Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using in vitro models, our laboratory in collaboration with those of Pierluigi Nicotera (University of Konstanz, Germany) and Stan Orrenius (Karolinska Institute) has recently shown that fulminant insults to the nervous system from excitotoxins or free radicals result in neuronal cell death from necrosis, while more subtle insults result in delayed apoptosis. Over the past dozen or so years, mounting evidence has suggested that excitotoxins, such as glutamate, result in neuronal cell death after stroke. More recent evidence has suggested that in addition to necrotic cell death in the ischemic core, a number of neurons may also undergo apoptosis. Thus, the hypothesis that intense injury leads to necrosis while mild insult (perhaps in the penumbra) leads to apoptosis may hold in focal cerebral ischemia. Another neurological malady with mounting evidence for a pathogenesis that is mediated at least in part by excitotoxins is HIV-1-associated cognitive/motor complex (originally termed the AIDS Dementia Complex and, for convenience, designated here AIDS dementia). AIDS dementia appears to be associated with several neuropathological abnormalities, including giant cell formation by microglia, astrogliosis, and neuronal injury or loss. Recently, neuronal and other cell injury in AIDS brains has been shown to result in apoptotic-like cell death. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the virus? Experiments from several different laboratories, including our group in collaboration with that of Howard Gendelman (University of Nebraska Medical Center), have lent support to the existence of HIV- and immune-related toxins in a variety of in vitro and in vivo paradigms. In one recently defined pathway to neuronal injury, HIV-infected macrophages/ microglia as well as macrophages activated by HIV-1 envelope protein gp120 appear to secrete excitants/ neurotoxins. These substances may include arachidonic acid, platelet-activating factor, free radicals (NO. and O2.-), glutamate, quinolinate, cysteine, cytokines (TNF-alpha, IL1-beta, IL-6), amines, and as yet unidentified factors emanating from stimulated macrophages and possibly reactive astrocytes. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke and several neurodegenerative diseases. This mechanism involves excessive activation of N-methyl-D-aspartate (NMDA) receptor-operated channels, with resultant excessive influx of Ca2+ and the generation of free radicals, leading to neuronal damage. With the very recent development of clinically-tolerated NMDA antagonists, as discussed here, there is hope for future pharmacological intervention.
 ...
PMID:Similarity of neuronal cell injury and death in AIDS dementia and focal cerebral ischemia: potential treatment with NMDA open-channel blockers and nitric oxide-related species. 894 20

The potential of nitric oxide (NO) to influence positively or negatively the outcome of mechanically induced focal cerebral ischemia is still controversial. Recent evidence suggests that NO of vascular origin, whether synthesized from exogenously administered L-arginine (L-Arg) or from NO donor compounds, is beneficial but that of neuronal origin is not. However, the therapeutic potential of NO to ameliorate stroke induced by arterial thrombosis has not been reported. We assessed the therapeutic effect of L-Arg administration in spontaneously hypertensive rats (SHR) subjected to permanent photothrombotic occlusion of the distal middle cerebral artery (dMCA). The ipsilateral carotid artery was left unligated to enhance L-Arg delivery into the putative penumbral region. Local CBF (LCBF) was assessed at 30 min by the [14C]iodoantipyrine technique (n = 9), while histological infarct volumes and index of peripheral ischemic cell change were determined at 3 days (n = 7). Rats (n = 9) given 300 mg/kg L-Arg at 18 and 3 h before photothrombotic dMCA occlusion and at 5 min afterward displayed no significant differences in LCBF compared with animals (n = 8) injected with water (the carrier vehicle) and similarly irradiated. Infarct volumes were also similar, being 37.0 +/- 9.7 mm3 (SD) in the vehicle-treated and 49.1 +/- 17.2 mm3 (SD) in the L-Arg-treated groups (both n = 7), as were assessments of ischemic neuronal density in the penumbra. In contrast, L-Arg administered intravenously in a dose of 300 mg/kg to nonischemic SHR (n = 5) increased cortical CBF by approximately 75% during a 70-min observation period. We conclude that thrombotic processes superimposed upon cerebral ischemia may facilitate tissue reactions that offset the potentially beneficial effect of L-Arg, and this caveat must be considered when proposing L-Arg for clinical treatment of focal thrombotic stroke.
 ...
PMID:L-arginine does not improve cortical perfusion or histopathological outcome in spontaneously hypertensive rats subjected to distal middle cerebral artery photothrombotic occlusion. 896

It is the purpose of this review to critically consider and organize the literature dealing with the ephemeral electroencephalographic (EEG) pattern periodic lateralized epileptiform discharges (PLEDs). Although the retrospective nature of these studies limits their ability to discuss accurately the clinical and pathophysiological aspects of this EEG entity, the available data strongly emphasize stroke as the dominant etiology and its high association with seizures. Recent evidence, particularly from functional neuroimaging studies, strongly suggests that PLEDs might reflect a key pattern for focal hyperexcitability in the penumbra zone of ischemic stroke. The authors prefer to consider PLEDs as an EEG signature of a dynamic pathophysiological state in which unstable neurobiological processes create an ictal-interictal continuum, with the nature of the underlying neuronal injury, the patient's preexisting propensity to have seizures, and the co-existence of any acute metabolic derangements all contributing to whether seizures occur or not. This review underlines the need for further sophisticated prospective controlled studies implementing early continuous EEG monitoring in order to contribute to an understanding of the incidence, dynamics, and relevance of this pattern.
 ...
PMID:Periodic lateralized epileptiform discharges--a critical review. 897 24

Current routine clinical techniques, including angiography and perfusional single-photon emission tomography, can be used to indicate problems in cerebral vascular supply and areas of cerebral hypoperfusion following a stroke, but cannot distinguish between ischaemic core and penumbra. In order to image specifically the penumbra, a method or indicator should be able to define areas with reduced blood flow, and a degree of metabolic compromise. In this context, the tissue could be regarded as hypoxic rather than ischaemic, and we have therefore chosen to investigate the potential of radio-labelled hypoxic markers in the study of ischaemia. In order to combine a hypoxic marker with a blood flow marker we used technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) and iodine-125 iodoazomycin arabinoside (125I-IAZA), during cerebral ischaemia in the rat middle cerebral artery occlusion model. 99mTc-HMPAO and 125I-IAZA were injected simultaneously 2 h following occlusion of the middle cerebral artery, and 5 h before decapitation. Paired autoradiograms were produced and compared. Three distinct patterns emerged from the autoradiograms: slightly decreased perfusion with no uptake of the hypoxic marker indicating an area of misery perfusion; moderately decreased perfusion with concomitant uptake of iodoazomycin arabinoside, a region of hypoxia; and severely decreased perfusion with no retention of the hypoxic tracer. In conclusion, we present a new use for an imaging agent in the investigation of cerebral hypoxia. This agent, IAZA together with HMPAO, provides a means of separating the penumbra into regions of misery perfusion and hypoxia. The potential impact of this may be important in the clinical investigation of stroke.
 ...
PMID:Autoradiographic imaging of cerebral ischaemia using a combination of blood flow and hypoxic markers in an animal model. 904 70

Stroke is the most prevalent life-threatening neurologic disease. The opportunity to intervene in the acute setting with the use of thrombolytics or neuroprotective agents has led to an evolving interest in obtaining physiologic data points during the acute event. Several imaging techniques are available that can provide pertinent information during the acute phase of an ischemic episode. Some of these techniques, such as diffusion-weighted and perfusion-weighted MR imaging, show exciting promise for defining the ischemic penumbra zone, which is the target of acute intervention.
 ...
PMID:Brain attack. Clinical monitoring of early pathophysiologic events. 911

The expression of 70 kDa heat shock protein (HSP-70) in focal ischemia occurs in regions that sustain sub-lethal ischemic injury, and may therefore be considered as a biological marker of the ischemic penumbra. In a rat embolic stroke model, using fibrin-rich emboli, we correlated the expression of HSP-70 mRNA with diffusion magnetic resonance imaging (MRI) to determine if HSP-70 mRNA expression was associated with alterations in the apparent diffusion coefficient (ADC) of brain tissue water, a putative early marker of cytotoxic injury that is readily measured in vivo. Serial ADC measurements were made for 120 min following embolic infarction in the right carotid artery territory. HSP-70 mRNA expression was observed at the boundaries of the densely ischemic zone, as judged by diffusion imaging. ADC values observed in HSP-70 mRNA-positive regions were intermediate between those observed in the ischemic core or in control regions. In addition, the volume of HSP-70 mRNA-positive tissue correlated positively with the volume of tissue showing intermediate ADC values at 120 min. These findings suggest that intermediate ADC values occur in penumbral regions. Heterogeneity of ischemic cellular injury is suggested as the basis for the intermediate ADC values observed in these regions.
 ...
PMID:Correlation of diffusion MRI and heat shock protein in a rat embolic stroke model. 912 12

Microcirculatory impairments have theoretically been proposed as a potential factor in the development of ischemic injury, but few attempts have been made to directly assess microvascular patency following stroke. To address this issue we investigated the temporal changes in microvascular perfusion induced by permanent focal ischemia. Halothane-anesthetized spontaneously hypertensive rats were subjected to middle cerebral artery occlusion (MCAO) of 5 min to 4 h duration. Two fluorescent tracers (FITC-dextran and Evans blue) were then sequentially administered i.v. and allowed to circulate for 10 and 5 s respectively. Tissue sections were examined by fluorescent microscopy, and the mean number of perfused microvessels/mm2 calculated for cortical areas representing non-ischemic (Region A), perifocal/penumbral (Region B) and core ischemic (Region C) regions. For sham-operated controls, virtually all microvessels perfused with tracer within 5 s. In contrast MCAO induced significant reductions in the number of perfused microvessels in Regions B and C. The most marked impairments in perfusion were observed in core MCA territory (e.g. 2-10% of control values for 5 s circulation period) while, initially, the deficit was less severe in penumbral cortex. However, a secondary perfusion impairment developed over time in the perifocal/penumbral region, so that the deficit was greater 4 h after MCAO than at earlier time points (e.g. 72%, 71% and 22% of control value for 0.5, 1 and 4 h MCAO respectively; 10 s circulation period). In conclusion, MCAO induced severe impairments in microcirculatory perfusion within the core ischemic region, and to a lesser extent in the penumbra. However, the development of a more severe perfusion deficit in the penumbra within 4 h of MCAO supports the hypothesis that microcirculatory failure in this region contributes to its recruitment to the ischemic infarct.
 ...
PMID:Temporal impairment of microcirculatory perfusion following focal cerebral ischemia in the spontaneously hypertensive rat. 913 19

We review the molecular and biochemical events that occur within the brain during cerebral ischemia, based on recent investigations of focal cerebral ischemia models. Occlusion of the middle cerebral artery in rats produces focal ischemia. In contrast to the core where ischemia is severe and infarction develops rapidly, areas surrounding the core (called the penumbra) show a more moderate decrease of blood flow and can tolerate longer durations of ischemic stress. Reperfusion and pharmacological interventions can help to salvage the penumbra. Ischemic insult alters the genomic properties of the brain cells and selective production of heat shock proteins can be seen. Heat shock proteins are necessary in the repair of cell integrity, and is thought to be induced as a rescue program. Pre-ischemic induction of these proteins is known to cause ischemic tolerance, and methods to manipulate genes into inducing HSPs may be effective in protecting neurons from ischemia. Genes that promote apoptosis are also expressed after ischemia, and may cause secondary expansion of the infarction. Strategies to denote expression of these genes may be effective in reducing ischemic neuronal death. Activation of the inflammatory cells such as neutrophils and macrophages, in the ischemic region, may cause further post-ischemic damage. Investigations on the role and mechanics of inflammatory systems in ischemic neuronal injury may present a new target for therapeutic intervention against stroke.
 ...
PMID:Molecular and biochemical events within the brain subjected to cerebral ischemia (targets for therapeutical intervention). 918 39

The effects of mannitol infusion therapy on acute ischemic stroke were investigated by serial median nerve somatosensory evoked potentials (SEP) in 31 patients with abnormal SEP recordings within 72 hours after onset. In 10 patients with missing N20 waves mannitol had no effect. In 12 patients mannitol improved N20 and central conduction time (CCT) latencies. In 9 patients absent N20 waves appeared after mannitol. As regard to the location of infarcts, CT revealed 7 hemispheric infarcts in patients with absent N20 waves in spite of mannitol infusion. The remaining patients' CTs revealed cortical and subcortical infarcts. This study concludes that mannitol treatment improved microcirculatory flow in the ischemic penumbra of acute ischemic stroke patients. We suggest that SEPs can be used in evaluating the effects of drugs to be used in the therapy of acute cerebrovascular accidents.
 ...
PMID:The evaluation of mannitol therapy in acute ischemic stroke patients by serial somatosensory evoked potentials. 920 16

Positron emission tomography (PET) has been widely used in the study of stroke and related cerebrovascular diseases. It has shown the various stages leading to cerebral infarction and defined the significance of the ischaemic penumbra. PET scan can predict the clinical outcome of patients with acute ischaemic stroke. Several types of diaschisis can also be demonstrated by PET. They reflect different pathophysiological changes in supratentorial infarcts. Post-apoplectic seizures are shown to increase the ischaemic damage in the affected cerebral hemisphere. PET has contributed also to the concept of multi-infarct dementia, although the significance of chronic ischaemia in the pathogenesis of vascular dementia has not been fully investigated.
 ...
PMID:Is positron emission tomography useful in stroke? 934 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>