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Biomedical subjects

D I Graham

Publications and source records attributed to D I Graham.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of nitric oxide synthesis does not reduce infarct volume in a rat model of focal cerebral ischaemia.

The effect of the nitric oxide (NO) synthesis inhibitor Ng-nitro-L-arginine methylester (L-NAME) on ischaemic brain damage was determined in a rat model of focal cerebral ischaemia. Ischaemia was induced by permanent occlusion of the left middle cerebral artery (MCA) and infarction assessed 4 h post-occlusion by quantitative histopathology. L-NAME (30 mg/kg s.c.), administered 30 min pre- and 30 min post-MCA occlusion, did not significantly alter the volume of ischaemic damage in the cerebral hemisphere, neocortex or caudate nucleus compared with saline controls. This result provides no support for the view that NO generation is a key component in the post-ischaemic cascade leading to acute neuronal death.

Animals↗
PubMed1992

The cerebrovascular response to experimental lateral head acceleration.

A number of microvascular changes, such as the development of astrocyte lucency, increased endothelial pit/vesicle activity, development of crater like lesions, and endothelial microvilli have been reported after injury to the brain. Lateral head acceleration in the non-human primate, however, still provides the best experimental model for human diffuse axonal injury. No attempt has yet been made to document the spatial extent or time course of the microvascular response to acceleration injury to the head. We have examined the brains of baboons 1, 4, 6, and 12 h and 7 days after acceleration injury to the head to analyse the microvascular response. In the experimental animals there was a short-term rise in intracranial pressure followed by a long-term resolution, and a reduction in both mean arterial blood pressure and cerebral perfusion pressure which, however, never dropped below 75% of baseline for more than 5 min after injury in any animal. We found evidence for extravasation of blood in a small number of blood vessels in all parts of the brain. Interendothelial tight junctions are not disrupted. Pit/vesicle activity rises in the 1st h in the occipital cortex, but not until 4 h in the frontal cortex, and remains elevated for at least 7 days. There is little change in the thalamus. Development of microvilli is most rapid in the frontal cortex with peak values at 1 h, but slower in the thalamus and occipital cortex where peak values are only obtained at 6 h. Highest numbers of microvilli occur in parasagittal regions of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Acceleration↗
PubMed1992

Hippocampal pathology in fatal non-missile human head injury.

The hippocampus has been known to be involved in fatal non-missile human head injury, although detailed histopathology of this lesion has yet to be described. This report documents the frequency and distribution of hippocampal damage in a consecutive series of 112 fatal human non-missile head injuries. Damage to the hippocampus was noted in 94 cases (84%). Lesions always involved the CA1 subfield and were bilateral in 70 cases. Other subfields of the hippocampus were involved less frequently. Lesions were focal in the majority of cases (58%). Pathological evidence of high intracranial pressure was present in 86% of the cases. Hypoxic brain damage in other regions of the brain was present in 74% of cases. Thus, the hippocampus is frequently damaged in fatal non-missile human head injury. The pattern of this damage is similar to that observed in experimental head injury. Hypoxia and high intracranial pressure are likely to contribute to the occurrence of human traumatic hippocampal damage but other mechanisms, such as excitotoxicity, are likely to be operative.

Adolescent↗
PubMed1992

Changes in the choroid plexus, responses by intrinsic epiplexus cells and recruitment from monocytes after experimental head acceleration injury in the non-human primate.

We have examined, by scanning and transmission electron microscopy, morphological changes in the choroid plexus of the lateral ventricles of the non-human primate brain after lateral head acceleration. We demonstrate passage of plasma and blood cells either through tears in blood vessels and the choroidal epithelium, or through the cells of the choroidal epithelium, 20 min after injury, together with morphological changes in that epithelium. At 3 and 4 h small cells with a reniform nucleus accumulate in the connective tissue core of the choroid plexus. We suggest that these are monocytes. At 6 and 12 h cells can be seen in enlarged intercellular spaces within the choroidal epithelium. These cells possess surface ruffles and we suggest that they are monocytes differentiating into macrophages and epiplexus cells. Further evidence for transepithelial migration of monocytes/macrophages is obtained at 7 days. However, at 28 days all blood has been removed from the surface of the choroid plexus and epiplexus cells possess an appearance typical of that in uninjured animals. The possible sources of epiplexus cells are discussed with reference to studies of responses after brain insult and of development. We have obtained no evidence in support of emperipolesis by monocytes through the choroidal epithelium. We suggest that monocytes/macrophages migrate, via an intercellular route, to differentiate into epiplexus cells, thus providing additional numbers of epiplexus cells after head injury.

Acceleration↗
PubMed1992

Release of endogenous adenosine and its metabolites by the activation of NMDA receptors in the rat hippocampus in vivo.

1. The effects of N-methyl-D-aspartate (NMDA), KCl, and veratridine on the release of endogenous adenosine and its metabolites, inosine and hypoxanthine, from the rat hippocampus have been studied by in vivo microdialysis. 2. In the hippocampus of rats anaesthetized with urethane the adenosine level reached a stable state estimated at 0.93 microM during the first 2 h after the implantation of the dialysis probe. NMDA (50 microM to 25 mM) in the perfusate evoked a concentration-dependent release of adenosine, inosine and hypoxanthine with an EC50 of 180 microM. The release was reduced by 93% by the specific NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (2-AP5) at 200 microM, indicating an NMDA receptor-mediated process. In addition, the 100 mM KCl-evoked release of adenosine was also substantially reduced by 77% by 2-AP5, suggesting that a large component of the K(+)-evoked release is NMDA-receptor-mediated. 3. Perfusion with zero-Ca2+ artificial cerebrospinal fluid attenuated the NMDA-evoked release of adenosine only by 16% (not significant) but depressed the K(+)-evoked release by 62%, indicating that most of the NMDA-evoked release is directly receptor-mediated, whereas a large component of the K(+)-evoked release could be via the release of an excitatory amino acid acting at the NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1992

Diffuse axonal injury caused by assault.

The case reports of 50 fatal head injuries caused by assault and managed at the Institute of Neurological Sciences, Glasgow, were reviewed. Fifteen cases had diffuse axonal injury. Diffuse axonal injury is a well recognised type of brain damage brought about by a head injury, usually as a result of a road traffic accident or fall from a height. It does not seem to be widely appreciated that it may also occur as a result of an assault. This has important medicolegal implications.

Adolescent↗
PubMed1992

Transient glucose hypermetabolism after acute subdural hematoma in the rat.

Ischemic brain damage occurs in most patients with acute subdural hematoma, yet many aspects of the distribution and extent of this damage remain unexplained. Previous studies in rat model, which produces a region of infarction under the hematoma, have implicated an "excitotoxic" mechanism, suggesting that high concentrations of excitatory amino acids may exacerbate ischemic damage. A study is described in which local glucose utilization is measured 2 or 4 hours after induction of acute subdural hematoma in the rat. These changes are compared to those produced by introducing the same volume of inert silicone gel into the subdural space. Massive increases (up to 142%) in glucose utilization occurred throughout both hippocampi and in a variable zone around the ischemic core, but these had normalized by 4 hours after blood injection. Hippocampal hypermetabolism was not seen after introduction of the silicone mass, suggesting that diffusible substances from the clotted blood may be responsible for these changes. This transient hypermetabolism accords with an excitotoxic process, which may amplify brain damage after acute subdural hematoma.

Acute Disease↗
PubMed1991

beta A4 amyloid protein deposition in brain after head trauma.

Previous reports have suggested that both repetitive head trauma and a single injury can be associated with the presence of diffuse beta A4 amyloid protein plaques in long-term survivors. We have studied sixteen patients (aged 10-63 years) who sustained head injury and survived for only 6-18 days. Immunostaining with an antibody to beta A4 amyloid showed extensive deposits of the protein in the cortex in six of the sixteen patients (38%). Thus, severe head injury can trigger beta A4 deposition in the brain within days.

Adult↗
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

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

Selective vulnerability of hippocampal neurons in acceleration-induced experimental head injury.

Traumatically induced subtotal hippocampal neuronal loss traditionally has been considered a consequence of intracranial hypertension and impaired cerebral perfusion. We have examined the frequency and distribution of hippocampal lesions in an acceleration model of brain injury in 54 anesthetized nonhuman primates undergoing physiologic monitoring and subjected postinjury to comprehensive neuropathologic examination. Hippocampal lesions occurred in 32/54 animals (59%). These lesions always involved the CA-1 hippocampal subfield and were bilateral in 24 animals. Hippocampal involvement was not associated with marked elevation of intracranial pressure or depression of cerebral perfusion pressure. These lesions occurred in the absence of involvement of other brain regions considered selectively vulnerable to hypoxic insults. Hippocampal damage occurred in 46% of animals with mild injury characterized by brief periods of unconsciousness and no residual neurologic deficit. Ninety-four percent of animals with severe injuries and prolonged posttraumatic coma had hippocampal involvement. Traumatically induced selective neuronal necrosis of the hippocampus is a specific lesion not explained by the conventional mechanistic theories of head injury. An alternative hypothesis, such as excitotoxicity involving glutamate or other neurotransmitters, may account for the lesions demonstrated in this study.

Acceleration↗
PubMed1991

The microvascular response to stretch injury in the adult guinea pig visual system.

In a variety of brain injury models, both reactive axonal change and microvascular abnormalities occur. Development of a stretch injury model in the guinea pig optic nerve has allowed for the characterization of the early axonal response to injury. In this same model, we have now attempted to characterize those morphologic changes occurring in the visual system microvasculature after injury. Thirty adult guinea pigs were subjected to axonal stretch injury and killed at posttraumatic survival periods ranging from 10 minutes to 14 days. Twenty animals were examined by scanning electron microscopy (SEM) for the detection of posttraumatic changes in the surface morphology of the microvasculature, and 10 animals were processed for transmission electron microscopy (TEM) analysis. Through this approach, increased pit vesicle activity and formation of endothelial microvilli were recognized within 10 minutes of injury. Pit vesicle activity returned to control levels by 2 hours. The formation of endothelial microvilli was widespread, affecting the microvessels in both the stretched and unstretched optic nerves and in the chiasm. The greatest response developed most slowly in the stretched nerve, and it was faster but less marked in the unstretched nerve and chiasm. Microvilli were more numerous in larger vessels. Related astrocytic swelling/lucency was not apparent until 6 hours after injury. The astrocyte response was less marked than that documented after brain injury. The results of this investigation demonstrate a widespread microvascular response to stretch injury of the guinea pig optic nerve. Comparison with the documented responses to traumatic brain injury indicates different rates of response to different types of insult.

Animals↗
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

Glial swelling following human cerebral contusion: an ultrastructural study.

The ultrastructural features of cerebral contusion seen three hours to 11 days after head injury were studied in 18 patients undergoing surgery. Massive astrocytic swelling ("cytotoxic" oedema) was seen three hours to three days after injury, maximal in perivascular foot processes, and compressing some of the underlying capillaries. The tight junctions were not disrupted. Neuronal damage was most marked three to 11 days after injury. The pathophysiological mechanisms leading to oedema formation and neuronal degeneration are discussed.

Adult↗
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

Localisation of calcium ions and calcium-ATPase activity within myelinated nerve fibres of the adult guinea-pig optic nerve.

There is no published description of the distribution of free Ca2+, nor of the distribution of Ca(2+)-ATPase activity associated with the maintenance of low axoplasmic Ca2+ concentrations, in normal central myelinated nerve fibres. We have used the oxalate-pyroantimonate technique to localise free Ca2+, together with the lead-citrate technique to localise Ca(2+)-ATPase activity within myelinated fibres from the adult guinea-pig optic nerve. Pyroantimonate precipitate occurred within the axoplasm at nodes of Ranvier and the internode, at areas of myelin disruption, within Schmidt-Lanterman incisures (SLI) and glial paranodal loops. But precipitate was absent from the axoplasm beneath SLI and at the paranode. Ca(2+)-ATPase activity was localised in axonal smooth endoplasmic reticulum (SER), the outer membrane of mitochondria, the nodal axolemma, the glial membranes of the paranodal loops, the SLI and the external aspect of the myelin sheath. We have demonstrated large domains within the axons of CNS fibres where calcium is present or absent. Moreover, we have shown that, where calcium is absent, there is localisation of Ca(2+)-ATPase activity, which would serve to remove calcium from the adjacent axoplasm. Our results are compared with information obtained from PNS fibres and some differences of distribution discussed.

Animals↗