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)

We have characterized the induction of the mitogen-inducible form of cyclo-oxygenase, COX-2, during focal cerebral ischemia following permanent middle cerebral artery occlusion (MCAO) in the rat. Marked unilateral induction of COX-2 mRNA was detected in ischemic regions ipsilateral to the occlusion. A significant increase in COX-2 mRNA was detected in "core" and "penumbra" regions of the cerebral cortex between 4 and 24 h after occlusion; this was most marked at 4 h in the penumbra region, in which a 19-fold increase above untreated control levels was detected. A smaller but significant induction was also detected at 4 h in the caudate. A correlation was demonstrated between the extent of COX-2 mRNA induction in cortical regions at 4 h and the severity of tissue damage subsequently detected at 24 h post MCAO. MK-801 significantly attenuated the induction of COX-2 mRNA in the penumbra region at 4 h. The demonstration of COX-2 induction following experimental ischemia highlights the importance of this reaction and its products and by-products, for example, free radicals, in the tissue response to this insult.
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PMID:Cyclo-oxygenase-2 messenger RNA induction in focal cerebral ischemia. 889 13

Aspirin is a widely used and effective antithrombotic agent. Recent studies suggest that aspirin's anti-inflammatory effects are mediated via inhibition of an inducible isoform of cyclooxygenase in inflammatory cells (COX-2) and through blockade of the nuclear transcription factor, NF-kappa B. The optimal dose of aspirin for most clinical situations is 75 to 325 mg/d, but debate continues as to whether higher doses are needed to prevent cerebral ischemia. Aspirin is very effective for inhibition of platelet-mediated thrombosis at sites of vascular injury but does not reduce restenosis after coronary angioplasty or carotid endarterectomy, nor does it prevent a first stroke. Combined therapy with warfarin and aspirin has been shown to limit systemic embolic in high-risk patients with artificial heart valves, but at the cost of increased bleeding. A new aspirin derivative is currently being developed that appears to stimulate platelet nitric oxide release, inhibit thrombin-induced platelet aggregation, and lower gastric toxicity.
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PMID:Aspirin therapy for cardiovascular disease. 937 1

The evidence reviewed in this paper suggests that molecular and cellular events occurring in the late stages of cerebral ischemia (> 6 h) play an important role in the evolution of ischemic brain damage. We focused our inquiry on two inflammation-related genes iNOS and COX-2. iNOS is expressed in inflammatory and vascular cells in the post-ischemic brain. Pharmacological inhibition of iNOS activity ameliorates ischemic damage, whereas knockout mice lacking the iNOS gene are relatively protected from the consequences of cerebral ischemia. COX-2 is expressed in neurons at the infarct border and inhibition of COX-2 activity improves ischemic brain damage. These results indicate that expression of iNOS and COX-2 contributes to the late stages of ischemic brain damage. Consequently, inhibition of iNOS and COX-2 could be a valuable addition to treatment strategies for ischemic stroke. Most efforts to date have targeted the acute phase of cerebral ischemia. Inhibition of iNOS or COX-2 offers the prospect of treatments directed to the late stages of the damage. However, additional preclinical studies would be necessary before these new treatment strategies can be tested in human stroke.
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PMID:Molecular pathology of cerebral ischemia: delayed gene expression and strategies for neuroprotection. 961 75

Cyclooxygenase (COX) catalyzes synthesis of prostanoids after liberation of arachidonic acid, an important biochemical sequela of cerebral ischemia that aggravates brain injury. We investigated expression of inducible COX-2 in infarcted human brains (symptom duration, 15 hours to 18 days) and found that COX-2 protein was present in both neuronal and glial cells throughout the brain in accord with infarct topography and duration. These results emphasize the global yet temporally regulated nature of COX-2 induction during focal ischemia in humans, clearly different from the circumscribed acute expression reported in experimental animal models. We speculate that early induction of COX-2 may fuel tissue damage through prostanoids and free radicals, and delayed induction in remote brain areas may promote reconstitutive processes in the face of tissue scarring and remodeling of the surviving neural networks.
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PMID:Cyclooxygenase-2 is induced globally in infarcted human brain. 962 43

Cyclooxygenase isozymes (COX-1 and COX-2) are found to be constitutively expressed in brain, with neuronal expression of COX-2 being rapidly induced after numerous insults, including cerebral ischemia. Because overactivation of N-methyl-D-aspartate (NMDA) receptors has been implicated in the cell loss associated with ischemia, we characterized the expression of the COX isozymes in murine mixed cortical cell cultures and used isozyme-selective inhibitors to determine their relative contribution to NMDA receptor-stimulated prostaglandin (PG) production and excitotoxic neuronal cell death. Immunocytochemical analysis of mixed cortical cell cultures revealed that COX-2 expression was restricted to neurons, whereas COX-1 was expressed in both neurons and astrocytes. Brief exposure to NMDA (5 min; 100 microM) elicited a time-dependent accumulation of PGs in the culture medium that preceded neuronal cell death and correlated with the induction of COX-2 mRNA. COX-1 expression remained unchanged. Flurbiprofen, a nonselective COX-1/COX-2 inhibitor, blocked NMDA-stimulated PG production and attenuated neuronal death in a concentration-dependent manner. Similar results were obtained with the specific COX-2 inhibitor NS-398 (10-30 microM) but not with the selective COX-1 inhibitor valeryl salicylate (10-300 microM). Inhibition of total constitutive COX activity with aspirin (100 microM, 1.5 h) before NMDA exposure did not prevent subsequent NMDA-mediated neuronal cell death. However, neuronal injury in aspirin-pretreated cultures was attenuated by flurbiprofen administration after NMDA exposure. Finally, the protection afforded by COX-2 inhibition was specific for NMDA because neither flurbiprofen nor NS-398 protected neurons against kainate-mediated neurotoxicity. Together, these results support the conclusion that newly synthesized COX-2 protein contributes to NMDA-induced neuronal injury.
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PMID:Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. 1077 11

Previous studies have demonstrated that cerebral ischemia stimulated the increased abundance of immunoreactive PGHS-2, but not PGHS-1, in brain tissue homogenates in late-gestation fetal sheep. The goal of the present study was to detect PGHS-1 and PGHS-2 mRNA in specific fetal brain regions, and to semi-quantitatively detect changes in the abundance of the respective mRNA's in response to cerebral hypoperfusion. Fetal brain tissues were collected from control fetuses and from fetuses 30 min and 2 h after cerebral hypoperfusion (produced by brachiocephalic occlusion). Messenger RNA was studied by RT-PCR, and expressed semiquantitatively as a ratio of PGHS-1 or PGHS-2 mRNA abundance to beta-actin mRNA abundance. PGHS-2 mRNA was only detected in the fetal hippocampus, hypothalamus, and brain stem and it was induced by cerebral hypoperfusion. In contrast, PGHS-1 mRNA was detected in all fetal brain tissues but was not induced. We conclude that cerebral hypoperfusion induced PGHS-2 gene expression in hippocampus, hypothalamus, and brainstem, and we speculate that the increased abundance of the enzyme is likely to be important for control of reflex responses to hypotension in the fetus.
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PMID:Induction of PGHS-2 mRNA in response to cerebral hypoperfusion in late-gestation fetal sheep. 1093 10

Prostaglandin H synthase (PGHS) is a rate-limiting enzyme in the production of prostaglandins and thromboxane, which are important regulators of vascular function. Under normal physiological conditions, PGHS-dependent vasodilators (such as prostacyclin) modulate vascular tone. However, PGHS-dependent vasoconstriction (mediated by thromboxane and/or its immediate precursor, PGH(2)) predominates in some vascular pathologies (eg, systemic hypertension, diabetes, cerebral ischemia, and aging). This review will discuss the role of PGHS-dependent modulation of vascular function in a number of vascular beds (systemic, pulmonary, cerebral, and uterine) with an emphasis on vascular pathophysiology. Moreover, the specific contributions of the different isoforms (PGHS-1 and PGHS-2) are discussed. Understanding the role of PGHS in vascular function is of particular importance because they are the targets of the commonly used nonsteroidal antiinflammatory drugs (NSAIDs), which include aspirin and ibuprofen. Importantly, with the advent of specific PGHS-2 inhibitors for treatment of conditions such as chronic inflammatory disease, it is an opportune time to review the data regarding PGHS-dependent modulation of vascular function.
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PMID:Prostaglandin H synthase and vascular function. 1159 87

This study was designed to investigate the time lag of effect of NS398, selective COX-2 inhibitor, on infarct volume and neurologic deficits in mice with experimentally-induced cerebral ischemia. Our results showed that the beneficial effect of NS398 on reduction of infarct volume and improvement of neurologic deficits were noted more than 24 h after the injection regardless of the administration timing.
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PMID:Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. 1250 83

Prostaglandins (PGs) originate from the degradation of membranar arachidonic acid by cyclooxygenases (COX-1 and COX-2). The prostaglandin actions in the nervous system are multiple and have been suggested to play a significant role in neurodegenerative disorders. Some PGs have been reported to be toxic and, interestingly, the cyclopentenone PGs have been reported to be cytoprotective at low concentration and could play a significant role in neuronal plasticity. They have been shown to be protective against oxidative stress injury; however, the cellular mechanisms of protection afforded by these PGs are still unclear. It is postulated that the cascade leading to neuronal cell death in acute and chronic neurodegenerative conditions, such as cerebral ischemia and Alzheimer's disease, would be mediated by free radical damage. We tested the hypothesis that the neuroprotective action of cyclopentanone could be caused partially by an induction of heme oxygenase 1 (HO-1). We and others have previously reported that modulation of HO total activity may well have direct physiological implications in stroke and in Alzheimer's disease. HO acts as an antioxidant enzyme by degrading heme into iron, carbon monoxide, and biliverdin that is rapidly converted into bilirubin. Using mouse primary neuronal cultures, we demonstrated that PGs of the J series induce HO-1 in a dose-dependent manner (0, 0.5, 5, 10, 20, and 50 micro g/ml) and that PGJ(2) and dPGJ(2) were more potent than PGA(2), dPGA(2), PGD(2), and PGE(2). No significant effects were observed for HO-2 and actin expression. In regard to HO-3 expression found in rat, with its protein deducted sequence highly homologous to HO-2, no detection was observed in HO-2(-/-) mice, suggesting that HO-3 protein would not be present in mouse brain. We are proposing that several of the protective effects of PGJ(2) could be mediated through beneficial actions of heme degradation and its metabolites. The design of new mimetics based on the cyclopentenone structure could be very useful as neuroprotective agents and be tested in animal models of stroke and Alzheimer's disease.
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PMID:Regulation of heme oxygenase expression by cyclopentenone prostaglandins. 1270 76

Intermittent hypoxia (IH) during sleep, a critical feature of sleep apnea, induces significant neurobehavioral deficits in the rat. Cyclooxygenase (COX)-2 is induced during stressful conditions such as cerebral ischemia and could play an important role in IH-induced learning deficits. We therefore examined COX-1 and COX-2 genes and COX-2 protein expression and activity (prostaglandin E2 [PGE2] tissue concentration) in cortical regions of rat brain after exposure to either IH (10% O2 alternating with 21% O2 every 90 seconds) or sustained hypoxia (10% O2). In addition, the effect of selective COX-2 inhibition with NS-398 on IH-induced neurobehavioral deficits was assessed. IH was associated with increased COX-2 protein and gene expression from Day 1 to Day 14 of exposure. No changes were found in COX-1 gene expression after exposure to hypoxia. IH-induced COX-2 upregulation was associated with increased PGE2 tissue levels, neuronal apoptosis, and neurobehavioral deficits. Administration of NS-398 abolished IH-induced apoptosis and PGE2 increases without modifying COX-2 mRNA expression. Furthermore, NS-398 treatment attenuated IH-induced deficits in the acquisition and retention of a spatial task in the water maze. We conclude that IH induces upregulation and activation of COX-2 in rat cortex and that COX-2 may play a role in IH-mediated neurobehavioral deficits.
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PMID:Cyclooxygenase 2 and intermittent hypoxia-induced spatial deficits in the rat. 1277 26


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