Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific binding of [3H]hemicholinium-3 ([3H]HCh-3) and high-affinity [3H]choline uptake were measured in rats with status epilepticus induced by lithium and pilocarpine. The specific binding of [3H]HCh-3 in cortex and hippocampus from rats with status epilepticus increased to 2- to 3-fold of control while the striatal [3H]HCh-3 binding increased minimally. Scatchard analyses revealed that the observed changes resulted from an increase in Bmax of [3H]HCh-3 binding. High-affinity [3H]choline uptake remained unchanged. These results further implicate phospholipase A2 in the regulation of [3H]HCh-3 binding sites.
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PMID:[3H]hemicholinium-3 binding in rats with status epilepticus induced by lithium chloride and pilocarpine. 165 Dec 49

There has been increasing biochemical evidence since 1970 that one of the targets for convulsion-induced changes is the cell membrane of neurons. This is partly based on the observation that following seizures, there are increased levels of diacylglycerols and free fatty acids, which are products of the degradation of the major component of cell membranes, phospholipids. In addition, the production of prostaglandins from the free fatty acid, arachidonic acid, is activated after convulsions. This implies that alterations in the metabolism of lipids in brain are a major effect of seizures, and that the further study of these biochemical pathways may reveal important information pertinent to defining the basic mechanism of seizures and seizure-related pathology and may help in the development of potentially effective treatments. The effects of seizures on brain lipid metabolism and some recent studies from our laboratory are described in this chapter. Our results demonstrate that in rat brain, dexamethasone--a phospholipase A2 inhibitor--attenuates bicuculline-induced free fatty acid accumulation in a dose-dependent manner; bicuculline-induced status epilepticus does not alter the activation (synthesis of arachidonoyl coenzyme A) or acylation of fatty acids as assayed in vitro, indicating that the availability of high-energy cofactors (ATP) may be the critical factor responsible for decreased fatty acid acylation in vivo; bicuculline-induced fatty acid accumulation is localized mainly in the synaptosomal fraction of the rat brain; induction of seizures in the rat by bicuculline treatment produces a marked stimulation of lipoxygenase activity in synaptosomes that, in turn, results in a large increase in the synthesis of hydroxyeicosatetraenoic acids (HETEs). This effect is also observed following membrane depolarization with 45 mM K+, and bicuculline-induced status epilepticus stimulates the synthesis of prostaglandin D2. Possible mechanisms and consequences of alterations in specific lipids are described. Also, the possible involvement of a stimulated arachidonic acid cascade, particularly of hydroxylated products, in the release of neurotransmitters is discussed. Other aspects of the interaction between neurotransmission and the production of eicosanoids are reviewed. The metabolic pathways leading to the "lipid effect"--i.e., the production of free fatty acids, diacylglycerols, and arachidonic acid metabolites (eicosanoids)--are numerous and involve a wide variety of enzymes. The mechanism of this "lipid effect" may involve a seizure-induced overstimulation of normal lipid pathways that operate in neurotransmission.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The accumulation of free arachidonic acid, diacylglycerols, prostaglandins, and lipoxygenase reaction products in the brain during experimental epilepsy. 301 Jun 83

The present study evaluated the neurotoxic potential of phospholipase A2 (PLA2) in in vitro (primary neuronal cultures) and in vivo (EEG and behavior) rat models of CNS excitability. In vitro, PLA2 (0.0038-5.8 nM) or melittin (a potent activator of endogenous PLA2; 100-5000 nM), were highly neurotoxic, causing approximately 500 units/ml LDH release. The neurotoxic EC50s for PLA2 and melittin were 1.8 (1.4-2.3) and 848 (501-1280) nM, respectively. Neurotoxic concentrations of PLA2 stimulated neuronal release of [3H]AA. Preliminary in vitro experiments evaluating changes in neuronal calcium flux indicated that PLA2 caused transient, and melittin sustained, increases in [Ca2+]i. In vivo, PLA2 (0.5-5 micrograms i.c.v.) or melittin (2.5-20 micrograms i.c.v.) produced nonconvulsive EEG seizures, which generalized to status epilepticus. While the onset of seizure development was markedly delayed for PLA2 (1.5-4.5 h), the seizure inducing effects of melittin were evident within 3.5 +/- 0.2 min and more severe. Both PLA2 and melittin were lethal, exhibiting LD50s of 0.62 micrograms and 8.4 micrograms, respectively. Pretreatment with (+)-MK801 (5 micrograms, i.c.v.) significantly attenuated melittin, but not PLA2, in vivo neurotoxicity. PLA2 induced neuropathology in surviving rats revealed extensive cortical and subcortical injury to forebrain neurons and fibre pathways. Collectively, these results demonstrate the potent neurotoxic potential of PLA2, the delayed clinical nature of its in vivo neurotoxicity and the applicability of these model systems to future studies on mechanisms of PLA2 neurotoxicity and the development of potential PLA2 antagonists.
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PMID:Phospholipase A2-induced neurotoxicity in vitro and in vivo in rats. 865 97

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo/ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage.SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A2, which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden.
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PMID:Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy. 3046 39