Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain prostanoid levels are normally low but can increase after ischemia and during inflammatory and infectious diseases. High prostanoid levels can affect brain function in several ways. In particular, prostaglandin E2 (PGE2) might exert both immunodepressive and proinflammatory actions. The present short review focuses on the regulation of prostanoid synthesis in microglial cultures and on the possible role of PGE2 in the down-regulation of microglial activation induced by lipopolysaccharide (LPS). Our studies were carried out using purified mouse or rat microglial cultures. LPS induced a dose-dependent expression of the inducible isoform of cyclooxygenase (COX-2), both in neonatal and adult microglial cultures. In the latter, the inducibility of COX-2 increased with time in culture, paralleling the acquisition of a more 'activated' microglial phenotype, and appeared to account for the time-dependent increase in the PGE2/TXB2 production ratio. The LPS-induced COX-2 expression and prostanoid production were down-regulated by potentially neurotoxic agents, such as nitric oxide (NO), the proinflammatory cytokine IFN-gamma (which acted both directly and indirectly, through its NO-inducing activity) and the HIV regulatory protein tat. On the other hand, COX-2 expression was up-regulated by the macrophage-deactivating cytokine TGF-beta 1, by exogenous PGE2 itself, which acted through EP2 receptors linked to cyclic AMP generation, and by non steroidal anti-inflammatory drugs. Interestingly, PGE2 utilized the same EP2 receptor-mediated signal transduction mechanism to down-regulate the expression of the inducible NO synthase and the production of NO. Largely, but not exclusively, through its effect on cyclic AMP, PGE2 can also: i) depress the expression of major histocompatibility complex class II antigens and of the costimulatory molecule B7-2; ii) down-regulate TNF and up-regulate IL-10 microglial production; iii) inhibit microglial IL-12 secretion. These observations, together with literature data on in vivo models of central nervous system (CNS) diseases, suggest a neuroprotective role of PGE2 in pathological conditions.
 ...
PMID:Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. 989 49

16,16-Dimethyl-PGE2 (PGE2) may interact with one of four prostaglandin type E (EP) receptors, which signal via cAMP (via EP2 or EP4 receptors) or intracellular Ca(2+) (via EP1 receptors). Furthermore, EP3 receptors have several splice variants, which may signal via cAMP or intracellular Ca(2+). We sought to determine the PGE2 receptor interactions that mediate recovery of transmucosal resistance (R) in ischemia-injured porcine ileum. Porcine ileum was subjected to 45 min of ischemia, after which the mucosa was mounted in Ussing chambers. Tissues were pretreated with indomethacin (5 microM). Treatment with the EP1, EP2, EP3, and EP4 agonist PGE2 (1 microM) elevated R twofold and significantly increased tissue cAMP content, whereas the EP2 and EP4 agonist deoxy-PGE1 (1 microM) or the EP1 and EP3 agonist sulprostone (1 microM) had no effect. However, a combination of deoxy-PGE1 and sulprostone stimulated synergistic elevations in R and tissue cAMP content. Furthermore, treatment of tissues with deoxy-PGE1 and the Ca(2+) ionophore A-23187 stimulated synergistic increases in R and cAMP, indicating that PGE2 triggers recovery of R via EP receptor cross talk mechanisms involving cAMP and intracellular Ca(2+).
 ...
PMID:PGE2 triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum. 1144 18

Prostanoids, consisting of the prostaglandins (PGs) and thromboxanes (TXs), exert various actions through activation of their specific receptors. They include the DP, EP, FP, IP, and TP receptors for PGD2, PGE2, PGF2alpha, PGI2, and TXA2, respectively. Moreover, EP receptors are classified into four subtypes, the EP1, EP2, EP3 and EP4 receptors. Using mice lacking prostanoid receptors, we intended to clarify in vivo roles of prostanoids under pathophysiological conditions of the cardiovascular system, which include ischemia-induced cardiac injury, pressure overload-induced cardiac hypertrophy, renovascular hypertension, tachycardia during systemic inflammation and thromboembolism. The results demonstrated that 1) PGI2 plays an important role in attenuating the ischemic injury and the pressure overload-induced hypertrophy of the hearts, and also contributes to the development of renovascular hypertension; 2) PGE2 plays a cardioprotective role against the ischemic injury via both the EP3 and EP4, and also participates in acute thromboembolism via the EP3; and 3) both PGF2alpha and TXA2, which have been produced during systemic inflammation, are responsible for tachycardia.
 ...
PMID:[Pathophysiological roles of the prostanoids in the cardiovascular system: studies using mice deficient in prostanoid receptors]. 1456 57

The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE2, a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMP-dependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE2 receptor subtype in brain that may provide a target for therapeutic intervention.
 ...
PMID:Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. 1471 58

Prostaglandins (PG) are produced by the enzymatic activity of cyclooxygenase (COX). PGs and COX have been implicated in the pathophysiology of excitotoxicity and neurodegeneration in the central nervous system (CNS). The PGE2 receptor EP3 is the most abundantly expressed PGE2 receptor subtype in the brain. So far, in the innate rat brain EP3 receptors have been found exclusively in neurons. The aim of this study was to investigate whether EP3 expression in the brain changes under neurodegenerative circumstances such as an acute excitotoxic lesion. Intrastriatal injection of quinolinic acid (QUIN) resulted in a loss of EP3-positive striatal neurons, while simultaneously small glial-shaped EP3-positive cells appeared. Five days after lesioning, 63% of the glial-shaped EP3-positive cells could be identified as ED-1 expressing microglial cells. This percentage increased to 82% after 10 days, suggesting that most of the EP3-positive ED-1-negative cells on day 5 may be microglia which did not yet express ED-1. ED-1-positive microglia also expressed COX-1. These experiments show for the first time that activated microglial cells in excitotoxic lesions express in vivo the PGE2 receptor EP3 and the PGE2 synthesizing enzyme COX-1. Activation of EP3 receptor downregulates cAMP formation and may counteract the upregulation of cAMP formation via EP2 receptors, which has been linked to the anti-inflammatory effects of PGs. This change in EP3-receptor expression in microglia might participate in acute or chronic microglial activation in a variety of brain diseases such as ischemia or Alzheimer's disease (AD). Investigation of the expression of different PGE2 receptor subtypes might promote a better understanding of the pathophysiology of these diseases as well as leading to a modulation of microglial activation by a more specific interference with selective EP receptors than can be achieved by inhibiting global PG synthesis by selective or non-selective COX inhibitors.
 ...
PMID:Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum. 1523 7

The mechanisms of anti-ischemic effects of PGE1 in patients with peripheral arterial occlusive disease (PAD) are probably complex and clearly not limited to a direct vasodilator action. In addition to the known effects on blood flow, viscosity, fibrinolysis and platelet aggregation, the compound also inhibits monocyte and neutrophil function, suggesting that PGE1 will also have anti-inflammatory effects. Recent research has detected additional actions of PGE1 and prostacyclin analogs which might be relevant to its clinical efficacy. This includes inhibition of expression of adhesion molecules (E-selectin, ICAM-1, and VCAM-1), release of inflammatory cytokines (TNFalpha, MCP-1), matrix components and generation and release of growth factors (CYR61, CTGF). These actions may also contribute to the long-term effects of PGE1, particularly in more advanced stages of PAD. Gene-expression experiments with chemically stable prostacyclins and PGE1 suggest that several genes in vascular smooth muscle cells and fibroblasts are modified by prostaglandins at the transcriptional level. This includes TNFalpha-induced VCAM expression in vascular smooth muscle cells which appears to be inhibited via the prostaglandin EP2 receptor as well as IL-1-induced expression of the type-1 collagen gene in fibroblasts. Thus, regulation of gene transcription by PGE1 may contribute to tissue protection in critical ischemia of the lower limbs.
 ...
PMID:Mechanisms of anti-ischemic action of prostaglandin E1 in peripheral arterial occlusive disease. 1546 Oct 62

Recent studies suggest a neuroprotective function of the PGE2 EP2 receptor in excitotoxic neuronal injury. The function of the EP2 receptor was examined at time points after excitotoxicity in an organotypic hippocampal model of N-methyl-D-aspartate (NMDA) challenge and in a permanent model of focal forebrain ischemia. Activation of EP2 led to significant neuroprotection in hippocampal slices up to 3 hours after a toxic NMDA stimulus. Genetic deletion of EP2 resulted in a marked increase in stroke volume in the permanent middle cerebral artery occlusion model. These findings support further investigation into therapeutic strategies targeting the EP2 receptor in stroke.
 ...
PMID:Neuroprotection by the PGE2 EP2 receptor in permanent focal cerebral ischemia. 1585 74

Intrauterine growth restriction (IUGR) has a multifactorial pathogenesis and is an important cause of perinatal mortality. The relationship between fetal weight and placental blood flow in an animal model of IUGR has been investigated, showing that fetal growth is regulated by placental blood flow. The aim of the present study was to determine whether ischemia-reperfusion (I/R) injury stimulates the prostaglandin E2 (PGE2) system or the vascular endothelial growth factor (VEGF) system in the placenta of a rat IUGR model. COX-2 is reported to be involved in ischemic damage in many organs. There are 4 types of PGE2 receptor (EP1, EP2, EP3 and EP4). It is well known that EP1 and EP3 is associated with vasoconstriction. In the present study, vessels were occluded in the right uterine horn on day 17 of pregnancy in rats, and the clamps were removed after 30 min of ischemia. At 24h, 48 h, and 5 days after I/R injury, the live fetuses and placentas were obtained by cesarean section. This study revealed that I/R injury caused IUGR 5 days after the treatment. COX-2 expression and EP3 receptor expression were significantly elevated at 24h after I/R injury, but VEGF mRNA expression was not altered in the placenta from the ischemic horn compared with the non-ischemic horn. These results suggested that induction of the COX-2-EP3 system in the placenta may be one of the causes of IUGR induced by uterine ischemia, because the EP3 receptor and PGE2 are well known to mediate vasoconstriction in many organs.
 ...
PMID:Elevation of both cyclooxygenase-2 and prostaglandin E2 receptor EP3 expressions in rat placenta after uterine artery ischemia-reperfusion. 1599 Jan 66

We investigated the distribution and time course of expression of two subtypes of prostaglandin E(2) (PGE(2)) receptors, EP2 and EP4, in a rat model of cerebral ischemia and ischemic tolerance. Adult male Sprague-Dawley rats were subjected to either lethal global ischemia (10 min) with or without sublethal ischemic preconditioning (3 min), or ischemia only (3 min). A short 3-min cerebral ischemia and a 3-min ischemia followed by a second lethal ischemia enhanced the expression of EP2 and EP4 receptors in CA1 pyramidal neurons of the hippocampus. In tolerance-acquired CA1 neurons, the immunoreactivities of EP2 and EP4 were upregulated after 4 h and 12 h, respectively. The immunoreactivities were most prominent at 3 days and were sustained for at least 14 days, consistent with results of immunoblotting experiments. However, immunoreactivities for these PGE(2) receptors increased in reactive glial cells in the vulnerable CA1 and hilar regions of rats subjected to lethal ischemia without ischemic preconditioning. Most of the EP2 immunoreactivity occurred in microglial cells and some astrocytes, whereas increased immunoreactivity for EP4 was found only in astrocytes. These data suggest that ischemia and the induction of ischemia tolerance have different regulatory effects on the expression of EP2 and EP4 receptors. Moreover, PGE(2) may exert its unique pathophysiological functions in relation to delayed neuronal death and ischemic tolerance induction in the rat hippocampus via specific PGE(2) receptors.
 ...
PMID:Expression of prostaglandin E2 receptor subtypes, EP2 and EP4, in the rat hippocampus after cerebral ischemia and ischemic tolerance. 1643 7

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme converting arachidonic acid to prostaglandins (PGs), which is a key messenger in traumatic brain injury- and ischemia-induced neuronal damage and in neuroinflammation. COX-2 is implicated in the pathogeneses of neurodegenerative diseases. Growing evidence implies that the contribution of COX-2 to neuropathology is associated with its involvement in synaptic alteration. Elevation or inhibition of COX-2 has been shown to enhance or suppress excitatory glutamatergic neurotransmission and long-term potentiation (LTP). These events are mainly mediated via PGE2, the predominant reaction product of COX-2, and the PGE2 subtype 2 receptor (EP2). Thus, elucidation of COX-2 in synaptic signaling may provide a mechanistic basis for designing new drugs aimed at preventing, treating or alleviating neuroinflammation-associated neurological disorders.
 ...
PMID:[COX-2 regulation of prostaglandins in synaptic signaling]. 2141 30


1 2 Next >>