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)

In general, the acute treatment of ischemic stroke is intended to achieve three goals: a) reduce the volume of the infarct, b) prevent further embolism or thrombotic occlusion of vertebrobasilar or carotid arteries, and c) prevent or react quickly to complications. Methods to expedite clot lysis and restore circulation (thrombolysis) can limit the extent of brain injury and improve outcome. Further therapeutic aims are to optimize collateral perfusion in the penumbra--the area surrounding the core of the ischemic focus--and to reduce ischemia-related secondary injury mechanisms (neuroprotection). Patients at high risk of further embolism or those at risk of acute thrombotic occlusion of a major vessel may--under certain circumstances--be candidates for the application of high-dose heparin.
 ...
PMID:[Current therapy of cerebrovascular infarct]. 1052 92

In this article the pathophysiology of cerebral ischemia is reviewed. The concept of penumbra is explained, and a distinction is made between ischemic necrosis, which occurs in the severely ischemic regions and is associated with loss of calcium and glutamate homeostasis, and programmed cell death, or apoptosis, which is more likely to occur in the moderately ischemic regions, evolves more slowly and depends on the activation of a sequence of genes. Despite this knowledge, it is pointed out that currently only a small percentage of stroke patients can access therapies. Some thoughts are provided on future research directions and therapies.
 ...
PMID:[Physiology and pathology of cerebral ischemia]. 1052 40

Physiologic imaging has recently allowed major new insights into the pathophysiology of acute ischemic stroke in man. The main observation concerns the major heterogeneity in pathophysiological patterns, with three situations being encountered: 1) cortical ischemic penumbra persisting up till 16 hrs post onset, which would represent an ideal therapeutic target; 2) early spontaneous reperfusion, predictive of favourable clinical and tissular outcome, and a priori requiring no specific therapy; and 3) early extensive necrosis, predictive of malignant hemispheric infarction. Physiologic imaging should soon become a fundamental tool in the evaluation of the individual pathophysiologic situation before a therapeutic decision about entry into trials is made.
 ...
PMID:[The pathophysiology of acute cerebral ischemia: clinical approach using physiologic imaging]. 1052 41

Abnormalities in the homeostasis of the renin-angiotensin system have been implicated in the pathogenesis of vascular disorders, including stroke. The authors investigated whether angiotensinogen (AGN) knockout mice exhibit differences in brain susceptibility to focal ischemia, and whether such differences can be related to special features of the collateral circulation. Wild-type and AGN-knockout mice were submitted to permanent suture occlusion of the middle cerebral artery (MCA). The collateral vascular system was visualized by systemic latex infusion, and the ischemic lesions were identified by cresyl-violet staining. The core and penumbra of the evolving infarct were differentiated by bioluminescence and autoradiographic imaging of ATP and protein biosynthesis, respectively. In wild-type mice, mean arterial blood pressure was 95.0 +/- 8.6 mm Hg, and the diameter of fully relaxed anastomotic vessels between the peripheral branches of the anterior and middle cerebral arteries 26.6 +/- 4.0 microm. In AGN knockouts, mean arterial blood pressure was significantly lower, 71.5 +/- 8.5 mm Hg (P < .01), and the anastomotic vessels were significantly larger, 29.4 +/- 4.6 microm (P < .01). One hour after MCA occlusion, AGN-knockout mice exhibited a smaller ischemic core (defined as the region of ATP depletion) but a larger penumbra (the area of disturbed protein synthesis with preserved ATP). At 24 hours after MCA occlusion, this difference disappeared, and histologically visible lesions were of similar size in both strains. The observations show that in AGN-knockout mice the more efficient collateral blood supply delays ischemic injury despite the lower blood pressure. Pharmacologic suppression of angiotensin formation may prolong the therapeutic window for treatment of infarcts.
 ...
PMID:Larger anastomoses in angiotensinogen-knockout mice attenuate early metabolic disturbances after middle cerebral artery occlusion. 1053 33

Ischaemic stroke is a leading cause of death and long-lasting disability. Several neuroprotective drugs have been developed that have the potential to limit ischaemic brain damage and improve outcome for patients. While promising results with these drugs have been achieved in animal stroke models, all Phase III trials conducted so far indicate that these drugs have failed to live up to their promise. Despite the limits of animal models, which cannot mimic the clinical situation, the disappointing results of neuroprotective trials might largely be due to methodological problems. Future trials with neuroprotective drugs should be performed in stroke (care) units, after sufficient information regarding therapeutic time window, dosage, duration of therapy and safety has been gathered from pilot studies, and a better selection of target patients has been made. Much of this information can now be obtained by techniques that visualize the penumbra, such as combined diffusion-weighted and perfusion MRI. Consideration should also be given to clinical trials with well-designed combinations of treatments.
 ...
PMID:Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? 1083 91

There is strong evidence that severe hypoglycemia can worsen the prognosis in acute stroke. In contrast, the influence of acute hyperglycemia on cerebral ischemia remains controversial. The conflicting results of clinical and experimental studies can partly be explained if different stroke subtypes are regarded separately and the time course of the blood-glucose level during the acute insult is taken into account. Hyperglycemia seems to worsen the neuronal injury during the subacute period of cerebral ischemia if there is insufficient collateral blood supply. Furthermore, it increases the risk of hemorrhagic transformation in this time interval. In contrast, acute hyperglycemia may protect neuronal tissue from structural damage by improving the substrate supply if there is only a moderate decrease in cerebral blood flow. This situation is observed in the penumbra and if good collateral blood supply is provided. We therefore hypothesize that both negative and positive effects of acute hyperglycemia depend on the local cerebral blood flow.
 ...
PMID:[Blood glucose and stroke]. 1055 90

Silent stroke is one of the risk factors of dementia. In the present study, we used a novel focal ischemic animal model to investigate the effects of comparatively small changes of cerebral blood flow (CBF) on the expression of beta-amyloid precursor protein (APP) mRNA. Focal ischemia was achieved by introducing a 4-0 monofilament to the bifurcation of anterior and middle cerebral arteries. Brain samples were harvested from ischemic core and penumbra of cortices at 1, 4 and 7 days following ischemia. The expression of APP mRNA was assessed by RT-PCR. The CBF was decreased to 50% for 1 day after stroke and recovered to 90% at the fourth day after stroke. The changes of CBF were accompanied by an increase in the expression of APP mRNA. APP mRNA increased to 208% and 152% in the penumbra and core ischemic regions, respectively, on the fourth day after MCAO and remained high through the seventh day of ischemia. This study suggests brain hypoperfusion enhances APP mRNA expression and may contribute to the progression of cognitive impairment after silent stroke.
 ...
PMID:Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic rodent model. 1062 1

To characterize the development of tissue damage following cryogenic injury to the mouse cortex, the time course of histopathological changes, transcriptional responses and DNA strand breaks following application of a liquid nitrogen-cooled probe to the surface of the parietal bone were assessed. Distinct phases of tissue damage were observed: after 30 min, there was demarcation of a core lesion followed by mainly necrotic cell death starting 2 h after injury. At 12 hours, progressive apoptotic death of scattered cells in the periphery of the core lesion was detected, resembling the penumbra observed in ischaemic stroke. In situ hybridization for c-fos revealed an absence of expression in the core region, suggesting early cessation of transcription. There was strong induction of c-fos in the penumbra 30 min after the lesion, which had spread over the ipsilateral hemisphere at 2 h, possibly caused by peri-infarction depolarization. At later time points, sustained expression of c-fos was observed in some cells in the penumbra. Since a role for c-fos has been postulated in the initiation or execution of apoptotic pathways, the susceptibility of c-fos deficient mice was explored (n=4) in this model. Cryoinjury-induced tissue injury was markedly attenuated in c-fos deficient mice. A model of the phases and mechanisms of cryogenic injury is proposed, which discriminates an early phase characterized by physical changes caused by hypothermia and their immediate consequences (i.e. transcriptional block), an intermediate phase where secondary changes lead to necrosis in the core region, and a final phase of delayed apoptotic cell death in the penumbra.
 ...
PMID:Distinct phases of cryogenic tissue damage in the cerebral cortex of wild-type and c-fos deficient mice. 1063 97

Brain oedema is a major factor contributing to the poor outcome of subjects with acute ischaemic stroke but the use of mannitol and other hyperosmolar agents in this setting is controversial and hardly debated. Recent data have demonstrated that mannitol at concentrations which may be achieved in clinical conditions and hyperosmotic stress itself can activate the process of apoptotic cell death. This could have important clinical implications as apoptosis is involved in the more gradual loss of neurons in the penumbra zone surrounding the core of ischaemic stroke where neurons die immediately from oxygen starvation. Mannitol has the potential to activate inflammatory mediators, induce oxidant stress and produce rebound cell swelling and, through these mechanisms, can further aggravate the neuronal injury due to ischaemia. Furthermore, apoptosis in ischaemic areas closely parallels the timing of brain oedema and this suggests that a cause-effect relationship links the two phenomena rather than simply a temporal correlation. On this basis, it is crucial that emergency-physicians critically rethink the management strategy of brain oedema associated with ischaemic stroke.
 ...
PMID:The puzzle of neuronal death and life: is mannitol the right drug for the treatment of brain oedema associated with ischaemic stroke? 1064 27

Immunocytochemical and quantitative studies on vascular reaction (angiogenesis) in cortical border zone of infarct were undertaken. Intensity and temporal profile of angiogenesis was assessed in 60 patients aged between 48 and 69 (younger group), and between 70 and 92 (older group), with cerebral infarct in the area of middle cerebral artery vascularization, who died during the first six weeks following the stroke. We have found that angiogenesis was a multistage process in which four stages were distinguished: phase of primary activation of endothelial cells, two consecutive phases of active angiogenesis and final phase of only sporadic proliferation of vessels. The distinction of phases in a multiphase angiogenic cascade helped us to evaluate the correlation with survival time and the age of patients. The most pronounced intensification of angiogenesis and increased density of CD 31 positive capillaries in penumbra were observed in the second phase, especially in younger patients. The duration of the penumbral neovascularization decreased in the older age patient. Our results indicate that sprouting angiogenesis is a quantitatively significant source of vessels in the cerebral infarct border zone. However, non-therapeutically stimulated angiogenesis developed only 3-4 days after the stroke, that is beyond the period of reversible changes in ischemic penumbra recognized as a "therapeutical window" in the human brain. The angiogenic therapy opens a new way towards the revascularization of ischemic brain infarct.
 ...
PMID:Border zone neovascularization in cerebral ischemic infarct. 1070 49


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