was present at 30 minutes, 4 hours, and 24 hours after induction of the lesion, compared to the contralateral cortex (superficial lamina, ipsilateral 50 +/- 7 ml/100 g/minute, contralateral 112 +/- 26 ml/100 g/minute). The CBF was significantly reduced at the ipsilateral entorhinal cortex at 30 minutes postinjury but no significant reduction was demonstrated at later time points. Although marked alterations in CBF occurred in this cortical injury model, the magnitude and duration of the reduction in CBF are not consistent with those necessary for production of ischemic cell damage. These data indicate that this model of cortical injury can be used to examine biomechanical aspects of contusion without domination by ischemic pathophysiology.

Animals↗

PubMed1996

Neuroprotective drug development in stroke: blood pressure and its impact.

IMPORTANCE OF BLOOD PRESSURE IN STROKE RESEARCH: From the experimental animal to man, blood pressure is the most important physiologic variable in stroke research. Acutely, after the onset of stroke, modest alterations in arterial pressure are the major determinant of cerebral blood flow to the tissue at risk and ultimately of the anatomical extent of infarction. Whether in animals or man, moderate drug-induced hypotension counteracts the brain protection afforded by even the most powerful anti-ischaemic drugs, the discovery of which has transformed stroke research in the last decade. Chronic hypertension is strongly associated with stroke risk in man whereas anti-ischaemic drug development has been based on normotensive animals with limited use of genetically (or surgically induced) hypertensive animals. ADVANCES IN STROKE RESEARCH: Major advances have taken place in stroke research in recent years. These include the development of pharmacological approaches which are peculiar to the brain (modulation of excitotoxicity) or which are common to many vascular beds (flow enhancement strategies using calcium entry blockers or endothelin receptor antagonists). It is clear that blood pressure is particularly important for all aspects of brain ischaemia research, both in animals and man.

Animals↗

PubMed1995

AMPA receptor antagonism attenuates MK-801-induced hypermetabolism in the posterior cingulate cortex.

The effect of pretreatment with an AMPA receptor antagonist, NBQX, on MK-801-induced alterations in glucose use was examined using [14C]-2-deoxyglucose autoradiography. NBQX (7 mg/kg) had minimal effect on glucose utilisation in all anatomical regions examined. The intravenous administration of MK-801 (0.2 mg/kg) induced increases in glucose use in the limbic system and cingulate cortex. MK-801 reduced glucose utilisation in the sensory motor and auditory cortices. Pretreatment with NBQX attenuated the MK-801-induced hypermetabolism in the posterior cingulate cortex. The decreases in glucose utilisation induced by MK-801 were not exacerbated by the pretreatment with NBQX. The interaction between NBQX and MK-801 suggests a possible method of attenuating some of the adverse effects of the non-competitive NMDA receptor antagonists in the posterior cingulate cortex.

Animals↗

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↗