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)

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, COX-2 has been shown to be upregulated by convulsive nerve activity. Various earlier studies have given conflicting reports on the effect of COX inhibitors on seizures. This study investigates the effect of pretreatment with celecoxib alone, or in combination with phenytoin, on electroshock-induced convulsions. Both percentage protection (i.e., the percentage of animals not showing Tonic Hind Limb Extension [THLE] when a fixed dose of current is administered) and CC50 (i.e., the threshold current inducing THLE in 50%) was determined using a technoconvulsometer. Celecoxib and phenytoin were administered 1 and 2 h, respectively, prior to the experiments. When administered alone, celecoxib showed an increase in percentage protection at increasing doses, with maximum percentage protection (66.6%) occurring at a 30 mg/kg-1 dose. The ED25 value of celecoxib was calculated to be 8.03 mg/kg-1. The CC50 values for the treatment groups were significantly increased compared with the control group (CC50 values for control, celecoxib 10 mg/kg-1, celecoxib 20 mg/kg-1 and celecoxib 30 mg/kg-1, respectively, were 36.3, 49.12, 100.3 and 125.02 mA). An increase in percentage protection was noted when celecoxib 8.03 mg/kg-1 was coadministered with phenytoin 6 mg/kg-1 (66.6% with the combination vs. 16.6% when administered individually). A significant increase was noted in the CC50 value in a combination regimen (CC50 = 79.06) compared with either drug administered alone (CC50 = 49.12 with celecoxib 8.03 mg/kg-1 and 62.06 with phenytoin 6 mg/kg-1). This study may stimulate further interest in the role of COX-2 inhibitors in the modulation of seizure activity.
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PMID:Anticonvulsant action of celecoxib (alone and in combination with sub-threshold dose of phenytoin) in electroshock induced convulsion. 1273 53

Brain cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis, is rapidly and transiently induced by convulsions in hippocampal and cortical neurons. Therefore, we examined the effects of COX-2 on the 'rapid kindling' development in COX-2 knockout mice and in mice treated with nimesulide, a COX-2-selective inhibitor. Rapid kindling development was examined based on the incidence of hippocampal EEG seizures and behavioral seizures following repetitive electrical stimulation of the perforant path at an interval of 40 s, and on the total afterdischarge (AD) duration induced by 50 stimulations. In addition, we measured COX-2 mRNA expression by in situ hybridization and PGE2 concentration using enzyme immunoassay following rapid kindling stimulation. The results suggested that brain COX-2 mRNA levels were markedly increased in the hippocampal neurons and the concentration of PGE2 was elevated significantly, and that the incidence of AD and seizure behavior induction and the total AD duration were significantly decreased under conditions of COX-2 deficiency. Therefore, we concluded that inducible COX-2 facilitates the recurrence of hippocampal seizures.
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PMID:Inducible brain COX-2 facilitates the recurrence of hippocampal seizures in mouse rapid kindling. 1451 62

Electroconvulsive seizure therapy (ECS) is a clinically proven treatment for depression and is often effective even in patients resistant to chemical antidepressants. However, the molecular mechanisms underlying the therapeutic efficacy of ECS are not fully understood. One theory that has gained attention is that ECS and other antidepressants increase the expression of select neurotrophic factors that could reverse or block the atrophy and cell loss resulting from stress and depression. To further address this topic, we examined the expression of other neurotrophic-growth factors and related signaling pathways in the hippocampus in response to ECS using a custom growth factor microarray chip. We report the regulation of several genes that are involved in growth factor and angiogenic-endothelial signaling, including neuritin, stem cell factor, vascular endothelial growth factor (VEGF), VGF (nonacronymic), cyclooxygenase-2, and tissue inhibitor of matrix metalloproteinase-1. Some of these, as well as other growth factors identified, including VEGF, basic fibroblast growth factor, and brain-derived neurotrophic factor, have roles in mediating neurogenesis and cell proliferation in the adult brain. We also examined gene expression in the choroid plexus and found several growth factors that are enriched in this vascular tissue as well as regulated by ECS. These data suggest that an amplification of growth factor signaling combined with angiogenic mechanisms could have an important role in the molecular action of ECS. This study demonstrates the applicability of custom-focused microarray technology in addressing hypothesis-driven questions regarding the action of antidepressants.
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PMID:Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. 1464 77

Protoplasmic astrocytomas are rare gliomas whose nosology remains enigmatic. This study retrospectively reviews the clinicopathologic features of eight tumors, including evaluation of these neoplasms for chromosome 1p loss, Bcl-2 immunoreactivity, and cyclooxygenase-2 immunoreactivity. Patients ranged in age from 3 to 49 years (median 25.5 years) and included six males and two females. All patients presented with a period of seizures (median duration of period, 54 months) before surgery. Five tumors were either totally or partially based in the temporal lobe. In the six patients for whom follow-up information was available, there was no evidence of recurrence at last known follow-up (range 5 to 171 months; median 134 months). Histologically, all tumors were marked by a proliferation of cells with rounded to oval nuclear contours and a paucity of cytoplasmic processes, arranged against a microcystic background. A rare mitotic figure was observed in only one tumor. Vascular proliferative changes and necrosis were not seen in any of the tumors. None of the tumors showed allelic loss on chromosome 1p by fluorescent in situ hybridization (FISH) analysis. Cyclooxygenase-2 (an enzyme involved in the conversion of arachidonate to prostaglandin H2 and G2) immunoreactivity was observed in two tumors. Bcl-2 (an anti-apoptotic protein) immunoreactivity was also confined to two tumors. In conclusion, protoplasmic astrocytomas appear to be low-grade neoplasms, as evidenced by their relatively benign clinical course. Although they histologically resemble microcystic oligodendrogliomas, none of the tumors showed allelic loss on chromosome 1p, a finding that has been described in the majority of low-grade oligodendrogliomas. This suggests that the protoplasmic astrocytoma is a distinct entity from low-grade oligodendroglioma. Similar to other low-grade astrocytomas, only a minority of tumors show evidence of cyclooxygenase-2 and Bcl-2 immunoreactivity.
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PMID:Cyclooxygenase-2, Bcl-2, and chromosome 1p analysis in protoplasmic astrocytomas. 1501 87

In the present study, the expression of pro-inflammatory transcripts was assessed across the brain of mice having undertaken pilocarpine-induced seizures. Pilocarpine-induced marked neurodegeneration and demyelination in multiple regions of the forebrain. The pattern of genes encoding toll-like receptor type 2 (TLR2) and I kappa B alpha (index of NF-kappa B activation) was associated with the neurodegenerating areas, but this was not the case for the mRNA encoding other inflammatory proteins. Scattered tumor necrosis factor-alpha (TNF-alpha)-expressing cells were found across brain, whereas the signals for monocyte-chemoattractant protein-1 and microsomal prostaglandin mPGES E synthase were robust in thalamus and cerebral cortex and weak in the hippocampus and amygdala. TLR2 and TNF-alpha transcripts were expressed mainly in microglia/macrophages. Cyclooxygenase-2 was induced specifically in the hippocampus and piriform cortex. A low increase in interleukin-12 mRNA was detected in the brain, but the signal for interferon gamma (IFN-gamma) remained undetectable. Although pro-inflammatory markers were induced in a different manner across the CNS, their patterns were not characteristic of those caused by other inflammatory challenges, such as endotoxin. These data suggest a different mechanism involved in regulating the innate immune reaction in response to seizures and could have direct implications for the neuropathology associated with epilepsy.
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PMID:Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. 1647 16

To better understand the role of inflammatory responses in temporal lobe epilepsy, we characterized Interleukin1-beta (IL1-beta), Nuclear Factor-kappaB (NF-kappaB), and Cyclooxygenase-2 (COX-2) expression together with neurodegeneration in the rat lithium-pilocarpine model. The immunohistochemical expression of IL1-beta, NF-kappaB, and COX-2 started by 12 h post-injection, persisted for 24 h (status epilepticus period), and returned to basal levels by 3 and 6 days (latent period). The regional distribution of IL1-beta, NF-kappaB, and COX-2 occurred mainly in structures prone to develop neuronal damage. Using double-staining protocols, we detected IL1-beta expression in glial cells, COX-2 expression in neurons, and NF-kappaB in both cell types. The presence of Fluoro-Jade-B-positive degenerating neurons was associated with IL1-beta, NF-kappaB, and COX-2 proteins expression during status epilepticus but not during the latent period while neurons were still degenerating. These data suggest that seizure-related IL1-beta, NF-kappaB, and COX-2 expression may contribute to the pathophysiology of epilepsy by inducing neuronal death and astrocytic activation.
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PMID:Temporal patterns of the cerebral inflammatory response in the rat lithium-pilocarpine model of temporal lobe epilepsy. 1557 75

Cyclooxygenase-2 (COX-2) is the predominant isoform of cyclooxygenase in brain. COX-2 activity produces oxidative stress and results in the production of prostaglandins that have many injurious effects. COX-2 transcription is induced by synaptic activity; therefore, COX-2 activity could contribute to epileptic neuronal injury. To address this hypothesis, COX-2 protein expression and PGE2 production were determined after kainate-induced limbic seizures in rats. The effects of a specific COX-2 inhibitor, SC58125, on neuronal survival and PGE2 concentration in the hippocampus were also determined. COX-2 protein expression was increased in CA3, dentate gyrus, and cortex at 18-24 h after seizures. Hippocampal PGE2 levels were increased at 24 h following seizures, and treatment with the selective COX-2 inhibitor SC58125, 3 mg/kg p.o., attenuated the increase in PGE2 concentration. The survival of CA3 neurons at 7 days after seizures was increased in rats treated with SC58125 compared to vehicle controls. There was no effect of drug treatment on body or brain temperature, nor on the duration or rate of Type IV EEG activity. These results suggest that COX-2 activity can contribute to epileptic neuronal injury and that selective COX-2 inhibitors are neuroprotective.
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PMID:Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. 1597 90

We investigated whether prostaglandins (PGs), proinflammatory mediators implicated in excitatory activity, are involved in Shigella-related seizures. Pretreatment with S. dysenteriae sonicate (2LD(50)) enhanced mice response to pentylenetetrazole-induced seizures, without increase of brain concentrations of PGE(2), PGD(2) or PGF(2alpha). Preinjection of NS-398, an inhibitor of cyclooxygenase-2, before treatment with Shigella sonicate, had no effect on seizures. The anticonvulsive PGD(2) increased after injection of 8 LD(50) of Shigella sonicate, which did not enhance seizures (32 pg/mg vs 26 pg/ml, p=0.0063). The findings indicate that PGs are not involved in the enhanced seizure response after exposure to Shigella. However, induction of PGD(2) may play an inhibitory role.
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PMID:Involvement of prostaglandins in an animal model of Shigella-related seizures. 1613 98

Glutamate release activates signaling pathways important for learning and memory, and over-stimulation of these pathways during seizures leads to aberrant synaptic plasticity associated with hyper-excitable, seizure-prone states. Seizures induce rapid accumulation of membrane lipid-derived fatty acids at the synapses which, evidence suggests, regulate maladaptive connectivity. Here we give an overview of the significance of the arachidonyl- and inositol-derived messengers, prostaglandins (PGs) and diacylglycerol (DAG), in experimental models of epilepsy. We use studies conducted in our own laboratory to highlight the pro-epileptogenic role of cyclooxygenase-2 (COX-2) and its products, the PGs, and we discuss the possible mechanisms by which PGs may regulate membrane excitability and synaptic transmission at the cellular level. We conclude with a discussion of AA-DAG signaling in synaptic plasticity and seizure susceptibility with an emphasis on recent studies in our laboratory involving DAG kinase epsilon (DGKepsilon)-knockout mice.
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PMID:Lipid signaling in experimental epilepsy. 1618 19

Kainate-induced seizures result in hippocampal neurodegeneration and spatial learning deficits in rodents. Previous studies show that rofecoxib, a selective cyclooxygenase-2 inhibitor, protects against kainate-induced hippocampal cell death 3 days after seizures. Our aim was to determine whether rofecoxib attenuates visuospatial learning deficits and late neuronal death after kainate-induced seizures. Seizures were induced in Sprague-Dawley rats with kainic acid (10 mg/kg, i.p.). Eight hours later, animals received rofecoxib (10 mg/kg; n = 15) or vehicle (dimethylsulfoxide, n = 11). Animals were then treated daily for additional 2 or 9 days. Visuospatial learning was assessed in the Morris water maze (MWM) on days 5-9 after seizures. Seizure animals learned the MWM task significantly slower than non-seizure controls, but seizure animals showed higher swim speed (P < 0.05). Seizure animals receiving rofecoxib for 2 days showed no significant improvement in acquisition of the task compared to the vehicle group, even though mean latencies in the rofecoxib group were shorter from the third trial day onwards. This tendency was lost when rofecoxib was given for 9 days. TdT-mediated dUTP nick end labelling showed cell death in limbic structures 9 days after seizures. The time course of kainate-induced hippocampal cell death might be delayed by rofecoxib treatment, as the attenuation of cell death observed 3 days after seizures was no longer present after 9 days. We conclude that even though increasing evidence points to an injurious role of cyclooxygenase-2 products in acute brain injury processes, rofecoxib treatment failed to attenuate seizure-induced visuospatial learning deficits and the late phase of hippocampal neurodegeneration.
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PMID:Assessment of the effects of the cyclooxygenase-2 inhibitor rofecoxib on visuospatial learning and hippocampal cell death following kainate-induced seizures in the rat. 1626 51


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