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Biomedical subjects

D I Graham

Publications and source records attributed to D I Graham.

At least 91 records · Page 5Linked to original sources
PubMed1997

The attenuation of kainate-induced neurotoxicity by chlormethiazole and its enhancement by dizocilpine, muscimol, and adenosine receptor agonists.

Systemically administered kainate (10 mg.kg-1) caused neuronal loss in both the hippocampus and the entorhinal regions of the rat brain. This resulted in a loss of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyramidal neurones in the hippocampal CA1 and CA3a regions, respectively. Chlormethiazole attenuated the loss of neurones in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10 +/- 7.7%). The neuroprotective activity of chlormethiazole was apparent in the presence or absence of a low dose of clonazepam (200 micrograms.kg-1 i.p.). The kainate-induced damage could also be measured by the increase in binding of the peripheral benzodiazepine ligand ([3H]PK11195) in the hippocampus. In kainate-treated rats there was a 350-500% increase in binding indicative of reactive gliosis. Chlormethiazole prevented this elevation in a dose- and time-dependent manner, with an ED50 of 10.64 mg.kg-1 and an effective therapeutic window from 1 to 4 h posttreatment. Dizocilpine also attenuated damage significantly. The GABAA agonist muscimol was also able to attenuate the increase in [3H]PK11195 binding in a dose-dependent manner, with an ED50 of approximately 0.1 mg.kg-1. If muscimol, dizocilpine, or the adenosine A1 receptor agonist R-N6-phenylisopropyl-adenosine were administered together with chlormethiazole at their respective ED25 doses, a potentiation was apparent in the degree of neuroprotection. It is concluded that the combination of neuroprotective agents with different mechanisms of action can lead to a synergistic protection against excitotoxicity.

Adenosine↗
PubMed1997

Axonal cytoskeletal changes after non-disruptive axonal injury.

In animal models of human diffuse axonal injury, axonal swellings leading to secondary axotomy occur between 2 and 6 h after injury. But, analysis of cytoskeletal changes associated with secondary axotomy has not been undertaken. We have carried out a quantitative analysis of cytoskeletal changes in a model of diffuse axonal injury 4 h after stretch-injury to adult guinea-pig optic nerves. The major site of axonal damage was the middle portion of the nerve. There was a statistically significant increase in the proportion of small axons with a diameter of 0.5 micron and smaller in which there was compaction of neurofilaments. Axons with a diameter greater than 2.0 microns demonstrated an increased spacing between cytoskeletal elements throughout the length of the nerve. However, in the middle segment of the nerve these larger axons demonstrated two different types of response. Either, where periaxonal spaces occurred, there was a reduction in axonal calibre, compaction of neurofilaments but no change in their number, and a loss of microtubules. Or, where intramyelinic spaces occurred there was an increased spacing between neurofilaments and microtubules with a significant loss in the number of both. Longitudinal sections showed foci of compaction of neurofilaments interspersed between regions where axonal structure was apparently normal. Neurofilament compaction was correlated with disruption of the axolemma at these foci present some hours after injury. We suggest that the time course of these axonal cytoskeletal changes after stretch-injury to central axons is shorter than those changes documented to occur during Wallerian degeneration.

Animals↗
PubMed1997

Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion.

1. The aim of this study was to investigate whether delayed treatment with the anti-oxidant and anti-inflammatory agent ebselen reduces the volume of infarction in a rodent model of permanent focal cerebral ischaemia. 2. Ebselen (10 or 30 mg kg-1) or vehicle was administered by gavage 30 min and 12 h after the induction of cerebral ischaemia by permanent occlusion of the left middle cerebral artery (MCA). Animals were killed 24 h following MCA occlusion, and the volumes of ischaemic damage in the ebselen and control groups were evaluated by quantitative histopathology. 3. Ebselen was quickly absorbed following oral (gavage) administration and reached peak levels in the plasma by 1 h post-administration (plasma selenium level of 0.68 +/- 0.04 and 0.84 +/- 0.1 microgram ml-1 for 10 and 30 mg kg-1, respectively, compared to control level of 0.51 +/- 0.02 microgram kg-1). 4. Treatment with the lower dose of ebselen (10 mg kg-1) significantly (P < 0.01) reduced the volume of infarction in the cerebral hemisphere and cerebral cortex (by 31.8% and 36.7%, respectively compared with the placebo group). 5. The neuroprotective efficacy of the higher dose ebselen (30 mg kg-1) was less than that of the lower dose ebselen (10 mg kg-1). The volume of ischaemic damage in the cerebral hemisphere was reduced by 23.7% (P < 0.02), and cerebral cortex by 27.5% (P < 0.01). 6. Both doses of ebselen (10, 30 mg kg-1) had no therapeutic efficacy on the caudate nucleus, where ischaemia was most severe, in this model. 7. Free radical-mediated injury is normally associated with reperfusion of ischaemic tissue. The present results suggest that oxidative injury is also a significant contributor to brain damage in models of maintained (permanent) ischaemia and that ebselen is effective in attenuating this free radical-induced damage.

Animals↗
PubMed1997

Kainate-evoked release of adenosine from the hippocampus of the anaesthetised rat: possible involvement of free radicals.

Using microdialysis in the hippocampus of anaesthetised rats, the concentration of extracellular adenosine was estimated to be 0.8 microM. Kainic acid (0.1-25 mM) in the perfusate evoked a concentration-dependent release of adenosine with an EC50 of 940 microM. Two 5-min pulses of 1 mM kainic acid in the perfusate increased the dialysate levels with an S2/S1 ratio of 0.52 +/- 0.03. Kainate-evoked release of adenosine was reduced significantly by 10 microM tetrodotoxin and by a kappa-receptor agonist, U50, 488H (100 microM). The S2/S1 ratio was reduced by 4.5 microM 6-cyano-7-nitroquinoxaline-2,3-dione, a non-NMDA receptor antagonist, but not by the NMDA receptor blockers (+)-MK-801 (dizocilpine; 100 microM) or (+/-)-2-amino-5-phosphonopentanoic acid (1 mM), indicating a non-NMDA receptor-mediated process. The S2/S1 ratio was also reduced significantly by 10 mM ascorbic acid, 10 mM glutathione (a scavenger of hydroperoxides), and 1 mM oxypurinol (a xanthine oxidase inhibitor), indicating the possible involvement of free radicals. Neither the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (100 microM) nor the A1 adenosine receptor agonist R(-)-N6-(2-phenylisopropyl)adenosine (100 microM) affected release. Adenosine release evoked by kainic acid is therefore mediated by activation of non-NMDA receptors and may involve the propagation of action potentials and the production of free radicals.

Adenosine↗
PubMed1997

Loss of axonal microtubules and neurofilaments after stretch-injury to guinea pig optic nerve fibers.

Axonal swellings, characterized by focal accumulations of membranous organelles at presumed sites of interrupted axonal transport, occur in diffuse axonal injury (DAI) in human, blunt head injury and in animal models of nondisruptive axonal injury. Membranous organelles are transported by fast axonal transport in association with microtubules. Although loss of microtubules has been documented at levels of injury severe enough to result in permeabilization of the axolemma to tracers such as horseradish peroxidase, there has been no detailed analysis of responses by microtubules in less severe or milder forms of nondisruptive axonal injury. To test the hypothesis that in less severe forms of axonal injury there is a rapid response by axonal microtubules that might provide an explanation for loss of fast axonal transport, we have carried out a morphometric analysis of microtubules in CNS axons after stretch-injury. There is loss of microtubules at nodes of Ranvier with nodal blebs within 15 min of injury, and in internodal axonal swellings between 2 and 4 h. There is a return to control values at nodes of Ranvier by 4 h, and at the internode by 24 h. There is no loss of microtubules at paranodes, although there is a reduction in their density in the first 2 h after injury. The greatest loss of microtubules occurs at sites of axolemma infolding. Hypothetical mechanisms that might lead to this loss resulting in focal disruption of fast axonal transport and the formation of axonal swellings are discussed.

Analysis of Variance↗
PubMed1997

Progressive atrophy and neuron death for one year following brain trauma in the rat.

Although atrophic changes have been well described following traumatic brain injury (TBI) in humans, little is known concerning the mechanisms or progression of brain tissue loss. In the present study, we evaluated the temporal profile of histopathological changes following parasagittal fluid-percussion (FP) brain injury in rats over 1 year postinjury. Anesthetized 3-4 month-old Sprague-Dawley Rats (n = 51) were subjected to FP brain injury of high severity (2.5-2.9 atm, n = 51) or sham treatment (n = 27). At 1 h, 2 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6 months and 1 year after brain injury or sham treatment, these animals were humanely euthanized. Brain sections were analyzed with image-processing techniques to determine the extent of cortical tissue loss and shrinkage of the hippocampal pyramidal cell layer. In addition, cell counting was performed to determine the number of neurons in the dentate hilus of the hippocampus, and glial fibrillary acidic protein (GFAP) immunostaining was used to reveal reactive astrocytosis. Examination of the injured brains revealed substantial and progressive tissue loss with concomitant ventriculomegaly in the hemisphere ipsilateral to injury. The regions with the most notable progressive atrophy included the cortex, hippocampus, thalamus, and septum. Quantitative analysis demonstrated a significantly progressive loss of cortical tissue as well as shrinkage of the hippocampal pyramidal cell layer ipsilateral to injury over 1 year following injury. In addition, reactive astrocytosis in regions of atrophy and progressive bilateral death of neurons in the dentate hilus was observed for 1 year following injury. These results suggest that a chronically progressive degenerative process may be initiated by brain trauma. Thus, there is a temporally broad window within which to introduce novel therapeutic strategies designed to ameliorate the short and long-term consequences of brain trauma.

Animals↗
PubMed1997

Aging-associated changes in human brain.

A wide variety of anatomic and histological alterations are common in brains of aged individuals. However, identification of intrinsic aging changes--as distinct from changes resulting from cumulative environmental insult--is problematic. Some degree of neuronal and volume loss would appear to be inevitable, but recent studies have suggested that the magnitudes of such changes are much less than previously thought, and studies of dendritic complexity in cognitively intact individuals suggest continuing neuronal plasticity into the eighth decade. A number of vascular changes become more frequent with age, many attributable to systemic conditions such as hypertension and atherosclerosis. Age-associated vascular changes not clearly linked to such conditions include hyaline arteriosclerotic changes with formation of arterial tortuosities in small intracranial vessels and the radiographic changes in deep cerebral white matter known as "leukoaraiosis." Aging is accompanied by increases in glial cell activation, in oxidative damage to proteins and lipids, in irreversible protein glycation, and in damage to DNA, and such changes may underlie in part the age-associated increasing incidence of "degenerative" conditions such as Alzheimer disease and Parkinson disease. A small number of histological changes appear to be universal in aged human brains. These include increasing numbers of corpora amylacea within astrocytic processes near blood-brain or cerebrospinal fluid-brain interfaces, accumulation of the "aging" pigment lipofuscin in all brain regions, and appearance of Alzheimer-type neurofibrillary tangles (but not necessarily amyloid plaques) in mesial temporal structures.

Aging↗
PubMed1996

Presenilin-1 polymorphism and amyloid beta-protein deposition in fatal head injury.

Approximately 30% of patients with fatal head injuries have deposits of amyloid beta-protein (A beta); these are predominantly individuals carrying the epsilon 4 allele of apolipoprotein E (apoE). A beta deposition occurs in Alzheimer's disease (AD), for which approximately 50% of the genetic risk is attributed to apoE epsilon 4. The 1,1 genotype of a presenilin-1 (PS-1) polymorphism has been suggested to account for about half of the remaining genetic risk for AD. We related the PS-1 genotypes of 90 head-injured individuals to A beta deposition and apoE genotype. There was no difference in PS-1 genotype or allele frequencies between individuals with and without A beta deposits. Eighteen of 23 individuals with A beta deposits had apoE epsilon 4 as a risk factor. Three of five individuals without apoE epsilon 4 had the PS-1 1,1 genotype. If PS-1 genotype influences A beta deposition the effect is small and is overwhelmed by that of apoE genotype.

Adolescent↗
PubMed1996

Increased tau immunoreactivity in oligodendrocytes following human stroke and head injury.

Tau immunohistochemistry was performed on post-mortem brain tissue from patients who died following head injury or stroke and from neurologically normal controls. Tau-positive oligodendrocytes were detected with three different tau antibodies in head injured or stroke patients, but not in control cases. Tau-positive oligodendrocytes were detected 2 h following head injury indicating that accumulation of tau may be an acute response of these cells to brain injury. The mechanisms underlying accumulation of tau in oligodendrocytes after acute brain injury may be similar to those which occur in chronic neurodegenerative conditions such as progressive supranuclear palsy (PSP) and multi-system atrophy (MSA).

Adult↗
PubMed1996

Ascorbate attenuates the systemic kainate-induced neurotoxicity in the rat hippocampus.

The neuronal damage induced by systemic administration of kainic acid reproduces the cellular and regional pattern of damage produced by repeated seizures. The ability of kainic acid to induce lipid peroxidation, and the ability of free radical inhibitors to prevent ischaemically-induced cell death, has led us to examine the possible role of free radicals in kainate-induced injury. Ascorbic acid was able to reduce kainate-induced damage of the rat hippocampus, measured by means of the gliotic marker ligand [3H]PK11195. Ascorbate was significantly effective at doses of 30 mg kg-1 and above, with total protection against kainate at 50 mg kg-1. Histologically, ascorbate at 50 mg kg-1 was able to prevent kainate-induced neuronal loss in the hippocampal CA1 and CA3a cell layers. The antioxidant was also effective when administered simultaneously with, or 1 h before the kainate. Protection was also obtained by allopurinol, 175 mg kg-1 and by oxypurinol, 40 mg kg-1. Ascorbate did not modify synaptically evoked potentials or long-term potentiation in hippocampal slices, ruling out any blocking activity at glutamate receptors. It is concluded that the neuronal damage produced by systemically administered kainate involves the formation of free radicals.

Analysis of Variance↗
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

Prevention by a purine analogue of kainate-induced neuropathology in rat hippocampus.

Systemic injection of kainic acid produces a characteristic regional and cellular pattern of neuronal loss in the central nervous system by mechanisms which may be relevant to an understanding of neurodegenerative disorders. It has previously been found, by measuring the binding of a glial marker ligand, that analogues of adenosine, such as R-N6-phenylisopropyladenosine (R-PIA), can prevent kainate-induced damage of the hippocampus at doses as low as 10 micrograms/kg, i.p. The use of gliotic markers, however, is open to misinterpretation, and the present work was designed to re-examine purine protection against kainate using histological methods. The results show that R-PIA, at a dose of 25 micrograms/kg i.p. in rats, can protect against the neuronal damage caused by kainate and that this protection could be completely prevented by the simultaneous administration of 1,3-dipropyl-8-cyclopentylxanthine, indicating the involvement of adenosine A1 receptors in the protection.

Animals↗
PubMed1996

Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat.

Recent reports suggest a relationship between traumatic brain injury and the precocious development of neurodegenerative cascades, including diffuse deposits of beta-amyloid peptides (A beta) in the injured brain. Because the lateral fluid-percussion (FP) model of experimental brain injury produces clinically relevant neuropathological sequelae in the rat brain, we used this model together with a series of antibodies specific for amyloid precursor proteins (APPs), APP-like proteins (APLPs), or A beta to identify acute neurodegenerative changes after brain trauma. Male Sprague-Dawley rats were anesthetized and subjected to lateral FP brain injury of moderate to high severity. At 1 hr, 2 hr, 48 hr, 1 week, or 2 weeks after injury, animals were killed and their brains were removed for immunohistochemical analysis. APP/APLP immunoreactivity increased in specific brain regions as early as 1 hr after injury and persisted for at least 2 weeks. Axons in the thalamus and subcortical white matter showed the greatest APP/APLP accumulation. Injured cortex, striatum, cingulum, and hippocampus also demonstrated significant axonal accumulations of APP/APLP. Accumulation of APP/APLPs occurred primarily ipsilateral to the injury, although bilateral changes were observed in some brain regions. No deposition of A beta was observed in any brain region at any time point examined. These results demonstrate a pattern of widespread axonal pathology after lateral FP brain injury in the rat, characterized by intra-axonal accumulations of APP/APLP immunoreactivity in the absence of plaque-like deposits of A beta in the traumatized brain.

Amyloid beta-Peptides↗
PubMed1996

Amyloid beta-protein, APOE genotype and head injury.

Deposition of amyloid beta-protein (A beta) in the brain plays a key role in the pathogenesis of Alzheimer's disease. Head injury is an epidemiological risk factor for Alzheimer's disease, and deposition of A beta occurs in approximately one third of individuals dying shortly after a severe head injury. Of the three common apolipoprotein E alleles (APOE-epsilon 2, epsilon 3, and epsilon 4) APOE-epsilon 4 allele is a strong risk factor for both sporadic and some familial cases of Alzheimer's disease and there is in vitro evidence that apolipoprotein E is directly involved in A beta deposition. We have examined the frequency of APOE-epsilon 4 in those individuals with A beta deposition following head injury and found that the APOE-epsilon 4 frequency (0.52) is higher than in most studies of sporadic Alzheimer's disease. In those head-injured individuals without amyloid deposition the APOE-epsilon 4 frequency (0.16) is similar to that in non-Alzheimer's disease controls (p < 0.00001). Our data indicate an interaction between known environmental and genetic risk factors for Alzheimer's disease and underlines the importance of convergence of data around the common mechanism of A beta deposition. Furthermore, it indicates a genetic susceptibility to the effects of a head injury which may be of significance both to those who have recently sustained such an injury and to those whose activities put them at risk of trauma.

Aging↗
PubMed1996

Alteration in brain presenilin 1 mRNA expression in early onset familial Alzheimer's disease.

The expression of the presenilin 1 (PS-1) gene has been investigated by in situ hybridization in early onset familial Alzheimer's disease (FAD), late onset Alzheimer's disease (AD) and normal control brain. Mutations in this gene are responsible for chromosome 14-linked FAD. We have found that presenilin 1 mRNA is present throughout the human brain with a distribution consistent with both a glial and neuronal localization. The in situ hybridization pattern was similar for the controls, the early onset FAD cases and the late onset AD cases. However, one of the two forms of the mRNA for PS-1, the long form (which contains a sequence encoding a four amino acid (VRSQ) insert at its 5' end) was significantly reduced in early onset FAD brain compared with late onset AD. We suggest that this long transcript may alter the normal pathway for processing of amyloid precursor protein, the protein which appears to be central in the pathogenesis of AD.

Adult↗
PubMed1996

Altered beta-APP metabolism after head injury and its relationship to the aetiology of Alzheimer's disease.

There is increasing evidence of a link between head injury and the subsequent onset of Alzheimer's disease. Deposits of amyloid beta-protein (A beta) are found not only in cases of dementia pugilistica but in some 30% of patients dying after a single episode of severe head injury. Detailed clinicopathological studies have shown that A beta deposition is most likely, but not exclusively, to occur, the older the patient at the time of injury, and if the injury is the result of a fall. Distribution studies have shown that the A beta is widely deposited in the neocortex and there is no apparent association with any of the multiple primary or secondary pathologies of traumatic brain injury. There is an increased expression of beta-APP particularly in the pre-alpha cells of the entorhinal cortex and in areas of axonal damage. Recent molecular genetic studies have shown that there is a strong association between deposits of A beta and the apolipoprotein E genotype of the individual.

Alzheimer Disease↗