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)

Capillary endothelial cells are critical targets in both ischemia and reperfusion of the brain. Arachidonic acids and oxygen free radicals have been shown to cause disruption of blood-brain barrier (BBB) by destruction of capillary endothelial cell membrane. However, the exact mechanism of BBB breakdown by cerebral ischemia/reperfusion remains undetermined. The aim of the present study is to clarify the mechanism of intracellular calcium ion ([Ca2+]i) change in brain capillary endothelial cells under anoxia/reoxygenation. Brains capillary endothelial cells were isolated from ten male Sprague-Dawley rats by a two step enzymatic process. [Ca2+]i was measured by means of a confocal laser scanning microscope using Indo 1-A/M as a calcium indicator. The endothelial cells were subjected to anoxia and reoxygenization under different conditions. [Ca2+]i increased gradually during anoxia and slightly decreased after reoxygenation. Indomethacin and SOD suppressed the elevation of [Ca2+]i during anoxia. NG-nitro-L-arginine methyl ester and catalase moderately suppressed the elevation, however nifedipine did not suppress it at all. In this model, rapid [Ca2+]i change was not observed during the reoxygenation phase. The results indicate that the anoxia induced elevation of [Ca2+]i in the brain capillary endothelial cells depends on superoxide and peroxynitrite generation.
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PMID:The role of calcium ion in anoxia/reoxygenation damage of cultured brain capillary endothelial cells. 941 62

Indomethacin-sensitive mechanisms involved in inducible heat shock protein 70 (iHSP 70) synthesis were investigated at 6 h after global cerebral ischemia in parietal cortex and hippocampus. In anesthetized piglets, increased intracranial pressure was used to produce 5 or 10 min of cerebral ischemia. Brain regions were sampled for immunoblot analysis, immunohistochemistry and morphology. Immunoblots revealed differential expression of iHSP 70 in untreated brains. Cerebellum contained substantial amounts of iHSP 70 while lower levels were present in parietal cortex and hippocampus. Detectable increases in iHSP 70 were observed at 2 h after ischemia in parietal cortex and hippocampus. Using immunoblot data, calculation of percent change from control at 6 h after ischemia revealed significant (p<0.05) increases in iHSP 70 of 111&plusmn;39% (&xmacr;&plusmn;sem) (n=6) in parietal cortex and 195&plusmn;69% (n=8) in hippocampus. Increased iHSP 70 immunoreactivity occurred primarily in the granular/subgranular area of the dentate gyrus 6 h after ischemia. Histological staining revealed little cellular injury at 6 h after ischemia in the granular/subgranular region injury whereas the CA3 region, which lacked iHSP 70 staining, displayed modest cellular injury. Cellular injury was also observed in cortical layers II/III and VI. At 6 h after ischemia, indomethacin pretreatment (5 mg/kg, i.v.) attenuated the iHSP 70 increases in parietal cortex and hippocampus (7&plusmn;30% and 89&plusmn;30%, respectively n=5; p<0.05 compared to ischemia). Also, the increase in iHSP 70 immunoreactivity and appearance of cellular injury were not detected with indomethacin pretreatment. Thus, prior administration of indomethacin is associated with attenuation of ischemia-induced increases in iHSP 70 and cellular injury.
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PMID:Indomethacin attenuates early increases in inducible heat shock protein 70 after cerebral ischemia/reperfusion in piglets 947 26

Indomethacin-sensitive mechanisms involved in inducible heat shock protein 70 (iHSP 70) synthesis were investigated at 6 h after global cerebral ischemia in parietal cortex and hippocampus. In anesthetized piglets, increased intracranial pressure was used to produce 5 or 10 min of cerebral ischemia. Brain regions were sampled for immunoblot analysis, immunohistochemistry and morphology. Immunoblots revealed differential expression of iHSP 70 in untreated brains. Cerebellum contained substantial amounts of iHSP 70 while lower levels were present in parietal cortex and hippocampus. Detectable increases in iHSP 70 were observed at 2 h after ischemia in parietal cortex and hippocampus. Using immunoblot data, calculation of percent change from control at 6 h after ischemia revealed significant (p < 0.05) increases in iHSP 70 of 111 +/- 39% (x +/- sem) (n = 6) in parietal cortex and 195 +/- 69% (n = 8) in hippocampus. Increased iHSP 70 immunoreactivity occurred primarily in the granular/subgranular area of the dentate gyrus 6 h after ischemia. Histological staining revealed little cellular injury at 6 h after ischemia in the granular/subgranular region injury whereas the CA3 region, which lacked iHSP 70 staining, displayed modest cellular injury. Cellular injury was also observed in cortical layers II/III and VI. At 6 h after ischemia, indomethacin pretreatment (5 mg/kg, i.v.) attenuated the iHSP 70 increases in parietal cortex and hippocampus (7 +/- 30% and 89 +/- 30%, respectively n = 5; p < 0.05 compared to ischemia). Also, the increase in iHSP 70 immunoreactivity and appearance of cellular injury were not detected with indomethacin pretreatment. Thus, prior administration of indomethacin is associated with attenuation of ischemia-induced increases in iHSP 70 and cellular injury.
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PMID:Indomethacin attenuates early increases in inducible heat shock protein 70 after cerebral ischemia/reperfusion in piglets. 949 86

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin (PG) synthesis, augment production of tumor necrosis factor (TNF) in most experimental models. We investigated the effect of two NSAIDs, indomethacin and ibuprofen, on the production of TNF in the CNS induced by intracerebroventricular injection of lipopolysaccharide (LPS). Indomethacin and ibuprofen, administered intraperitoneally, augmented (three- to ninefold) the levels of TNF in serum and peripheral organs of mice injected intraperitoneally with LPS and in rats with adjuvant arthritis (up to a sevenfold increase). However, NSAIDs (intraperitoneally or intracerebroventricularly) did not increase brain TNF production induced by intravenous LPS. In fact, indomethacin decreased (1.4-1.8-fold) TNF levels in the spinal cord of rats with experimental autoimmune encephalomyelitis and in the cortex of rats with focal cerebral ischemia. Systemic administration of iloprost inhibited serum TNF levels after intraperitoneal LPS, whereas intracerebroventricular injection of iloprost or PGE2 did not inhibit brain TNF induced by intracerebroventricular LPS. Both peripheral and central TNF productions were inhibited by cyclic AMP level-elevating agents or dexamethasone. Thus, a PG-driven negative feedback controls TNF production in the periphery but not in the CNS.
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PMID:Nonsteroidal anti-inflammatory drugs increase tumor necrosis factor production in the periphery but not in the central nervous system in mice and rats. 979 31

Cyclooxygenase-2 (COX-2) in the brain is expressed constitutively and also increased in pathological conditions such as seizure, cerebral ischemia, and inflammation. This study examined the role of COX-2 in kainic acid-induced seizure and in the following neuronal death by using selective inhibitors. Systemic kainate injection (50 mg/kg; i.p.) in mice evoked seizure within 15 min and led to 29% mortality within 2 h. TUNEL-positive neuronal death peaked at 3 days after injection and was prominent in CA(3a) regions of the hippocampus. NS-398 or celecoxib (10 mg/kg, COX-2 selective inhibitor) and indomethacin (5 mg/kg, nonselective inhibitor) exaggerated kainic acid-induced seizure activity and mortality. COX-2 selective inhibitors induced the seizure at earlier onset and more severe mortality within the first hour than indomethacin and aspirin. NS-398 also aggravated kainic acid-induced TUNEL positive neuronal death and decreased Cresyl violet stained viable neurons, and extended lesions to CA(1) and CA(3b). Kainic acid increased the levels of PGD(2), PGF(2a) and PG E(2) in the hippocampus immediately after injection. Indomethacin attenuated the production of basal and kainic acid-induced prostaglandins. In contrast, NS-398 failed to reduce until the first 30 min after kainic acid injection, during which the animals were severely seizured. It has been challenged the endogenous PGs might have anticonvulsant properties. Thus, COX-2 selective inhibitor, including nonselective inhibitor such as indomethacin, aggravated kainic acid-induced seizure activity and the following hippocampal neuronal death even with variable prostaglandin levels.
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PMID:Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. 1052 18

We investigated antioxidative activity and the effect of indomethacin, an agent that inhibits cyclooxygenase, on extracellular glutamate and cerebral blood flow in cerebral ischemia in gerbils. Pre-ischemic administration of indomethacin (5 mg/kg, i.p.) significantly rescued hippocampal CA1 neurons (9+/-6 cells/mm in the ischemia, 87+/-43 cells/mm in the indomethacin group, P<0.001). DNA fragmentation induced by ischemia was also examined using the terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) method and indomethacin reduced TUNEL positive cells (140+/-21 in the ischemia, 99+/-31 in the indomethacin group, P<0.01). In addition, indomethacin attenuated the increase in hippocampal blood flow during reperfusion, but not increased extracellular glutamate by ischemia. Eight-hydroxydeoxyguanosine (8-OH-dG), a highly sensitive marker of DNA oxidation, was measured 90 min following ischemia using high-pressure liquid chromatography. Indomethacin significantly decreased the level of ischemia-induced 8-OH-dG in the hippocampus (P<0.05). These results suggest that indomethacin may protect neurons by attenuating oxidative stress and reperfusion injury in ischemic insult.
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PMID:Suppression of hyperemia and DNA oxidation by indomethacin in cerebral ischemia. 1252 44

Indomethacin has been suggested as a therapeutic tool to manage elevated intracranial pressure in patients with severe head injury and patients undergoing craniotomy for brain tumors. Indomethacin is a non-selective cyclooxygenase inhibitor. Compared to other cyclooxygenase inhibitors indomethacin has unique effects on cerebral blood flow. Administration of indomethacin causes cerebral vasoconstriction and decreases cerebral blood flow, which elicits a decrease in intracranial pressure. The mechanism of indomethacin-induced cerebral vasoconstriction is not completely understood and controversies exist whether indomethacin causes cerebral ischemia. The primary aims of this article were to review the existing knowledge of indomethacin's influence upon cerebral hemodynamics and elevated ICP in patients with brain pathology. Furthermore, indomethacin's mechanism of action and whether it causes cerebral ischemia are discussed.
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PMID:Treatment of elevated intracranial pressure with indomethacin: friend or foe? 1622 16

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a cerebrovascular dilator and was found neuroprotective in numerous in vitro and in vivo models of cerebral ischemia. However, the mechanism of its cerebrovascular action is poorly known, especially in newborns. Therefore, we tested pial arteriolar responses to the two naturally occurring forms PACAP27 and 38 as well as to shorter sequences (PACAP6-27, 6-38, 1-15, 6-15, 20-31). We also investigated the involvement of nitric oxide synthase (NOS), cyclooxygenase-1 and -2 (COX-1 and -2) activity in PACAP-induced pial arteriolar responses using the NOS inhibitor N-omega-nitro-l-arginine methyl ester (L-NAME 15 mg/kg iv), the non-selective COX inhibitor indomethacin (5 mg/kg iv), and the selective COX-1 and COX-2 inhibitors SC-560 (1 mg/kg iv) and NS-398 (1 mg/kg iv), respectively. Anesthetized, ventilated piglets (n=127) were equipped with closed cranial windows, and pial arteriolar diameters were determined via intravital microscopy. Topical application of both natural PACAPs, but none of the PACAP segments, resulted in prominent, repeatable, dose-dependent vasodilation. Percentage changes ranged 5+/-1-29+/-6 (n=7) and 4+/-1-36+/-7 (n=9) to 10(-)(8) to 10(-)(6) M PACAP27 and 38 (mean+/-SEM), respectively. Vasodilation to both natural PACAPs was significantly reduced by co-application with PACAP6-27 or 6-38, but not by L-NAME. Indomethacin abolished PACAP38 but not PACAP27-induced vasodilation. Arteriolar responses to PACAP38 were also sensitive to SC-560 but not to NS-398 suggesting the unique involvement of COX-1 activity in this response. In summary, PACAP27 and 38 are potent vasodilators in the neonatal cerebral circulation with at least two distinct mechanisms of action: a COX-dependent and a COX-independent pathway.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces pial arteriolar vasodilation through cyclooxygenase-dependent and independent mechanisms in newborn pigs. 1765 92


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