Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

To elucidate the protective mechanism of whole-body hypoxic preconditioning (WHPC) on pulmonary ischemia-reperfusion injury focussing on nitric oxide synthases (NOS), mice were placed in a hypoxic chamber (FIO(2)=0.1) for 4h followed by 12h of normoxia. Then, pulmonary ischemia for 1h followed by 5h of reperfusion was performed by clamping the left hilum in vivo (I/R). WHPC protected WT mice from pulmonary leukocyte infiltration as assessed by myeloperoxidase (MPO) activity, associated with a mild further increase in endothelial permeability (Evans Blue extravasation). When all NOS isoforms were inhibited during WHPC by L-NAME, mortality and MPO activity after I/R markedly increased. To determine the responsible NOS isoform, quantitative RT-PCR was performed for eNOS and iNOS mRNA, showing that only eNOS was upregulated in response to WHPC. While eNOS total protein expression remained unchanged, the amount of phosphorylated eNOS also increased. The WHPC/IR experiments were then repeated with eNOS knockout mice. Here, we found that the protective effect of WHPC on pulmonary leukocyte sequestration was abrogated, and endothelial leakage was further exacerbated. We conclude that WHPC limits neutrophil sequestration via an eNOS-dependent mechanism, and that eNOS helps preserve endothelial permeability during hypoxia and I/R.
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PMID:Endothelial nitric oxide synthase mediates protective effects of hypoxic preconditioning in lungs. 1691 27

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood-brain barrier (BBB) disruption and edema formation after ischemia-reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl (PJ34); (10 mg/kg, i.v.) before ischemia. After 40 mins, 24, and 48 h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia-reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170+/-9, saline: 760+/-95, PJ34: 472+/-61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24 h. PARP inhibition decreased the brain edema seen at 48 h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction
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PMID:Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats. 1721 62

Blood-brain barrier (BBB) leakage plays a role in the pathogenesis of many pathological states of the brain including ischemia and some neurodegenerative disorders. In recent years, erythropoietin (EPO) has been shown to exert neuroprotection in many pathological conditions including ischemia in the brain. This study aimed to investigate the effects of EPO on BBB integrity, infarct size and lipid peroxidation following global brain ischemia/reperfusion in rats. Wistar male rats were divided into four groups (each group n=8); Group I; control group (sham-operated), Group II; ischemia/reperfusion group, Group III; EPO treated group (24 h before decapitation--000 U/kg r-Hu EPO i.p.), Group IV; EPO+ ischemia/reperfusion group (24 h before ischemia/reperfusion--3000 U/kg r-Hu EPO i.p.). Global brain ischemia was produced by the combination of bilateral common carotid arteries occlusion and hemorrhagic hypotension. Macroscopical and spectrophotometrical measurement of Evans Blue (EB) leakage was observed for BBB integrity. Infarct size was calculated based on 2,3,5-triphenyltetrazolium chloride (TTC) staining. Lipid peroxidation in the brain tissue was determined as the concentration of thiobarbituric acid-reactive substances (TBARS) for each group. Ischemic insult caused bilateral and regional BBB breakdown (hippocampus, cortex, corpus striatum, midbrain, brain stem and thalamus). EPO pretreatment reduced BBB disruption, infarct size and lipid peroxide levels in brain tissue with 20 min ischemia and 20 min reperfusion. These results suggest that EPO plays an important role in protecting against brain ischemia/reperfusion through inhibiting lipid peroxidation and decreasing BBB disruption.
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PMID:The relationship between erythropoietin pretreatment with blood-brain barrier and lipid peroxidation after ischemia/reperfusion in rats. 1730 Aug 15

Increased levels of glutamate and aspartate have been detected after subarachnoid hemorrhage (SAH) that correlate with neurological status. The NMDA receptor antagonist felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an anti-epileptic drug that elicits neuroprotective effects in different experimental models of hypoxia-ischemia. The aim of this dose-response study was to evaluate the effect of FBM after experimental SAH in rats on (1) behavioral deficits (employing a battery of assessment tasks days 1-5 post-injury) and (2) blood-brain barrier (BBB) permeability changes (quantifying microvascular alterations according to the extravasation of protein-bound Evans Blue by a spectrophotofluorimetric technique 2 days post-injury). Animals were injected with 400 muL of autologous blood into the cisterna magna. Within 5 min, rats received daily oral administration of FBM (15, 30, or 45 mg/kg) for 2 or 5 days. Results were compared with sham-injured controls treated with oral saline or FBM (15, 30, or 45 mg/kg). FBM administration significantly ameliorated SAH-related changes in Beam Balance scores on days 1 and 2 and Beam Balance time on days 1-3, Beam Walking performance on days 1 and 2, and Body Weight on days 3-5. FBM also decreased BBB permeability changes in frontal, temporal, parietal, occipital, and cerebellar cortices; subcortical and cerebellar gray matter; and brainstem. This study demonstrates that, in terms of behavioral and microvascular effects, FBM is beneficial in a dose-dependent manner after experimental SAH in rats. These results reinforce the concept that NMDA excitotoxicity is involved in the cerebral dysfunction that follows SAH.
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PMID:NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat. 1743 55

Prior prolonged oxygen exposure is associated with some protection against ischemia-reperfusion (IR) injury to rat brain tissue, but also with toxic effects. We sought to compare the magnitude of protection offered by prolonged and intermittent oxygen pretreatments against IR injury to the rat brain. Rats were divided into four experimental groups, each of 21 animals. The first two were exposed to 95% inspired (normobaric hyperoxia, NBHO) for 4 h/day for 6 consecutive days (intermittent NBHO) or for 24 continuous hours (prolonged NBHO). The second two groups acted as controls were exposed to 21% oxygen. After 24 h, they were subjected to 60 min of right middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. The animals were sacrificed for assessment of infarct volume, brain edema, and blood-brain barrier (BBB) permeability, respectively. Prolonged and intermittent NBHO pretreatment reduced infarct volume by 63.3% and 73.7%, respectively, when compared to the respective NBNO groups. Intermittent NBHO (when compared to intermittent NBNO) also reduced the post-ischemic increment of brain water content significantly (81.53+/-0.8%, vs. 80.12+/-0.79%) and Evans Blue extravasation (7.49+/-2.89+/-g/g tissue vs. 3.9+/-0.79 microg/g tissue, P<0.001), while prolonged NBHO had no significant effect on brain water content (81.69+/-1.16% vs. 80.74+/-0.94%) and EB extravasations (6.48+/-2.42 microg/g tissue vs. 4.31+/-1.07 microg/g tissue). Intermittent hyperoxia had relatively more significant effects on brain edema and BBB protection. Although preconditioning with both prolonged and intermittent oxygen exposure protects rat brain tissue against IR injury, the intermittent hyperoxia could have relatively more protective effects in this regard.
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PMID:Prolonged and intermittent normobaric hyperoxia induce different degrees of ischemic tolerance in rat brain tissue. 1747 25

Previous experimental studies have shown that aminoguanidine (AG) is beneficial in the late phase of cerebral ischemia. Recently, it has been reported that AG reduces cerebral edema in traumatic brain injury. However, the effects of AG on post-ischemic cerebral edema and blood-brain barrier (BBB) permeability are not clear. Under chloral hydrate anesthesia, transient focal cerebral ischemia was induced in rats by 60 min of middle cerebral artery occlusion (MCAO), followed by 23 h of reperfusion. Saline as vehicle or AG at the doses of 75, 150 and 300 mg/kg, i.p., was administered at the beginning or at 1 or 3 h after induction of ischemia. Subsequently, 24 h after MCAO brain edema, BBB permeability and infarct volume were evaluated. Administration of AG (150 mg/kg) at the beginning or at 1 or 3 h after MCAO, significantly reduced cerebral edema (P<0.001), while AG at the doses of 75 and 300 mg/kg had no effect. Moreover, treatment with AG (150 mg/kg) significantly reduces Evans Blue extravasation by 48% into ischemic brain compared to the saline group (P<0.001). Additionally, AG at the doses of 75 and 150 mg/kg significantly reduces cortical and striatal infarct volumes (P<0.001), while AG at the dose of 300 mg/kg did not change striatal infarct volumes (P>0.05). Our findings show that AG significantly reduced post-ischemic increase of brain edema with a 3-h therapeutic window in the transient model of focal cerebral ischemia. Moreover, it seems that at least part of the anti-edematous effects of AG is due to decrease of BBB disruption.
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PMID:Effect of aminoguanidine on post-ischemic brain edema in transient model of focal cerebral ischemia. 1769 46

Angiopoietin-like protein (Angptl) 1, a member of the angiopoietin-related protein family, modulates angiogenesis but little else is known of its physiological role. We found that angptl1 was upregulated at the 7th day after focal cerebral ischemia in normal mice. In order to understand the role of angptl1 in cerebral infarction, we induced focal cerebral ischemia in normal and glial fibrillary acidic protein promoter-angptl1 transgenic mice. In the transgenic mice without ischemia, overexpression of angptl1 in the whole brain led to a decrease in cortical microvascular density. Following focal cerebral ischemia, edema, but not infarct size, was less in transgenic mice relative to wild type littermates. This effect might be due to a reduction in the blood brain barrier breakdown, as confirmed by a decrease in Evans Blue leakage in the early post-ischemic phase. We conclude that angptl1 may have a beneficial role in the preservation of vascular integrity following focal cerebral ischemia.
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PMID:Angiopoietin-like protein 1 decreases blood brain barrier damage and edema following focal cerebral ischemia in mice. 1791 82

In this study, the involvement of 5-HT2A receptors on mesenteric ischemia-reperfusion injury was examined in mice. Intestinal ischemia produced by 45 min occlusion of superior mesenteric artery was followed by 24h reperfusion (I/R). The 5-HT2A selective antagonist, ketanserin (0.5 mgkg(-1)) or the 5-HT2A agonist DOI (0.25 mgkg(-1)) was intravenously administered before ischemia and 8h after the beginning of reperfusion. The effects were compared with those obtained in sham operated animals (S). Ketanserin prevented the upper gastrointestinal transit delay induced by I/R (P<0.01), protected intestine from leukocyte recruitment as indicated by jejunal myeloperoxidase activity (P<0.05) and reverted Evans Blue extravasation elicited by I/R in lung, colon and jejunum (P<0.05). On the other hand, 5-HT2A activation by DOI mimicked the effects of I/R in S mice prolonging small intestine transit (P<0.05) and enhancing neutrophil accumulation in jejunal tissues (P<0.05). Furthermore, the reduction of ADP-induced platelet aggregation in plasma of I/R mice was prevented by ketanserin treatment. All together, these findings support the critical involvement of 5-HT2A receptor subtype in mediating the damage induced by mesenteric I/R in mice.
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PMID:Evidence for the involvement of 5-HT2A receptors in mild mesenteric ischemia/reperfusion dysfunctions in mice. 1802 56

Exercise reduces ischemia and reperfusion (I/R) injury in the rat stroke model. We investigated whether pre-ischemic exercise ameliorates blood-brain barrier (BBB) dysfunction in stroke by reducing matrix metalloproteinase (MMP)-9 expression and strengthening basal lamina. Adult male Sprague-Dawley rats were subjected to a 30 min exercise program on a treadmill 5 days a week for 3 weeks. Stroke was induced by a 2-h middle cerebral artery (MCA) occlusion using an intraluminal filament in the exercised and non-exercised groups. Brain infarction was measured and neurological deficits were scored. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Expression of collagen IV, the major component of basal lamina essential for maintenance of the endothelial permeability barrier, was quantitatively detected by Western blot and immunocytochemistry. Ex vivo techniques were used to compare collagen IV-labeled vessels in response to ischemic insult. Temporal relationship of expression of MMP-9 and its endogenous inhibitor, the tissue inhibitors of metalloproteinase-1 (TIMP-1), was determined by real-time PCR for mRNA and Western blot for protein during reperfusion. Brain edema and Evans Blue leakage were both significantly (P<0.01) reduced after stroke in the exercised group, in association with reduced brain infarct volume and neurological deficits. Western blot analysis indicated that exercise enhanced collagen IV expression and reduced the collagen loss after stroke. Immunocytochemistry demonstrated that collagen IV-labeled vessels were significantly (P<0.01) increased in exercised rats. In the ex vivo study, after exercised brains were incubated with ischemic brain tissue, a significantly (P<0.01) higher level of collagen IV-labeled vessels was observed as compared with non-exercised brains following the same treatment. The ex vivo study also revealed a key role of MMP-9 in exercise-strengthened collagen IV expression against I/R injury. TIMP-1 protein levels were significantly (P<0.01) increased by exercise. Our results indicate that pre-ischemic exercise reduces brain injury by improving BBB function and enhancing basal lamina integrity in stroke. This study suggests that the neuroprotective effect of physical exercise is associated with an imbalance of MMP-9 and TIMP-1 expression.
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PMID:Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke. 1816 Feb 27

The blood-brain barrier (BBB) is the principal regulator of blood-borne substance entry into the brain parenchyma. Therefore, BBB leakage, which leads to cerebral edema and influx of toxic substances, is common in pathological conditions such as cerebral ischemia, inflammation, trauma, and tumors. The leakage of BBB after ischemia-reperfusion injury has long been considered to be biphasic, although a considerable amount of discrepancies as for the timing of the second opening does exist among the studies. This led us to evaluate systematically and quantitatively the dynamics of BBB leakage in a rat model of 90-min ischemia-reperfusion, using gadolinium-enhanced (small molecule) magnetic resonance imaging and fluorescent dye Evans Blue (large molecule). BBB leakage was assessed at the following time points after reperfusion: 25 min, 2, 4, 6, 12, 18, 24, 36, 48, and 72 h, and 1, 2, 3, 4, and 5 weeks. We observed BBB leakage for both gadolinium and Evans Blue as early as 25 min after reperfusion. Thereafter, BBB remained open for up to 3 weeks for Evans Blue and up to 5 weeks for gadolinium. Our results show that BBB leakage after ischemia-reperfusion injury in the rat is continuous and long-lasting, without any closure up to several weeks. This is the first systematic and extensive study fully demonstrating BBB leakage dynamics following transient brain ischemia and the findings are of major clinical and experimental interest.
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PMID:The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia. 1836 42


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