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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke is the third leading cause of death and the leading cause of long-term disability in the United States. Approximately 80% of all strokes are ischemic and there are limited therapies approved for the treatment of acute ischemic stroke. Understanding the mechanisms of ischemic brain damage is necessary for the development of innovative treatment strategies. In this review, we discuss the hemodynamic and molecular mechanisms of ischemic brain damage and the potential therapeutic strategies, including reperfusion and primary and secondary neuroprotection, and strategies for recovery of function, such as neural plasticity and stem cell transplantation. The effective treatment of ischemic stroke is likely to result from a combination of therapeutic modalities aimed at different mechanisms of ischemic brain damage and delivered at specific times after acute cerebral ischemia.
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PMID:Mechanisms of ischemic brain injury. 1475 56

Examination of the clinical therapeutic efficacy of using bone marrow stromal cells, including mesenchymal stem cells (MSC), has recently been the focus of much investigation. MSC were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we transfected telomerized human MSC with the BDNF gene using a fiber-mutant F/RGD adenovirus vector and investigated whether these cells contributed to improved functional recovery in a rat transient middle cerebral artery occlusion (MCAO) model. BDNF production by MSC-BDNF cells was 23-fold greater than that seen in uninfected MSC. Rats that received MSC-BDNF showed significantly more functional recovery than did control rats following MCAO. Specifically, MRI analysis revealed that the rats in the MSC-BDNF group exhibited more significant recovery from ischemia after 7 and 14 days. The number of TUNEL-positive cells in the ischemic boundary zone was significantly smaller in animals treated with MSC-BDNF compared to animals in the control group. These data suggest that MSC transfected with the BDNF gene may be useful in the treatment of cerebral ischemia and may represent a new strategy for the treatment of stroke.
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PMID:BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. 1475 3

Using a novel in vivo model for cerebral ischemia produced by short-lasting compression of a well-defined brain area of sensorimotor cortex we studied neuroprotective effects of the NMDA NR2B subunit selective antagonist, CP-101,606, in Sprague-Dawley rats. Cortical compression for 30 min produced a consistent and highly reproducible functional impairment, that is paresis of contralateral hind and fore limbs. The neurological deficit was accompanied by marked brain damage in cerebral cortex, hippocampus and thalamus as identified by Fluoro-Jade, a marker of general neuronal cell death. Using a daily performed beam walking test it was shown that untreated animals recovered from their functional impairment within 5-7 days following surgery. Intravenous administration of increasing doses (1, 5, 10, 20 mg/kg) of the NMDA NR2B subunit receptor specific antagonist, CP-101,606, dose-dependently improved the rate of functional recovery and protected against the ischemic brain damage in cerebral cortex, hippocampus, and thalamus as identified 2 days after the ischemic insult. Based upon these results, we conclude that NMDA NR2B receptor subunits represent potential targets to reduce not only the functional deficits, but also neuronal death in cortex and several midbrain regions produced by moderate, transient, cerebral ischemia.
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PMID:The NMDA NR2B subunit-selective receptor antagonist, CP-101,606, enhances the functional recovery the NMDA NR2B subunit-selective receptor and reduces brain damage after cortical compression-induced brain ischemia. 1498 68

Increased neurogenesis after cerebral ischemia suggests that functional recovery after stroke may be attributed, in part, to neural regeneration. In this study, we investigated the role of neurogenesis in the behavioral performance of gerbils after cerebral global ischemia. We used ionizing radiation to decrease neural regeneration, and 2 weeks later cerebral global ischemia was induced by bilateral common carotid artery occlusion. One month after the occlusion, the animals were behaviorally tested. Irradiation alone reduced neurogenesis but did not change vascular or dendritic morphology at the time of behavioral testing. Neither did irradiation, ischemia, or combined treatment impair rotor-rod performance or alter open-field activity. Gerbils subjected to both irradiation and ischemia demonstrated impaired performance in the water-maze task, compared with those that received only ischemia, radiation, or no treatment. These impairments after cerebral global ischemia under conditions of reduced neurogenesis support a role for the production of new cells in mediating functional recovery.
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PMID:Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. 1499 16

Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved in ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3-24 h after ischemia. Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia. The effect of nimesulide on prostaglandin E(2) (PGE(2)) levels in the injured brain was also investigated. Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE(2) accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage.
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PMID:Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat. 1506 40

The age-related decline in plasticity of the brain may be one factor underlying poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity in old age could be the result of an altered temporal relationship between factors promoting brain plasticity [microtubule-associated protein 1B (MAP1B)] and neurotoxic factors such as C-terminal betaAPP. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14 and 28 days after surgery. At the indicated timepoints, brains were removed and immunostained for C- and N-terminal betaAPP and MAP1B. At 2 weeks poststroke, we found an age-related increase in the amount of the C-terminal fragment of betaAPP in the peri-infarcted area and the infarct core as well as an early, vigorous incorporation of N-terminal betaAPP into the developing astroglial scar. The recovery of the plasticity-associated protein MAP1B following stroke was delayed in both age groups and became prominent between days 14 and 28. As aged rats showed diminished functional recovery compared with young rats, these results suggest that the accumulation of C-terminal betaAPP, together with the early incorporation of N-terminal betaAPP into the glial scar, may over-ride the beneficial role of plasticity factors such as MAP1B.
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PMID:Accelerated accumulation of N- and C-terminal beta APP fragments and delayed recovery of microtubule-associated protein 1B expression following stroke in aged rats. 1509 53

Ischemic stroke is caused by the interruption of cerebral blood flow that leads to brain damage with long-term sensorimotor deficits. Stem cell transplantation may recover functional deficit by replacing damaged brain. In this study, we attempted to test whether the human neural stem cells (NSCs) can improve the outcome in the rat brain with intravenous injection and also determine the migration, differentiation and the long-term viabilities of human NSCs in the rat brain. Focal cerebral ischemia was induced by intraluminal thread occlusion of middle cerebral artery (MCA). One day after surgery, the rats were randomly divided into two groups: NSCs-ischemia vs. Ischemia-only. Human NSCs infected with retroviral vector encoding beta galactosidase were intravenously injected in NSCs-ischemia group (5 x 10(6) cells) and the same amount of saline was injected in Ischemia-only group for control. The animals were evaluated for 4 weeks using turning in an alley (TIA) test, modified limb placing test (MLPT) and rotarod test. Transplanted cells were detected by X gal cytohistochemistry or beta gal immunohistochemistry with double labeling of other cell markers. The NSCs-ischemia group showed better performance on TIA test at 2 weeks, and MLPT and rotarod test from 3 weeks after ischemia compared with the Ischemia-only group. Human NSCs were detected in the lesion side and labeled with marker for neurons or astrocytes. Postischemic hemispheric atrophy was noted but reduced in NSCs-ischemia group. X gal+ cells were detected in the rat brain as long as 540 days after transplantation. Our data suggest intravenously transplanted human NSCs can migrate and differentiate in the rat brain with focal ischemia and improve functional recovery.
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PMID:Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. 1524 50

Thrombo-occlusive cerebrovascular disease resulting in stroke and permanent neuronal loss is an important cause of morbidity and mortality. Because of the unique properties of cerebral vasculature and the limited reparative capability of neuronal tissue, it has been difficult to devise effective neuroprotective therapies in cerebral ischemia. Our results demonstrate that systemic administration of human cord blood-derived CD34(+) cells to immunocompromised mice subjected to stroke 48 hours earlier induces neovascularization in the ischemic zone and provides a favorable environment for neuronal regeneration. Endogenous neurogenesis, suppressed by an antiangiogenic agent, is accelerated as a result of enhanced migration of neuronal progenitor cells to the damaged area, followed by their maturation and functional recovery. Our data suggest an essential role for CD34(+) cells in promoting directly or indirectly an environment conducive to neovascularization of ischemic brain so that neuronal regeneration can proceed.
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PMID:Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. 1528 94

Cerebral ischemia often results in neuronal loss, leading to the neurological deficits in stroke patients. To obtain the functional recovery after stroke, cell transplantation and enhancement of endogenous neurogenesis may have potential application. Recent evidence has demonstrated that neural stem cells exist in the adult mammalian brain. After cerebral ischemia, newly born neurons were found not only in hippocampal dentate and olfactory bulb but also in hippocampal CA1 and striatum, where neurons were lost after ischemia. Administration of neurotrophic factors or genes encoding them into the lateral venticule could enhance endogenous neurogenesis in experimental ischemia model. Furthermore, we have recently developed non-invasive gene transfer into macrophages infiltrating an infarct to stimulate proliferation of neural stem cells in cerebral infarction. Several strategies including gene therapy and pharmacological approach will be tried in stroke patients in near future. However, it remains unclear whether the number of new-born neurons from endogenous neural stem cells is sufficient for replacement of damaged neurons. Cell transplantation will have the advantage of preparing the large amount of transplanted cells. Human neural stem cells, embryonic stem cells and bone marrow-derived cells will be donor cells in stroke patients. Surprisingly, neuron-like cells derived from human teratoma cell line were already applied in stroke patients. However, ethical aspect will have to be discussed carefully before cells from other individuals are used as donor cells in stroke patients.
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PMID:[Therapeutic application of cell transplantation and increased neurogenesis in cerebral infarction]. 1565 Dec 83

BACKGROUND: Previous studies suggest that the cyclooxygenase-2 (COX-2) inhibitor nimesulide has a remarkable protective effect against different types of brain injury including ischemia. Since there are no reports on the effects of nimesulide on permanent ischemic stroke and because most cases of human stroke are caused by permanent occlusion of cerebral arteries, the present study was conducted to assess the neuroprotective efficacy of nimesulide on the cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion (pMCAO) in the rat. METHODS: Ischemia was induced by permanent occlusion of the middle cerebral artery in rats, via surgical insertion of a nylon filament into the internal carotid artery. Infarct volumes (cortical, subcortical and total) and functional recovery, assessed by neurological score evaluation and rotarod performance test, were performed 24 h after pMCAO. In initial experiments, different doses of nimesulide (3, 6 and 12 mg/kg; i.p) or vehicle were administered 30 min before pMCAO and again at 6, 12 and 18 h after stroke. In later experiments we investigated the therapeutic time window of protection of nimesulide by delaying its first administration 0.5-4 h after the ischemic insult. RESULTS: Repeated treatments with nimesulide dose-dependently reduced cortical, subcortical and total infarct volumes as well as the neurological deficits and motor impairment resulting from permanent ischemic stroke, but only the administration of the highest dose (12 mg/kg) was able to significantly (P < 0.01) diminish infarct volume. The lower doses failed to significantly reduce infarction but showed a beneficial effect on neurological function. Nimesulide (12 mg/kg) not only reduced infarct volume but also enhanced functional recovery when the first treatment was given up to 2 h after stroke. CONCLUSIONS: These data show that nimesulide protects against permanent focal cerebral ischemia, even with a 2 h post-treatment delay. These findings have important implications for the therapeutic potential of using COX-2 inhibitors in the treatment of stroke.
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PMID:Effects of the cyclooxygenase-2 inhibitor nimesulide on cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion in the rat. 1565 9


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