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)

The protective effects of 17beta-estradiol in cerebral ischemia may be partially due to the blockade of leukocyte adhesion in cerebral endothelial cells, although the molecular mechanisms are not well understood. We report that 17beta-estradiol (E(2)), but not the alpha-enantiomer, inhibited the basal and interleukin-1beta (IL-1beta)-mediated expression of the intercellular adhesion molecule type 1 (ICAM1) and NFkappaB activation, in cultured brain endothelial cells. However, the degradation of IkappaB-alpha, which is an essential requirement for the translocation of NFkappaB to the nucleus, and a common biological target to suppress NFkappaB activation, was not halted by E(2). These findings indicate that decreased expression of adhesion molecules may account for the capacity E(2) to reduce adhesion of leukocytes in cerebral endothelium in vivo, and suggest the existence of brain-specific, estrogen-sensitive pathways, other than IkappaB-alpha_-regulation, to modulate NFkappaB. The stereoselectivity of the E(2) effect is consistent with an estrogen receptor-mediated mechanism.
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PMID:Estrogen inhibits NF kappa B-dependent inflammation in brain endothelium without interfering with I kappa B degradation. 1216 75

Mild hypothermia is an established neuroprotectant against cerebral ischemic injury. Studies have shown that inflammation potentiates cerebral ischemic injury, particularly in the setting of reperfusion. To further elucidate the mechanism by which mild hypothermia attenuates the inflammatory response, we assessed endothelial intercellular adhesion molecule-1 (ICAM-1) expression, neutrophil and monocyte infiltration, and microglial activation following 2 h of transient focal cerebral ischemia under normothermic and mildly hypothermic conditions. Ischemia was induced using the intraluminal suture method in Sprague-Dawley rats. Immunohistochemistry was used to detect endothelial ICAM-1, infiltrating neutrophils and monocytes, and microglia at 1, 3, and 7 days post-ischemia. Immunopositive cell and vessel densities were measured in the peri-infarct region. Mild hypothermia was associated with decreased neutrophils at 1 and 3 days post-ischemia, decreased ICAM-1-positive vessels at 1, 3, and 7 days, and decreased monocytes/activated microglia at 3 and 7 days, but not at 1 day. These data demonstrate that mild hypothermia significantly reduces endothelial adhesion molecule expression, acute (neutrophil) and subacute (monocyte) leukocyte infiltration, and microglial activation up to 7 days following insult in a rodent model of transient focal cerebral ischemia.
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PMID:Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. 1237 61

Sixteen patients with acute middle cerebral artery stroke were studied to correlate neuroinflammatory markers with perfusion- and diffusion-weighted magnetic resonance imaging (MRI) lesion volumes (PWI and DWI). At arrival (less than 6 hours), plasmatic matrix metalloproteinase (MMP)-9, MMP-2, interleukin (IL)-6, IL-8, intercellular adhesion molecule (ICAM)-1, and tumor necrosis factor (TNF)-alpha were serially measured (by ELISA), and MRI was performed. In cerebral ischemia, tissue destruction seems related to matrix metalloproteinases expression because baseline MMP-9 was the only predictor of the infarct volume measured as a DWI lesion (lineal regression: b = 0.50, 0.25-0.74; P < 0.001). Moreover, the extent of hypoperfused brain area (PWI) was associated with a proinflammatory cytokine release in the next hours (TNF-alpha and IL-6).
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PMID:Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke. 1466 35

Gene expression in frontal, occipital, and hippocampal regions of rat brains at 15 min of ischemic injury was studied in a rat model by producing focal cerebral ischemia through middle cerebral artery (MCA) occlusion without reperfusion. Catalase, epithelial glycoprotein (EGP-314), cytochrome C oxidase-subunit 1, ribosomal L31 protein, and ceruloplasmin were found to be differentially expressed. Specific primers were designed to study this newly reported brain EGP-314, a cellular adhesion molecule involved in cell-cell and cell-extracellular matrix interactions and related with cytoskeletal organization, differentiation, and proliferation. In the frontal and occipital lobes, EGP-314 expression was low in control and ischemic conditions and increased in sham injured conditions, whereas in the hippocampal region its expression was induced only by ischemia. In situ hybridization and immunohistochemistry revealed that EGP-314 mRNA and the protein were present in the ischemic hippocampus pyramidal neurons. DNA fragmentation was demonstrated by TUNEL and LM-PCR analysis in hippocampus region. TUNEL positive pyramidal neurons were observed at 15 min of ischemia. DNA ladder was found at 12 and 15 min of ischemia.
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PMID:EGP-314 is expressed differentially in three brain zones at an early time in an experimentally induced ischemia rat model. 1595 Jul 61

PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (alpha, beta/delta and gamma) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARalpha and PPARgamma activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARalpha or PPARgamma activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARalpha activators as well as thiazolidinediones and other non-thiazolidinedione PPARgamma agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARalpha activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases.
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PMID:PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. 1707 15

Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone after SCI in adult rats. Both pioglitazone and rosiglitazone (1.5 mg/kg i.p.; four doses at 5 min and 12, 24, and 48 h) significantly decreased the lesion size (by 57 to 68%, p < 0.05), motor neuron loss (by 3- to 10-fold, p < 0.05), myelin loss (by 66 to 75%, p < 0.05), astrogliosis (by 46 to 61%, p < 0.05), and microglial activation (by 59 to 78%, p < 0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over the vehicle group; p < 0.05), but the treatment was effective only when the first injection was given by 2 h after SCI. At 28 days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p < 0.05) in the pioglitazone group compared with the vehicle group. At 6 h after SCI, the pioglitazone group showed significantly less induction of inflammatory genes [interleukin (IL)-6 by 83%, IL-1beta by 87%, monocyte chemoattractant protein-1 by 75%, intracellular adhesion molecule-1 by 84%, and early growth response-1 by 67%] compared with the vehicle group (p < 0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat shock proteins and antioxidant enzymes. Pretreatment with a PPARgamma antagonist, 2-chloro-5-nitro-N-phenyl-benzamide (GW9662), prevented the neuroprotection induced by pioglitazone.
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PMID:Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. 1716 71

The complement anaphylatoxin C3a contributes to injury after cerebral ischemia in mice. This study assesses the effect of C3a receptor antagonist (C3aRA) on leukocyte infiltration into the ischemic zone. Transient or permanent middle cerebral artery occlusion (MCAO) was induced in wild-type C57Bl/6 mice. Intraperitoneal C3aRA or vehicle was administered 45 mins before or 1 h after occlusion. Twenty-four hours after occlusion, we harvested brain tissue and purified inflammatory cells using flow cytometry. Soluble intercellular adhesion molecule (ICAM)-1 protein levels were assessed using enzyme-linked immunosorbent assays, and ICAM-1 and C3a receptor (C3aR) expression was confirmed via immunohistochemistry. In the transient MCAO model, animals receiving C3aRA showed smaller strokes, less upregulation of C3aR-positive granulocytes, and less ICAM-1 protein on endothelial cells than vehicle-treated animals; no significant differences in other inflammatory cell populations were observed. C3a receptor antagonist-treated and vehicle-treated animals showed no differences in stroke volume or inflammatory cell populations after permanent MCAO. These data suggest that blocking the binding of C3a to C3aR modulates tissue injury in reperfused stroke by inhibiting the recruitment of neutrophils to the ischemic zone. It further establishes antagonism of the C3a anaphylatoxin as a promising strategy for ameliorating injury after ischemia/reperfusion.
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PMID:C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent. 1819 78

The mechanisms leading to cellular damage from ischemia-reperfusion (I/R) injury are complex and multi-factorial. Accumulating evidence suggests an important role for oxidative stress in the regulation of neuro-inflammation following stroke. Gene expression studies have revealed that the increase in oxygen radicals post-ischemia triggers the expression of a number of pro-inflammatory genes. These genes are regulated by the transcription factor, nuclear factor-kappa-B (NF-kappaB) which is redox-sensitive. It is hypothesised that changes in the oxidative state may modulate alterations in the neuro-inflammatory response following an I/R injury. Furthermore, NF-kappaB is involved in the transcriptional regulation of adhesion molecules, which play an important role in leukocyte-endothelium interactions. Recent studies have demonstrated that adhesion molecule-mediated leukocyte recruitment is associated with increased tissue damage in stroke, while mice lacking key adhesion molecules conferred neuro-protection. Nevertheless, the involvement of oxidative stress in leukocyte recruitment and the subsequent regulated cell injury is yet to be elucidated. While leukocyte infiltration into the ischemic brain is detrimental, leukocyte accumulation in the microvasculature was shown to be one of the many factors implicated in reduced reperfusion. Although this "no-reflow" phenomenon was confirmed in a variety of animal models of cerebral ischemia, the exact mechanism is still uncertain. This review aims to highlight the impact that oxidative stress has in the regulation of post-ischemic neuro-inflammation and the implication for the cerebral microvasculature after injury.
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PMID:Modulation of neuro-inflammation and vascular response by oxidative stress following cerebral ischemia-reperfusion injury. 1822 Jul 59

Human E-selectin, an endothelial adhesion molecule, is induced in the brain arteries by cerebral ischemia and participates in the infiltration of leukocytes that cause inflammatory reaction leading to brain damage. To prevent leukocyte infiltration in the brain, we designed gene therapeutic constructs to suppress E-selectin expression. The constructs were composed of microRNAs (miR-E1 and miR-E2) complementary to the human E-selectin cDNA, which were directed by a minimum cis-element of the human E-selectin promoter. Transfection in human aorta endothelial cells (HAECs) with these constructs revealed that the E-selectin promoter was sufficiently activated in response to tumor necrosis factor-alpha (TNF-alpha), and miR-E1 and miR-E2 could suppress E-selectin expression resulting in the significant inhibition of leukocyte adhesion. These results suggested that the combination of the E-selectin promoter and microRNAs could allow the restricted expression of transgenes in activated endothelial cells and diminish leukocyte recruitment.
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PMID:Conditional expression of microRNA against E-selectin inhibits leukocyte-endothelial adhesive interaction under inflammatory condition. 1847 97

The purpose of this study was to investigate the short-term effects of rosuvastatin (RSV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on transient, focal cerebral ischemia in C57BL/6J ob/ob mice with insulin resistance (IR). Male ob/ob, lean, or wild-type (WT) mice were treated with RSV (10 mg/kg per day, i.p.) or vehicle for 3 days. Ischemia was induced by 60 mins of middle cerebral artery occlusion (MCAO) and cortical blood flow (CBF) was monitored by laser-Doppler flowmetry. Infarct volumes were measured 24 h after reperfusion. IR mice exhibited a higher infarct volume compared with Lean or WT mice, and RSV reduced infarct volume only in obese mice (40%+/-3% versus 32%+/-3%, P<0.05). Blood cholesterol and insulin levels were elevated in ob/ob mice but were unaffected by RSV. The CBF reductions during MCAO were similar in all groups and were not affected by RSV. Although RSV did not increase cortical endothelial NO synthase (eNOS) levels in the ob/ob mice, it attenuated the increased cortical expression of intracellular adhesion molecule-1 (ICAM-1) after MCAO from ob/ob mice. Thus, RSV protects against stroke in IR mice by a mechanism independent of effects on the lipid profile, CBF, or eNOS but dependent on suppression of post-MCAO ICAM-1 expression.
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PMID:Acute treatment with rosuvastatin protects insulin resistant (C57BL/6J ob/ob) mice against transient cerebral ischemia. 1866 82


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