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

This study was designed to determine if altered release of prostaglandins contributes to impaired pial artery dilation to the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ), following hypoxia/ischemia in newborn pigs equipped with a closed cranial window. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, while hypoxia (10 min) decreased P(O(2)) to 35+/-3 mmHg with unchanged P(CO(2)). NOC/oFQ (10(-8) and 10(-6) M) modestly increased cerebrospinal fluid (CSF) 6-Keto PGF(1alpha) and TXB(2), the stable breakdown products of PGI(2) and TXA(2), in sham animals (1199+/-39 to 1704+/-104 and 299+/-9 to 409+/-12 pg/ml for control and 10(-6) M NOC/oFQ 6-Keto PGF(1alpha) and TXB(2), respectively). In 1 h post ischemia/reperfusion (I+R) animals, basal levels of 6-Keto PGF(1alpha) and TXB(2) were elevated. NOC/oFQ-stimulated release of 6-Keto PGF(1alpha) was blocked while such release of TXB(2) was enhanced (526+/-15 to 822+/-36 pg/ml for control and 10(-6) M NOC/oFQ CSF TXB(2)). Similar, though more pronounced, changes were observed in hypoxia/ischemia/reperfusion (H+I+R) animals. Pretreatment with indomethacin (5 mg/kg i.v.) or SQ 29,548 (10(-4) M), cyclooxygenase and PGH(2)/TXA(2) receptor antagonists, partially restored attenuated NOC/oFQ pial artery dilation 1 h after I+R (9+/-1 and 18+/-1 vs. 3+/-1 and 6+/-1 vs. 8+/-1 and 13+/-1% for 10(-8) and 10(-6) M NOC/oFQ in sham, I+R, and I+R - SQ 29,548 pretreated animals). In contrast, NOC/oFQ-induced vasodilation was reversed to vasoconstriction in H+I+R animals and indomethacin or SQ 29,548 similarly partially restored such pial vasodilation. These data indicate that altered stimulated prostaglandin release contributes to hypoxic/ischemic impairment of NOC/oFQ-mediated pial artery dilation.
 ...
PMID:Altered release of prostaglandins contributes to hypoxic/ischemic impairment of NOC/oFQ cerebrovasodilation. 1072 Jun 19

The disturbance of microcirculation following cerebral ischemia leads to an enlargement of cerebral infarct volume. Endogenous thrombin may play a role in this disturbance of microcirculation following cerebral ischemia. Therefore, the inhibition of thrombin may improve neurodegeneration and the accumulation of cerebral edema following cerebral ischemia in gerbils. The effects of thrombin inhibitor (argatroban) on cerebral ischemia were investigated in comparison with thromboxane A2 synthase inhibitor (ozagrel) and cyclooxygenase inhibitor (aspirin) following bilateral common carotid artery occlusion and reperfusion (CCA:O/R) in male Mongolian gerbils. This study consisted of three experiments: (1) morbidity and survival ratio (n=40 for each), (2) histopathology (n=12 for each), and (3) mean arterial blood pressure, local cerebral blood flow (CBF), and cerebral specific gravity (n=8 for each). Argatroban treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex and hippocampus and cerebral edema in cortex compared with aspirin and saline, in concert with the fast recovery of local CBF without reactive hyperemia following bilateral CCA:O/R. Ozagrel treatment also improved those factors compared with saline, in concert with the fast recovery of local CBF with reactive hyperemia. Aspirin treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex. Thrombin inhibition with argatroban decreases neurodegeneration and cerebral edema following bilateral CCA:O/R in gerbils.
 ...
PMID:Thrombin inhibition attenuates neurodegeneration and cerebral edema formation following transient forebrain ischemia. 1138 20

Prostaglandins and leukotrienes (eicosanoids), metabolites of the arachidonic acid pathway, are subjected to altered synthesis or relocation after an ischemic insult. Although cyclooxygenase (COX) expression has been reported in human cerebral ischemia, no information is available on the expression of 5-lipoxygenase (5-LO) and its topographical correlation to COX induction. The objective of this study was to elucidate the comparative distribution of eicosanoids in ischemic tissues. COX and 5- LO, key enzymes for the synthesis of prostaglandins and leukotrienes, respectively, were examined in autopsied brains. COX1 was expressed intensely in the microglia but weakly in the neurons in control brains. These COX1-immunoreactive microglia showed a more activated form following ischemic damage and hypoxemia. In contrast, COX2 was absent in the control brains, and was induced robustly in the neuronal cell bodies and dendrites during the acute stages of focal ischemic damage, and then subsided at the subacute stages. These COX2-immunoreactive neurons accumulated in the peri-infarct regions, but were absent from the distant regions. In focal ischemic damage and Binswanger's disease, COX2 was up-regulated in the microglia. Neuronal immunostaining for 5-LO was up-regulated occasionally during hypoxemia and focal ischemic damage. Glial cells immunoreactive for 5-LO appeared in the foci of the ischemic damage, with small blood vessels being infiltrated by 5-LO-immunoreactive mononuclear leukocytes. These findings indicate that the isozymes of COX are differentially regulated depending on the cellular source and the types of ischemic damage, and that vascular 5-LO may accelerate the migration of leukocytes and augment the blood-brain barrier permeability. The possibility of increased substrate availability for the other should be noticed in specific inhibition of either COX or 5-LO since these two enzymes are accumulated in parallel in ischemic tissues.
 ...
PMID:A comparative study on the expression of cyclooxygenase and 5-lipoxygenase during cerebral ischemia in humans. 1241 Mar 81

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.
 ...
PMID:Suppression of hyperemia and DNA oxidation by indomethacin in cerebral ischemia. 1252 44

Reactive oxygen species produced by neutrophils contribute to the pathogenesis of focal cerebral ischemia/reperfusion injury and signal the inflammatory response. We have previously shown that honokiol, an active principle extracted from Magnolia officinalis, has a protective effect against focal cerebral ischemia/reperfusion injury in rats that paralleled a reduction in reactive oxygen species production by neutrophils. To elucidate the underlying mechanism(s) of the antioxidative effect of honokiol, peripheral neutrophils isolated from rats were activated with phorbol-12-myristate-13-acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) in the presence or absence of honokiol. In this study, we found that honokiol inhibited PMA- or fMLP-induced reactive oxygen species production by neutrophils by three distinct mechanisms: (1) honokiol diminished the activity of assembled-NADPH oxidase, a major reactive oxygen species producing enzyme in neutrophils by 40% without interfering with its protein kinase C (PKC)-dependent assembly; (2) two other important enzymes for reactive oxygen species generation in neutrophils, i.e., myeloperoxidase and cyclooxygenase, were also inhibited by honokiol by 20% and 70%, respectively; and (3) honokiol enhanced glutathione (GSH) peroxidase activity by 30%, an enzyme that triggers the metabolism of hydrogen peroxide (H2O2). These data suggested that honokiol, acting as a potent reactive oxygen species inhibitor/scavenger, could achieve its focal cerebral ischemia/reperfusion injury protective effect by modulating enzyme systems related to reactive oxygen species production or metabolism, including NADPH oxidase, myeloperoxidase, cyclooxygenase, and GSH peroxidase in neutrophils.
 ...
PMID:The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production. 1295 55

Metabolism of arachidonic acid by cyclooxygenase is one of the primary sources of reactive oxygen species in the ischemic brain. Neuronal overexpression of cyclooxygenase-2 has recently been shown to contribute to neurodegeneration following ischemic injury. In the present study, we examined the possibility that the neuroprotective effects of the cyclooxygenase-2 inhibitor nimesulide would depend upon reduction of oxidative stress following cerebral ischemia. Gerbils were subjected to 5 min of transient global cerebral ischemia followed by 48 h of reperfusion and markers of oxidative stress were measured in hippocampus of gerbils receiving vehicle or nimesulide treatment at three different clinically relevant doses (3, 6 or 12 mg/kg). Compared with vehicle, nimesulide significantly (P<0.05) reduced hippocampal glutathione depletion and lipid peroxidation, as assessed by the levels of malondialdehyde (MDA), 4-hydroxy-alkenals (4-HDA) and lipid hydroperoxides levels, even when the treatment was delayed until 6 h after ischemia. Biochemical evidences of nimesulide neuroprotection were supported by histofluorescence findings using the novel marker of neuronal degeneration Fluoro-Jade B. Few Fluoro-Jade B positive cells were seen in CA1 region of hippocampus in ischemic animals treated with nimesulide compared with vehicle. These results suggest that nimesulide may protect neurons by attenuating oxidative stress and reperfusion injury following the ischemic insult with a wide therapeutic window of protection.
 ...
PMID:Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils. 1451 50

Free fatty acids (FFAs) are elevated in the brain following both ischemic and traumatic injury. Phospholipase activation, with the subsequent release of FFAs from membrane phospholipids, is the likely mechanism. In addition to phospholipases A1, B, C, and D, there are at least 19 groups of PLA2, including multiple cytosolic, calcium independent, and secretory isoforms. Phospholipase activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. These enzymes normally function in the physiological remodeling of cellular membranes, whereby FFAs are removed by phospholipase activity and then reacylated with a different FFA. However, reductions in the cell's ability to maintain normal metabolic function and the resultant fall in ATP levels can cause the failure of reacylation of membrane phospholipids. Alterations to membrane phospholipids would be expected to compromise many cellular functions, including the ability to accumulate excitotoxic amino acids. This review presents evidence for a central role of phospholipases and their products in the etiology of damage following injury to the brain. Phospholipase expression and activity is increased in animal models of cerebral ischemia and trauma. FFA release from the in vivo rat brain is reduced following the application of selective phospholipase inhibitors, and this inhibition also decreases the severity of cortical damage following forebrain ischemia, focal (middle cerebral artery occlusion) ischemia, and cerebral trauma. Mice with knockouts of PLA2 have decreased infarct volumes. Human data demonstrate a correlation between the elevation of CSF FFAs and worsened outcome following stroke, traumatic brain injury, and subarachnoid hemorrhage. The released FFAs, especially arachidonic and docosahexaenoic acids, together with the production of lysophospholipids, can initiate a chain of events which may be responsible for the development of neuronal damage. Inhibitors of both cyclooxygenase and lipoxygenase pathways have been shown to reduce cerebral deficits following ischemia and trauma. These results suggest therapeutic strategies to reduce morbidity following cerebral injury using selective inhibitors of phospholipases, cyclooxygenases, and lipoxygenases, underlining the need for further investigation of their role in the development of cerebral damage.
 ...
PMID:The role of phospholipases, cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic injuries. 1451 63

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.
 ...
PMID:Treatment of elevated intracranial pressure with indomethacin: friend or foe? 1622 16

We conducted a Medline search for controlled studies evaluating currently available drugs for pharmacological neuroprotection. They had to be administered prior to transient global cerebral ischaemia without further non-pharmacological measures. We deliberately excluded focal ischaemia since its pathophysiology is substantially different from global ischaemia. A total of 45 articles conducted exclusively in laboratory animals met these criteria. The following classes of agents were evaluated: anaesthetics, GABAergic drugs, calcium-antagonists, anticonvulsives, sodium-channel blockers, potassium-channel activators, NMDA-receptor antagonists, hormones, vasodilators, dopamine- and alpha2-agonists, magnesium, xanthine oxidase- and cyclooxygenase inhibitors, a nootropic, a protease inhibitor, and immunosuppressants. Some of them were applied chronically and others administered via clinically impracticable routes. The available literature favours isoflurane, phenytoin, lamotrigine, magnesium, and potentially, nimodipine, and flunarizine. If factors like costs, toxicity, side effects, route and mode of application are considered, isoflurane and MgSO4 that have also been safely applied to patients with compromised left ventricular pump function are advantageous but their true role in human neuroprotection remains unclear.
 ...
PMID:A systematic review of currently available pharmacological neuroprotective agents as a sole intervention before anticipated or induced cardiac arrest. 1579 72

Up-regulation of cyclooxygenase (COX)-2 exacerbates neuronal injury after cerebral ischemia and contributes to neuronal cell death. The present study clarifies the function of cerebral peroxisome-proliferator-activated receptor(s) gamma (PPARgamma) in the expression of COX-2 in neurons of the rat brain after middle cerebral artery occlusion (MCAO) with reperfusion by immunohistochemistry, Western blot, and immunofluorescence staining. In peri-infarct cortical areas the PPARgamma was located in both microglia and neurons, whereas COX-2 was almost exclusively expressed in neurons. PPARgamma immunolabeling reached the peak 12 h after MCAO, whereas the number of COX-2 immunostained cells gradually rose and reached its peak at 48 h. Intracerebroventricular infusion of pioglitazone, an agonist of the PPARgamma, over a 5-day period before and 2 days after MCAO, reduced the infarct size, the expression of tumor necrosis factor alpha (TNF-alpha), COX-2, and the number of cells positively stained for COX-1 and COX-2 in the peri-infarct cortical regions. COX-2 induction was also attenuated in the ipsilateral but not in the contralateral hippocampus. In primary cortical neurons expressing the PPARgamma, pioglitazone suppressed COX-2 expression in response to oxidative stress. This protective effect was reversed after cotreatment with GW 9662, a selective antagonist of the PPARgamma, clearly demonstrating a PPARgamma-dependent mechanism. Our data provide evidence that activation of neuronal PPARgamma considerably contributes to neuroprotection by prevention of COX-2 up-regulation in vitro and in peri-infarct brain areas.
 ...
PMID:Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats. 1677 15


<< Previous 1 2 3 4 5 6 7 Next >>