Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcriptional expression of the mitogen-inducible cyclo-oxygenase (COX-2) was investigated by in situ hybridization of kainate-treated rat brains. Kainate treatment rapidly induced COX-2 mRNA in neurons throughout the forebrain which was blocked by pretreatment with MK-801 or NBQX. Transient expression of COX-2 mRNA lasting about 8 h occurred in areas that were resistant to neuronal necrosis, while COX-2 mRNA expression persisted for 24-72 h in regions that were vulnerable. These results show that seizures result in increased COX-2 expression and support the hypothesis that COX-2 could be an important factor in the pathogenesis of delayed neuronal necrosis due to kainate excitotoxicity.
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PMID:Expression of cyclo-oxygenase 2 in rat brain following kainate treatment. 775 2

Prostaglandins play important and diverse roles in the CNS. The first step in prostaglandin synthesis involves enzymatic oxidation of arachidonic acid, which is catalyzed by prostaglandin H(PGH) synthase, also referred to as cyclooxygenase. We have cloned an inducible form of this enzyme from rat brain that is nearly identical to a murine, mitogen-inducible cyclooxygenase identified from fibroblasts. Our studies indicate that this gene, here termed COX-2, is expressed throughout the forebrain in discrete populations of neurons and is enriched in the cortex and hippocampus. Neuronal expression is rapidly and transiently induced by seizures or NMDA-dependent synaptic activity. No expression is detected in glia or vascular endothelial cells. Basal expression of COX-2 appears to be regulated by natural synaptic activity in the developing and adult brain. Both basal and induced expression of COX-2 are inhibited by glucocorticoids, consistent with COX-2 regulation in peripheral tissues. Our studies indicate that COX-2 expression may be important in regulating prostaglandin signaling in brain. The marked inducibility in neurons by synaptic stimuli suggests a role in activity-dependent plasticity.
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PMID:Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. 835 45

We have characterised the induction of the mitogen-inducible form of cyclooxygenase, COX-2, in the rat cerebral cortex in response to excitotoxin injection into the nucleus basalis. This model is associated with intense stimulation of the ascending pathway to the cerebral cortex, seizure activity, and subsequent ipsilateral cortical induction of various immediate early genes (IEGs), including c-fos, c-jun, and zif268, and ornithine decarboxylase enzyme activity and mRNA, all of which processes are sensitive to treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. In this study we show that excitotoxin injection also causes a marked induction of COX-2 mRNA in ipsilateral cortex detectable at 1 h and peaking at 4 h, where COX-2 mRNA levels were 19 times those in unoperated animals. Levels of COX-2 mRNA remained significantly elevated at 24 h. The early induction of COX-2 at 1 h was also seen in sham-operated animals, but at 4 h the COX-2 mRNA level was significantly increased (4.4-fold) in animals injected with excitotoxin compared with sham-operated animals. The induction at this time point (4 h) was explored pharmacologically and found to be significantly attenuated by treatment with MK-801 (1.5 mg/kg), lamotrigine (10 mg/kg), which prevents presynaptic glutamate release by blocking voltage-sensitive Na+ channels, and the glucocorticoid dexamethasone (3 mg/kg), which has an indirect inhibitory effect on phospholipase A2 and COX activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation. 852 90

We explored the constitutive expression, maturational regulation, and relation to kainic-acid-induced apoptosis of cyclooxygenase (COX)-2 mRNA in rat brain. In adult rats, COX-2 mRNA was expressed primarily in limbic structures. Constitutive COX-2 mRNA expression increased markedly between Postnatal Day 7 (P7) and P14, reaching adult levels by P21. Despite intense KA-induced seizures, no COX-2 mRNA induction was found before P14 in any brain region examined. During response to KA-induced seizures in adult brain, COX-2 mRNA induction paralleled temporally and overlapped anatomically the appearance of cellular morphological features of apoptosis in subsets of cells of the pyramidal neuron layer of the hippocampal formation, amygdaloid complex, and pyriform cortex. While COX-2 mRNA showed KA-induced elevation in the granule cell layer of the dentate gyrus, no detectable morphological features of apoptosis were found in this region. Finally, monotypic culture of rat corticohippocampal neurons confirmed the neuronal expression of COX-2 in vitro and revealed that COX-2 is induced during response to glutamate treatment, leading to neuron death. These studies may provide novel insights into the role of COX-2 and mechanisms of action of nonsteroidal anti-inflammatory drugs in Alzheimer's disease.
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PMID:Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer's disease. 916 34

Given the potential role of mitogen-inducible cyclooxygenase (COX-2) in CNS damage, patterns of COX-2 induction were determined both before and after seizure generalization from the inferior collicular cortex into the forebrain. With midbrain seizures, no change was found in COX-2-like immunoreactivity, even at the site of seizure genesis. However, upon forebrain seizure generalization, dramatic, ipsilateral increases in COX-2-like immunoreactivity were found in layers II and II of perirhinal, entorhinal and temporal cortex, just dorsal to the perirhinal fissure, coursing from the level of the medial geniculate to the level of the inferior colliculus. No changes in COX-2-like immunoreactivity were found in contralateral cortical regions, retrosplenial cortex, dentate gyrus, subiculum, tenia tectum or inferior colliculus. Thus, initial seizure generalization into the forebrain induces COX-2 expression in a highly specific area of the cerebral cortex.
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PMID:Inferior collicular seizure generalization produces site-selective cortical induction of cyclooxygenase 2 (COX-2). 936 71

This study characterizes the differential targeting of recently synthesized immediate early gene (IEG) mRNAs to neuronal cell bodies versus dendrites and tests the hypothesis that this targeting is based on signals in the encoded proteins. A single electroconvulsive seizure induces the expression of a number of IEG mRNAs in granule cells of the dentate gyrus. Most of these IEG mRNAs remain in the cell body, including two that are characterized in the present study (the mRNAs for NGFI-A and COX-2). In contrast, the mRNA for Arc moved rapidly into dendrites at an apparent rate of approximately 300 micron/hr. Inhibiting protein synthesis with cycloheximide did not disrupt the differential mRNA sorting, demonstrating that the differential targeting of mRNAs is not dependent on translation.
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PMID:Differential intracellular sorting of immediate early gene mRNAs depends on signals in the mRNA sequence. 941 83

The systemic administration of kainate (10 mg/ml) into adult Wistar rats produces seizures and neurodegeneration. We have studied the effect of kainate administration on cPLA2 and COX-2 immunoreactivities after 3 days and 1, 2, 4 and 11 weeks. The cPLA2 immunoreactivity was increased in hippocampal neurons at 1 and 3 days after kainate injection suggesting that PLA2 may be involved in neurodegeneration. Increased cPLA2 and COX-2 immunoreactivities in astrocytes at 1, 2, 4 and 11 weeks after kainate injection indicate an adaptive astrocytic response that may be associated with gliosis.
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PMID:A light and electron microscopic study of cytoplasmic phospholipase A2 and cyclooxygenase-2 in the hippocampus after kainate lesions. 955 27

Synaptic activation leads to the formation of arachidonic acid, platelet-activating factor (PAF, 1-O-alkyl-2-acyl-sn-3-phosphocholine) and other lipid messengers. PAF is a potent bioactive phospholipid in synaptic plasticity. PAF enhances presynaptic glutamate release, is a retrograde messenger in long-term potentiation and enhances memory formation. PAF also couples synaptic events with gene expression by stimulating a FOS/JUN/AP-1 transcriptional signaling system, as well as transcription of COX-2 (inducible prostaglandin synthase). Since the COX-2 gene is also involved in synaptic plasticity, the PAF-COX-2 pathway may have physiological significance. Seizures, ischemia and other forms of brain injury promote phospholipase A2 (PLA2) overactivation, resulting in the accumulation of bioactive lipids at the synapse. PAF, under these pathological conditions, behaves as a neuronal injury messenger by at least two mechanisms: (a) enhancing glutamate release; and, (b) by sustained augmentation of COX-2 transcription. These events link PAF with neurodegeneration. The upstream intracellular pathways of signal transduction involved in neuronal or photoreceptor cell apoptosis are not well understood and involve stress sensitive kinases. PAF is a transcriptional activator of the COX-2 gene. BN 50730, a potent intracellular PAF antagonist, blocks COX-2 induction. COX-2 transcription and protein expression are upregulated in the hippocampus in kainic acid induced epileptogenesis. There is a selectively elevated induction of COX-2 (72-fold) by kainic acid preceding neuronal cell death. BN 50730 administered by i.c.v. injection blocks seizure-induced COX-2 induction. Overall, PAF is a dual modulator of neural function and becomes an endogenous neurotoxin when over produced.
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PMID:The neuromessenger platelet-activating factor in plasticity and neurodegeneration. 993 49

It has been suggested that cyclooxygenase (COX)-2 and prostaglandin play a role in epilepsy. We studied the expression of COX-2 in the hippocampus and the effect of oral administration of indomethacin, a COX inhibitor, on seizure activity in genetically seizure-susceptible El mice. COX-2 protein significantly increased in the hippocampi of El mice after epileptic seizure. Indomethacin did shorten the duration from seizure onset to full recovery in El mice although the threshold and the duration of seizure were not changed.
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PMID:Cyclooxygenase-2 expression in the hippocampus of genetically epilepsy susceptible El mice was increased after seizure. 1125 Dec 11

In the central nervous system (CNS), prostaglandin (PG) and other bioactive lipids regulate vital aspects of neural membrane biology, including protein-lipid interactions, trans-membrane and trans-synaptic signaling. However, a series of highly reactive PGs, free fatty acids, lysophospolipids, eicosanoids, platelet-activating factor, and reactive oxygen species (ROS), all generated by enhanced phospholipase A2 (PLA2) activity and arachidonic acid (AA) release, participate in cellular injury, particularly in neurodegeneration. PLA2 activation and PG production are among the earliest initiating events in triggering brain-damage pathways, which can lead to long-term neurologic deficits. Altered membrane-associated PLA2 activities have been correlated with several forms of acute and chronic brain injury, including cerebral trauma, ischemic damage, induced seizures in the brain and epilepsy, schizophrenia, and in particular, Alzheimer's disease (AD). Biochemical mechanisms of PLA2 overactivation and its pathophysiological consequences on CNS structure and function have been extensively studied using animal models and brain cells in culture triggered with PLA2 inducers, PGs, cytokines, and related lipid mediators. Moreover, the expression of both COX-2 and PLA2 appears to be strongly activated during Alzheimer's disease (AD), indicating the importance of inflammatory gene pathways as a response to brain injury. This review addresses some current ideas concerning how brain PLA2 and brain PGs are early and key players in acute neural trauma and in brain-cell damage associated with chronic neurodegenerative diseases such as AD.
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PMID:Prostaglandins and other lipid mediators in Alzheimer's disease. 1243 19


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