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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel temporal correlation technique was used to map the first-pass transit of iodinated contrast agents through the brain. Transit profiles after bolus injections were measured with dynamic computed tomography (CT) scanning (1 image/s over 50 s). A rabbit model of focal cerebral ischemia (n = 6) was used, and dynamic CT scans were performed at 30, 60, 90, and 120 min postocclusion. Within the ischemic core, no bolus transit was detectable, demonstrating that complete ischemia was present after arterial occlusion. In the periphery of the ischemic distribution, transit dynamics showed smaller peaks, broadened profiles, and overall delay in bolus transit. A cross-correlation method was used to generate maps of delays in ischemic transit profiles compared with normal transit profiles from the contralateral hemisphere. These maps showed that penumbral regions surrounding the ischemic core had significantly delayed bolus transit profiles. Enlargement of the ischemic core over time (from 30 to 120 min postocclusion) was primarily accomplished by the progressive deterioration of the penumbral regions. These results suggest that (a) temporal correlation methods can define regions of abnormal perfusion in focal cerebral ischemia, (b) peripheral regions of focal cerebral ischemia are characterized by delays in bolus transit profiles, and (c) these regions of bolus transit delay deteriorate over time and thus represent a hemodynamic penumbra.
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PMID:Temporal correlation analysis of penumbral dynamics in focal cerebral ischemia. 853 May 56

Cerebral ischemia can result in varying degrees of tissue damage. Conditions of severe ischemia can produce extensive areas of irreversible injury, whereas in conditions of moderate ischemia, tissue damage may be reversible, as in the region of the ischemic penumbra. The reversibility of tissue damage in the penumbral region is of clinical interest, because the characterization of conditions underlying this reversible state may provide information needed for the development of new therapeutic approaches for treatment. Our previous studies demonstrated neurochemical alterations in the levels of dopamine (DA) within the striatum after cerebral ischemia. In the present study, we postulate that these changes may be caused, in part, by alterations in transmitter release and reuptake. To test this hypothesis, forebrain ischemia was induced in Sprague-Dawley rats (Harlan, Indianapolis, IN) by means of bilateral common carotid artery occlusion and hemorrhagic hypotension. Cerebral blood flow (CBF) in the striatum was measured by the method of hydrogen clearance, and the extracellular DA ([DA]e) levels were measured by in vivo microdialysis. Varied reductions of CBF were induced and maintained for 5 hours. Three subgroups were established retrospectively according to the degree of CBF reduction: 67.7, 35.6, and 13.2% of normal CBF in the mild, moderate, and severe ischemic groups, respectively. The induction of ischemia resulted in 1.9-, 9.3-, and 122.3-fold increases in [DA]e above baseline in the mild, moderate, and severe ischemia groups, respectively. At 3 hours after the induction of ischemia, high potassium (100 mmol/L) or Nomifensin (Sigma, St. Louis, MO) (10 mmol/L), a DA uptake blocker, was administrated via a microdialysis probe to stimulate DA release while reductions in CBF were maintained continuously. Thirteen rats were used in the study of the release of DA by potassium or Nomifensin in nonischemic conditions. The administration of high potassium or Nomifensin stimulated DA release in conditions of mild and moderate ischemia. The increase in DA release by potassium stimulation was higher in rats with mild ischemia (106.6-fold) than that in normal rats (22.3-fold). This suggests a hyperexcitability of DA terminals under mild ischemia, as compared with nonischemic conditions. On the other hand, Nomifensin increased [DA]e levels more in moderately ischemic brains than in control brains, suggesting that DA uptake is up-regulated in the former case. The increased release of DA by potassium and Nomifensin was sustained after stimulation in conditions of mild and moderate ischemia. The high level of [DA]e with severe ischemia after ischemic induction was sustained throughout the period of study and was not stimulated by potassium or Nomifensin. We conclude that under conditions of mild and moderate ischemia, DA terminals become highly excitable and reuptake mechanisms are compromised. These changes of DA metabolism during mild and moderate ischemia may explain the sustainability of neurons in the "penumbra" condition of cerebral ischemia and the transformation of the ischemic penumbra to a necrotic core.
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PMID:Alterations in striatal dopamine release and reuptake under conditions of mild, moderate, and severe cerebral ischemia. 855 44

The objective of this article is to amalgamate previous results into a speculative synthesis that sheds light on the causes of secondary brain damage following either global/forebrain or focal ischemia. The hypothesis is based on the well-founded assumption that the pathophysiology of the brain damage incurred by global or forebrain ischemia is different from that of focal ischemia. In the former, the ischemia is usually dense and of brief duration and, provided that reperfusion is adequate, cell damage is conspicuously delayed, mostly affecting selectively vulnerable neurons. In contrast, focal ischemia is either long-lasting or permanent, and it is usually less severe, particularly in the perifocal penumbral regions. The lesion is typically pan-necrotic ("infarction"), initially affecting the focus supplied by the occluded artery, later invading the penumbra zone. Available results allow a restatement of the calcium hypothesis of cell death. In global or forebrain ischemia, calcium influx through channels gated by voltage or glutamate receptors is envisaged to trigger reactions that limit the survival of neurons during reperfusion, leading to secondary neuronal death after hours or days of survival. It can be hypothesized that the initial insult leads to a sustained alteration of membrane calcium handling, resulting in slow, gradual calcium overload of mitochondria. Alternatively, a sustained perturbation of the intracellular signal transduction pathway leads to changes in transcription or translation, bereaving the cells of heat shock and stress proteins, of trophic factors, or of enzymes required for survival. However, with the possible exception of the gerbil, neither microvascular failure nor primary mitochondrial dysfunction is believed to be involved. In focal ischemia, similar reactions are probably triggered by calcium influx, whether this is sustained (the focus) or intermittent (the penumbra). However, these play a minor role in cell death since they are overridden by reactions producing mediators of rapidly developing secondary damage, affecting either microvessels or mitochondria. Very probably, some of these mediators are free radicals, or nitric oxide, or other reactive metabolites, emanating from lipid hydrolysis and arachidonic acid metabolism. During continuous ischemia, or during recirculation following 1-3 h of ischemia, these mediators activate adhesion molecules in endothelial cells or polymorphonuclear leucocytes, or oxidize key proteins. The result is either failure of microcirculation ("capillary plugging"), or sustained mitochondrial failure. Since calcium influx is an initial event, agents reducing presynaptic depolarization and calcium entry through glutamate receptor-gated and other calcium channels have predictably a narrow therapeutic window; however, since spin trapping agents of the nitrone class act many hours after the induction of focal ischemia, their therapeutic window is potentially very wide. This may be because expression of mRNAs for adhesion molecules and their synthesis are relatively slow processes, and because the nitrones act on events that involve adhesion of leukocytes to the endothelial cells, with plugging of capillaries and postcapillary venules, and on the ensuing inflammatory response.
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PMID:Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis. 859 24

Severe traumatic brain injuries are extremely heterogeneous. At least seven of the secondary derangements in the brain that have been identified as occurring after most traumatic brain injuries also occur after cardiac arrest. These secondary derangements include posttraumatic brain ischemia. In addition, traumatic brain injury causes insults not present after cardiac arrest, i.e., mechanical tissue injury (including axonal injury and hemorrhages), followed by inflammation, brain swelling, and brain herniation. Brain herniation, in the absence of a mass lesion, is due to a still-to-be-clarified mix of edema and increased cerebral blood flow and blood volume. Glutamate release immediately after traumatic brain injury is proven. Late excitotoxicity needs exploration. Inflammation is a trigger for repair mechanisms. In the 1950s and 1960s, traumatic brain injury with coma was treated empirically with prolonged moderate hypothermia and intracranial pressure monitoring and control. Moderate hypothermia (30 degrees to 32 degrees C), but not mild hypothermia, can help prevent increases in intracranial pressure. How to achieve optimized hypothermia and rewarming without delayed brain herniation remains a challenge for research. Deoxyribonucleic acid (DNA) damage and triggering of programmed cell death (apoptosis) by trauma deserve exploration. Rodent models of cortical contusion are being used effectively to clarify the molecular and cellular responses of brain tissue to trauma and to study axonal and dendritic injury. However, in order to optimize therapeutic manipulations of posttraumatic intracranial dynamics and solve the problem of brain herniation, it may be necessary to use traumatic brain injury models in large animals (e.g., the dog), with long-term intensive care. Stepwise measures to prevent lethal brain swelling after traumatic brain injury need experimental exploration, based on the multifactorial mechanisms of brain swelling. Novel treatments have so far influenced primarily healthy tissue; future explorations should benefit damaged tissue in the penumbra zones and in remote brain regions. The prehospital arena is unexplored territory for traumatic brain injury research.
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PMID:Resuscitation from severe brain trauma. 860 6

Slow potential recording was used for long-term monitoring of the penumbra zone surrounding an ischemic region produced by middle cerebral artery (MCA) occlusion in adult hooded rats (n = 32). Four capillary electrodes (El-E4) were chronically implanted at 2-mm intervals from AP -3, L 2 (El) to AP 0, L 5 (E4). Spontaneous or evoked slow potential waves of spreading depression (SD) were recorded during and 4 h after a 1-h MCA occlusion and at 2- to 3-day intervals afterward for 3 weeks. Duration of the initial focal ischemic depolarization was maximal at E4 and decreased with distance from the focus. SD waves in the penumbra zone were high at El and E2, low and prolonged at E3, and almost absent at E4. Amplitude of elicited SD waves was further reduced 3 days later and slowly increased in the following week. Cortical areas displaying marked reduction of SD waves in the first days after MCA occlusion either remained low or showed substantial (60%) recovery, the probability of which decreased with the duration of the initial focal ischemic depolarization and increased with the distance from the focus. It is concluded that the outcome of ischemia monitored by long-term SD recovery in the perifocal region can be partly predicted from the acute signs of MCA occlusion.
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PMID:The use of spreading depression waves for acute and long-term monitoring of the penumbra zone of focal ischemic damage in rats. 862 1

Although the cerebroprotective effects of hypothermia in focal models of ischemia are undisputed, the underlying mechanisms of this protection are still subject to much controversy. To analyze whether mild hypothermia attenuates glutamate levels in the penumbra surrounding permanent focal infarcts, extracellular glutamate concentration was analyzed bilaterally by microdialysis 20 minutes before to 120 minutes after a middle cerebral artery occlusion (MCAO) in rats. Normothermic animals (n = 11) had a baseline glutamate concentration of 1.14 +/- 0.40 mumol/ml (standard error of the mean) before the MCAO. Extracellular glutamate levels increased gradually after vessel occlusion to peak at 10.1 +/- 1.45 mumol/ml 80 minutes after the MCAO. This level gradually decreased to 5.72 +/- 1.67 mumol/ml by 120 minutes. Hypothermic animals (n = 11) had a baseline glutamate concentration of 1.73 +/- 0.83 mumol/ml before the MCAO. Extracellular glutamate levels increased after vessel occlusion but stabilized at 3.47 +/- 1.37 mumol/ml 30 minutes after the MCAO and remained stable until completion of the experiment. There were no significant differences in cortical blood flow between the normothermic and hypothermic groups at any time during the experiment. Infarct volumes, expressed as a percentage of the volume of the right (ipsilateral) hemisphere, were 19.8 +/- 2.16% in the normothermic group and 13.0 +/- 1.42% in the hypothermic group (P < 0.02). Although the normothermic penumbral glutamate levels began to increase immediately after the MCAO, they did not peak until 80 minutes after occlusion. In contrast, the normothermic core glutamate levels peaked within 30 minutes after the MCAO. Glutamate diffusion from the core region to the penumbra might account for this delay. Hypothermic cerebroprotection might involve a reduction in the pool of potentially diffusable glutamate in the core region but have little direct effect on glutamate release in the penumbra.
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PMID:Mild hypothermia reduces penumbral glutamate levels in the rat permanent focal cerebral ischemia model. 872 54

Changes in diffusion NMR imaging are believed to be based on intra/extracellular water homeostasis and will therefore reflect early disturbances of ion and water homeostasis after the onset of an ischemic event. Diffusion-weighted NMR imaging (DWI) thus has the potential to be a sensitive tool for the observation of stroke evolution. The present state of information extracted from diffusion-weighted NMR imaging for the understanding of cerebral focal ischemia in experimental research has been compiled in this review. The emphasis was set on three essential aspects of the technique in relation to focal ischemia. Firstly, the sensitivity of diffusion-weighted imaging for ischemic alterations is described. A comparison with conventional NMR imaging using relaxation time changes is included. Secondly, the comparison of the diffusion-weighted imaging with invasive techniques is discussed. Here, interpretation of the physiological, metabolic and hemodynamic alterations reflected in the observed diffusion changes is presented. The importance of regionally resolved information for a meaningful assignment of DWI changes to pathophysiological alterations is demonstrated for the differentiation between ischemic core and penumbra from DWI and quantitative diffusion coefficient data. The time dependence of correlations with physiological, biochemical and hemodynamic variables as a further important aspect is stressed. Thirdly, the potential of the technique for the assessment of development and effectiveness of new therapeutical strategies against stroke is demonstrated.
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PMID:Diffusion-weighted NMR imaging: application to experimental focal cerebral ischemia. 873 71

We investigated whether the known neuroprotective effects of two selective glutamate receptor antagonists, the NMDA antagonist MK-801 and the AMPA antagonist NBQX, are reflected in the regional cerebral protein synthesis rates (CPSR) in rats with middle cerebral artery occlusion (MCAO). Rats treated with either saline, MK-801 (5 mg/kg i.p.) or NBQX (30 mg/kg i.p. x 3) were subjected to permanent MCAO. Regional CPSR and volumes of gray matter structures displaying normal CPSR were measured in coronal cryosections of the brain by quantitative autoradiography following an i.v. bolus injection of 35S-labelled L-methionine 2 h after occlusion. MCAO completely inhibited protein synthesis in the lateral part of striatum and part of the adjacent frontoparietal cortex corresponding to the ischemic focus. Surrounding this, a metabolic penumbra with approximately 50% reductions in CPSR was present. Treatment with MK-801 significantly increased the volume of tissue with normal CPSR in the ischemic hemisphere compared to controls, whereas this was not seen with NBQX treatment. The results suggest that MK-801 and NBQX have different effects on peri-infarct protein synthesis after MCAO. Since both compounds reduce infarct size, it is questionable that acute inhibition of protein synthesis in focal ischemia is of significant importance to the final outcome of a stroke lesion.
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PMID:Differential effect of NMDA and AMPA receptor blockade on protein synthesis in the rat infarct borderzone. 874 Nov 37

Cellular mechanisms, both destructive and protective, that are associated with cerebral ischemia are reviewed in this paper. Central to understanding the evolution of stroke are the concepts of ischemic core and surrounding penumbral region damage, delayed neuronal death, and neuronal rescue. The role of spreading depression in the evolution of subsequent ATP depletion, ion shifts, glutamate release, activation of glutamate receptors, intracellular Ca2+ changes, and generation of reactive oxygen species in the penumbra in relationship to neuronal and glial cell damage are discussed. We conclude that the most fruitful areas for future stroke research include traditional approaches as well as novel approaches. Traditional approaches include stroke prevention and examination of the effects of combinations of proven and promising effective therapeutic interventions. Novel approaches include delineating mechanisms whereby growth factors and compounds such as deprenyl and staurosporine afford neuroprotection, ultimately leading to direct manipulation of the signal transduction pathways that lead to neuronal dysfunction and death. This includes determining which genes are activated and repressed in specific response to hypoxia-ischemia and determining how such alterations in gene expression affect survival and function of neurons. We also suggest that advantage be taken of the blood-brain barrier compromise during stroke in designing neuroprotective therapies.
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PMID:Cellular mechanisms involved in brain ischemia. 878 4

Leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) are known to be highly potent cerebral vasoconstrictors which are formed from arachidonic acid (AA). They enhance vascular permeability, inducing vasogenic edema that may damage the ischemic penumbra after ischemia and reperfusion. The inhibitory effect of aqueous garlic extract (AGE) on AA metabolism in human platelets is known. In this study, following the global ischemic model application to the rats, all underwent 10 min ischemia and were reperfused for different periods. The levels of LTC4 and PGE2 in rat forebrain were then measured. One rat group consisted of 8 rats. In the combined reperfused groups both metabolites increased significantly when compared with the 10 min ischemia alone, no reperfusion group (p < 0.05). In the 8 min reperfused group, PGE2 and LTC4 levels increased significantly at 60 min of reperfusion compared with each corresponding control group (P < 0.005). PGE2 and LTC4 levels were reduced significantly at 60 min of reperfusion compared with the 8 min reperfused group (P < 0.005). AGE (1 ml/kg) reduced both LTC4 and PGE2 levels significantly in the 8 min and 60 min reperfused group (P < 0.001, P < 0.001, P < 0.05, P < 0.01). In conclusion, AGE reduced LTC4 and PGE2 levels at a dosage of 1 ml/kg following 8 and 60 min reperfusion. It may be helpful in reducing AA metabolite levels and preventing injury after ischemic phenomena.
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PMID:The effect of aqueous garlic extract on the levels of arachidonic acid metabolites (leukotriene C4 and prostaglandin E2) in rat forebrain after ischemia-reperfusion injury. 880 27


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