Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.
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PMID:The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia. 1864 35

Normal vasculature development of the central nervous system is extremely important because patients with vascular malformations are at life-threatening risk for intracranial hemorrhage or cerebral ischemia. The etiology and pathogenesis of abnormal vasculature development in the central nervous system are unknown, and progress is hampered by the lack of animal models for human cerebrovascular diseases. Here, we report our current study on cerebral microvascular dysplasia (CMVD) development. Using vascular endothelial growth factor hyper-stimulation, we demonstrated that aberrant microvessels could be developed in the rodent brain under certain conditions (such as genetic deficient background, local cytokine and chemokine release, or exogenous vessel dilating stimulation) that may speed up focal angiogenesis and lead to cerebral vascular dysplasia.
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PMID:Development of a cerebral microvascular dysplasia model in rodents. 1906 7

Researchers suggest that endoplasmic reticulum (ER) stress cause apoptosis after ischemia. Caspase-12 has been localized to the ER and is a signal for apoptosis. We sought to clarify the role of caspase-12 in the vascular endothelial growth factor (VEGF) induced neuroprotective effect. Transient focal cerebral ischemia was produced by occluding left middle cerebral artery in rabbit. The expressions of caspase-12 and caspase-3 were detected by immunohistochemistry. Neuronal apoptosis was detected by TUNEL staining. We confirmed that the number of apoptotic cells and the expressions of caspase-12 and caspase-3 significantly increased during reperfusion. VEGF inhibited the cell apoptosis and the expressions of caspase-12 and caspase-3. These results suggest that VEGF may protect neurons from apoptosis by inhibiting ER stress pathway.
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PMID:Effect of endoplasmic reticulum stress in VEGF-induced neuroprotection. 1919 Nov 55

We studied the effect of vasoactive intestinal peptide (VIP) on angiogenesis in the ischemic boundary area after focal cerebral ischemia. Adult male Sprague-Dawley rats underwent middle cerebral artery occlusion for 2 h. A single dose of VIP was given via i.c.v. injection at the beginning of reperfusion. Immunohistochemistry and Western blotting were performed to assay angiogenesis and brain levels of vascular endothelial growth factor (VEGF) protein, respectively. In addition, the expression of VEGF and its receptors (flt-1 and flk-1), as well as endothelial proliferation, was measured using rat brain microvascular endothelial cells. Immunohistochemical analyses revealed significant (P<0.05) increases in the numbers of bromodeoxyuridine (BrdU) positive endothelial cells and microvessels at the boundary of the ischemic lesion in rats treated with VIP compared with rats treated with saline. Western blotting analysis showed that treatment with VIP significantly (P<0.05) raised VEGF levels in the ischemic hemisphere. In addition, treatment with VIP increased flt-1 and flk-1 immunoreactivity in endothelial cells. In vitro, incubation with VIP significantly (P<0.01) increased the proliferation of endothelial cells and induced the expression of VEGF, flt-1 and flk-1 in endothelial cells. The stimulatory effect of VIP on the proliferation of endothelial cells was significantly (P<0.01) inhibited by SU5416, a selective inhibitor of VEGF receptor tyrosine kinase. Our data suggest that treatment with VIP enhances angiogenesis in the ischemic brain, and this effect may be mediated by increases in levels of VEGF and its receptors.
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PMID:Vasoactive intestinal peptide in rats with focal cerebral ischemia enhances angiogenesis. 1933 6

The aim of the present study was to assess the dose-effectiveness of intranasal (IN) vascular endothelial growth factor (VEGF)in the treatment of experimental stroke. Sprague-Dawley rats were randomized into four groups as IN low (100 microg/ml), IN middle (200 microg/ml) and IN high (500 microg/ml) VEGF-treated group, and IN saline-treated group (n=12), given recombinant human VEGF 165 or saline intranasally. Focal cerebral ischemia was induced by transient (90 min) middle cerebral artery occlusion (MCAO) method. Behavioral neurological deficits were assessed 1, 7 and 14 d after the onset of MCAO. Rats were sacrificed at 14 d, the brain sections were stained and an image analysis system was used to calculate the infarct volume. Microvessels were labeled by FITC-dextran and the segment lengths, diameters and number of microvessels were measured by Image Pro-Plus Version 6.0 software. Fourteen days post MCAO, infarct volume significantly reduced (P<0.01) in rats which received the middle dose of IN VEGF when compared to IN saline. And middle dose of VEGF significantly improved behavioral recovery (P<0.01). No significant difference in the behavioral recovery and infarct volume was observed between the saline-treated group and the low or high VEGF-treated groups (P>0.05). Compared to IN saline, middle and high doses of VEGF significantly increased the segment length, diameter and number of microvessels (P<0.01). No significant difference in the segment length, diameter and number of microvessels was observed between the IN saline-treated group and the low VEGF-treated group (P>0.05). The middle dose of IN VEGF was most effective on reducing infarct volume, improving behavioral recovery and enhancing angiogenesis in stroke brain, which can be used in the following treatments to further evaluate the effect of VEGF.
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PMID:The dose-effectiveness of intranasal VEGF in treatment of experimental stroke. 1955 76

The effect of hypoxia on glioma growth including pathological changes was investigated in an experimental model of brain ischemia in the rat C6 glioma model. C6 glioma cells were inoculated into the subcortex of adult Wistar rats. Focal cerebral ischemia near the implanted glioma area was induced by permanent middle cerebral artery occlusion (PMCAO). Ten days later, the rats were sacrificed to compare tumor volume of C6 glioma without PMCAO (control group) versus C6 glioma with PMCAO (hypoxia group). The histological features were also observed. The mean tumor volume in the hypoxia group was significantly larger than that in the control group. The most prominent histological finding in the hypoxia group was abundant formation of pseudopalisading around the necrotic areas. Immunohistological examinations showed intensive staining for vascular endothelial growth factor and hypoxia-inducible factor in these pseudopalisading cells. These findings suggest that cerebral ischemia positively modulates glioma mass growth by the formation of pseudopalisading necrosis, a characteristic histological finding of glioblastoma.
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PMID:Cerebral ischemia promotes rich pseudopalisading necrosis in the rat c6 glioblastoma model. 1963

The present study examined the effects of human umbilical cord blood-derived mesenchymal stem cells (HUCB-derived MSCs) delivered through the basilar artery in a canine thromboembolic brain ischemia model. Cerebral ischemia was induced through occlusion of the middle cerebral artery by injecting thrombus emboli into 10 beagles. In the HUCBC group (n = 5), 1 x 10(6) HUCB-derived MSCs were transplanted through the basilar artery 1 day after ischemic induction using an endovascular interventional approach. In the control group (n = 5), phosphate-buffered saline (PBS) was injected in the same manner in as the HUCBC group. Upon neurobehavioral examination, earlier recovery was observed in the HUCBC group. The HUCBC group showed a decrease in the infarction volume at 1 week after cerebral ischemic induction, whereas the control group showed an increase in the infarction volume at 1 week, by magnetic resonance image analysis. Transplanted cells had differentiated into neurons and astrocytes and were observed in and around endothelial cells that were positive for von Willebrand factor (vWF). HUCB-derived MSCs expressed neuroprotective factors, such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), at 4 weeks after the transplantation. The transplanted cells demonstrated their efficacy by reducing the infarction lesion volume and through earlier recovery from the neurological deficit. These results suggest that intraarterial transplantation of HUCB-derived MSCs could be useful in clinical treatment of cerebral ischemia.
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PMID:Intraarterially delivered human umbilical cord blood-derived mesenchymal stem cells in canine cerebral ischemia. 1964 3

The regional and cellular distribution of heme oxygenase (HO)-1 and -2 following cerebral ischemia has not been ascertained. Employing the transient middle cerebral artery occlusion (MCAO) and hypoxia-ischemia (HI) models of unilateral brain injury, the aim was to elucidate immunolocalization of HO-1 and HO-2. Animals were sacrificed 3 days post-ischemia and immunohistochemistry and Western blotting were utilized to determine HO-1 and HO-2 expression. In the ipsilateral hemisphere following HI, HO-1 immunoreactivity was significantly upregulated in many neuronal and glial populations (including the cortex, hippocampus and thalamus). HO-1 was also detected in macrophages/microglia within the infarct. In addition to widespread neuronal HO-2 labelling, HO-2 was also expressed in vascular endothelial cells. Inflammatory cells within the infarct of MCAO and HI animals were surprisingly immunoreactive for HO-2, but only HI animals had significantly elevated HO-2 protein expression in the ipsilateral hemisphere. This may be due to the presence of global hypoxia in the HI model which can upregulate vascular endothelial growth factor and subsequent proliferation of endothelial cells. This report of HO-2 protein expression upregulation following HI coupled with an increase in HO-1 immunoreactivity suggests that this response may be implicated in reducing cell death or repairing damage induced by cerebral ischemia.
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PMID:Cerebral heme oxygenase 1 and 2 spatial distribution is modulated following injury from hypoxia-ischemia and middle cerebral artery occlusion in rats. 1968 8

Some gene expression may be regulated by hypoxia-responsive element (HRE) that is bound by hypoxia-inducible factor-1 (HIF-1) which is up-regulated during cerebral ischemia. To explore ischemia/hypoxia-controlled expression and the neuroprotective effects of brain-derived neurotrophic factor (BDNF) after ischemic brain injury, an adenoviral vector using five copies of hypoxia response element (HRE) in the vascular endothelial growth factor gene to regulate the expression of BDNF gene (Ad5HRE:BDNF) was constructed, and its efficacy was verified for driving BDNF expression in cultured Hela cells under hypoxic condition by ELISA. We found that the concentration of BDNF in the Ad5HRE:BDNF-transfected culture media was 28-fold greater in a hypoxic condition than under normoxia. To examine the effect of Ad5HRE:BDNF on ischemic brain injury in vivo, Ad5HRE:BDNF was injected into right caudate putamen of adult mice 7 days prior to 60 min transient middle cerebral artery occlusion (MCAO). It was found that exogenous BDNF expression was increased in the Ad5HRE-BDNF-treated group and infarct volume of the Ad5HRE:BDNF-treated group at 3 days after MCAO was significantly smaller than that of vehicle- or AdNull-treated groups. Moreover, Ad5HRE:BDNF injection resulted in significantly improved sensorimotor scores 7 days after MCAO and induced a reduction in the number of Fluoro-Jade B-positive neurons and TUNEL-positive cells, compared with vehicle- or AdNull-injection. Our findings suggest that BDNF expression could be regulated in hypoxia/ischemia condition with five copies of HRE and ameliorates ischemic brain injury in a mouse focal cerebral ischemia model.
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PMID:Adenovirus-mediated brain-derived neurotrophic factor expression regulated by hypoxia response element protects brain from injury of transient middle cerebral artery occlusion in mice. 1970 19

Neuropilin 2 (NRP2) is a type I transmembrane protein that binds to distinct members of the class III secreted Semaphorin subfamily. NRP2 plays important roles in repulsive axon guidance, angiogenesis and vasculogenesis through partnering with co-receptors such as vascular endothelial growth factor receptors (VEGFRs) during development. Emerging evidence also suggests that NRP2 contributes to injury response and environment changes in adult brains. In this study, we examined the contribution of NRP2 gene to cerebral ischemia-induced brain injury using NRP2 deficient mouse. To our surprise, the lack of NRP2 expression does not affect the outcome of brain injury induced by transient occlusion of the middle cerebral artery (MCAO) in mouse. The cerebral vasculature in terms of the middle cerebral artery anatomy and microvessel density in the cerebral cortex of NRP2 deficient homozygous (NRP2(-/-)) mice are normal and almost identical to those of the heterozygous (NRP2(+/-)) and wild type (NRP2(+/+)) littermates. MCAO (1h) and 24h reperfusion caused a brain infarction of 23% (compared to the contralateral side) in NRP2(-/-) mice, which is not different from those in NRP2(+/- and +/+) mice at 22 and 21%, respectively (n=19, p>0.05). Correspondingly, NRP2(-/-) mouse also showed a similar level of deterioration of neurological functions after stroke compared with their NRP2(+/- and +/+) littermates. Oxygen-glucose-deprivation (OGD) caused a significant neuronal death in NRP2(-/-) cortical neurons, at the level similar to that in NRP(+/+) cortical neurons (72% death in NRP(-/-) neurons vs. 75% death in NRP2(+/+) neurons; n=4; p>0.05). Together, these loss-of-function studies demonstrated that despite of its critical role in neuronal guidance and vascular formation during development, NRP2 expression dose not affect adult brain response to cerebral ischemia.
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PMID:Neuropilin 2 deficiency does not affect cortical neuronal viability in response to oxygen-glucose-deprivation and transient middle cerebral artery occlusion. 2003 91


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