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)

12-Hydroxyeicosatetraenoic acid (12-HETE) production from arachidonic acid by cerebral microvessels isolated from perfused adult murine brain was reduced by the lipoxygenase inhibitors baicalein, esculetin, gossypol, nordihydroguaiaretic acid, and quercetin. Except for quercetin and gossypol, the IC50 did not exceed 10 microM. Each inhibitor, except baicalein, also decreased microvessel prostaglandin production when present in concentrations above their IC50 value for 12-HETE. In contrast, inhibitors of the cytochrome P450 monooxygenase system, clotrimazole, metyrapone, and proadifen (SKF-525A), had little effect on microvessel 12-HETE production. Chiral phase HPLC analysis revealed that only the (S) enantiomer of 12-HETE was formed. The major microvessel metabolite of eicosapentaenoic acid co-eluted with 12-hydroxyeicosapentaenoic acid (12-HEPE) on reverse-phase HPLC and the (S) enantiomer of 12-HEPE on chiral phase HPLC. Furthermore, like 12-HETE, 12-HEPE production was blocked by lipoxygenase inhibitors. These studies demonstrate that brain microvessels produce only the (S) enantiomeric 12-hydroxy derivatives of both arachidonic acid and eicosapentaenoic acid by the action of a lipoxygenase that can be selectively inhibited by baicalein. Since arachidonic acid and eicosapentaenoic acid are available to cerebral blood vessels in certain pathological settings, these 12-hydroxy acid lipoxygenase products may mediate some of the cerebrovascular dysfunction that occurs following stroke, brain trauma, or seizures.
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PMID:Brain microvessel 12-hydroxyeicosatetraenoic acid is the (S) enantiomer and is lipoxygenase derived. 190 12

Leukotrienes and prostaglandins are formed from arachidonic acid by activation of local phospholipases in pathological conditions such as cerebral ischemia, subarachnoid hemorrhage, cerebral tumors and seizures. These mediators, especially leukotrienes have a very potent vasoconstrictor effect on cerebral arteries. Experimental studies have shown that this effect, by increasing vascular permeability causes vasogenic edema that contributes to the ischemic penumbra. In this study, after developing an experimental animal model simulating the concept of ischemic penumbra in the rat, the levels of leukotriene C and prostaglandin E2 produced in the forebrain were measured and the effects of these mediators in prolonged ischemia were investigated. The results, in the first 4 min of ischemia, showed that the arachidonic acid metabolites, particularly, leukotriene C4, reached a peak in the ischemic cerebral tissue in association with leukocyte accumulation. Later in the 15th min, significant decreases in leukotriene C4 and prostaglandin E2 levels were seen. In the 1st and 4th h, probably due to the stimulation of the relevant enzymes by free oxygen radicals in the ischemic tissue; the levels increase again, returning to control values by the 12th h. It is concluded that the use of lipoxygenase inhibitors and free radical scavengers may be helpful to limit the infarct area in the first 4 h of ischemia.
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PMID:The alterations of leukotriene C4 and prostaglandin E2 levels following different ischemic periods in rat brain tissue. 201 13

Twenty-five years ago prostaglandin (PG) F2 alpha was identified as the first cyclooxygenase-derived metabolite of polyunsaturated fatty acid metabolism in the bovine central nervous system (CNS). On the other hand, 12-hydroxyeicosatetraenoic acid (12-HETE) was the first lipoxygenase product of polyunsaturated fatty acid metabolism to be identified in rat and gerbil brain. For various cyclooxygenase products of arachidonic acid metabolism a substantial body of evidence suggests a mediator role in CNS functions such as in the regulation of local blood flow, in the induction of fever and in the prevention or limitation of seizure activity. By contrast, rather limited information is available on the possible roles of lipoxygenase products of polyunsaturated fatty acid metabolism in the CNS. This review is intended to give a survey on biosynthesis, regional distribution and possible functional importance of HETEs and leukotrienes (LT) in the CNS.
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PMID:Lipoxygenase products of polyunsaturated fatty acid metabolism in the central nervous system: biosynthesis and putative functions. 212 58

In rats kainic acid-induced seizures were accompanied by time-dependent cerebral cysteinyl-leukotriene (LT) and prostaglandin (PG) F2 alpha formation. Cysteinyl-LT were identified in the rat brain tissue extracts by their immunoreactive properties and their retention times upon reversed phase HPLC profiling. In perfused blood-free brain tissue contents of LTC4-like material were significantly elevated in cortex, hippocampus, midbrain and hypothalamus at 3 h after kainic acid injection. PGF2 alpha tissue contents were significantly elevated in all brain areas studied with very large amounts in the hippocampus and smaller amounts in the cortex. The cyclooxygenase inhibitor indomethacin significantly inhibited formation of PGF2 alpha in whole brain tissue while leaving unaffected the production of cysteinyl-LT. A dose of indomethacin which nearly completely inhibited cyclooxygenase activity as monitored by cerebral PGF2 alpha contents also tended to aggravate behavioral changes and significantly increased the mortality. Phenidone, a lipoxygenase inhibitor, significantly and dose-dependently inhibited formation of cysteinyl-LT but did not significantly affect PGF2 alpha formation. Seizure activity tended to be attenuated by a higher dose of this compound. Dexamethasone which supposedly inhibits phospholipase A2 activity by induction of lipocortins, did not significantly reduce either cysteinyl-LT or PGF2 alpha biosynthesis. Flunarizine, trifluoperazine and diazepines protected a certain percentage of animals from kainic acid-induced seizures. In rats in which seizures occurred in spite of pretreatment with these compounds, the eicosanoid formation was not inhibited but in the case of flunarizine was even found to be somewhat enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cysteinyl-leukotriene production during limbic seizures triggered by kainic acid. 235 80

Cerebral microvessels isolated from perfused, adult murine brain produce a compound with the chromatographic properties of a monohydroxyeicosatetraenoic acid when incubated with arachidonic acid or stimulated with calcium ionophore A23187. The formation of this arachidonic acid metabolite is not reduced in the presence of the cyclooxygenase inhibitor ibuprofen, but it is abolished by the lipoxygenase inhibitor nordihydroguaiaretic acid. Analysis by gas chromatography combined with chemical ionization and electron impact mass spectrometry of reduced and nonreduced derivatives of the metabolite, indicate that the compound is 12-hydroxyeicosatetraenoic acid. Fractions of isolated microvessels enriched with capillaries produce 2.1 times more 12-hydroxyeicosatetraenoic acid per microgram of protein than do fractions of microvessels enriched with arterioles. These studies confirm that brain microvessels can produce 12-hydroxyeicosatetraenoic acid and strongly suggest that cerebral endothelia are the primary source of microvessel-derived 12-hydroxyeicosatetraenoic acid. They further suggest that in brain injury, the liberation and accumulation of arachidonic acid in cerebral tissues may lead to the production of 12-hydroxyeicosatetraenoic acid within microvessels. The 12-hydroxyeicosatetraenoic acid formed in this way may mediate some of the blood-brain barrier and cerebrovascular dysfunction that occurs following stroke, brain trauma, or seizures.
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PMID:Brain microvessels produce 12-hydroxyeicosatetraenoic acid. 250 50

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

In this study the effect of the anti-inflammatory drugs indomethacin, ibuprofen, ebselen (PZ 51, 2-phenyl-1,2-benzoisoselenazol-3(2H)-one), and BW755C (3-amino-1-(m-(trifluoromethyl-phenyl)-2-pyrazoline) on kainic acid (KA)-induced behavioral and neurochemical changes in rats was investigated. Rats injected with KA (10 mg/kg s.c.) developed seizure activity with a 20% mortality within the first 4 h and neuronal degeneration in the limbic system after 3 days. Pretreatment with the cyclooxygenase inhibitor indomethacin (10 mg/kg i.p.) augmented KA-induced epileptic activity and increased the mortality in status epilepticus to 80%. Another cyclooxygenase inhibitor, ibuprofen (20 mg/kg i.p.), and the lipoxygenase inhibitor ebselen (20 mg/kg i.p.) showed no effect on KA-induced symptoms and neurochemical changes. Application of the cyclooxygenase/lipoxygenase inhibitor BW755C (40 mg/kg i.p.) reduced the severity of seizures and protected significantly from irreversible brain lesions induced by KA. The marked reduction of glutamate decarboxylase (GAD; 53.3 +/- 12.2% of control) and choline acetyltransferase (ChAT; 60.9 +/- 9.1% of control) activities in amygdala/pyriform cortex and GAD activity in hippocampus (69.4 +/- 5.6% of control) observed 3 days after KA injection was abolished by BW755C treatment. Histopathological analyses of brain tissue showed that treatment with BW755C prevented the KA-induced nerve cell degeneration, edema, hemorrhages, and tissue necrosis in amygdala/pyriform cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The cyclooxygenase and lipoxygenase inhibitor BW755C protects rats against kainic acid-induced seizures and neurotoxicity. 806 64

We report direct electron spin resonance (ESR) evidence of extracellular free radical formation during kainic acid-induced seizures obtained using in vivo brain microdialysis in freely moving rats. Saline solution containing the spin trap agent alpha-(4-pyridyl-N-oxide)-N-tert-butylnitrone was perfused through the hippocampus. ESR analysis of the dialysate samples revealed a six-line spectra, for which the hyperfine coupling constants corresponded to those of the ESR signal from the lipoxygenase/linoleic acid system, a lipid radical generating system. This result is direct evidence that lipid peroxidation of the neuronal membrane progresses during seizure activity. Increased formation of lipid radicals may participate in the cascade of reactions leading to neuronal damage in the hippocampus following kainic acid-induced seizure activity.
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PMID:Generation of lipid radicals in the hippocampal extracellular space during kainic acid-induced seizures in rats. 909 94

To determine the possible role of cyclooxygenase/lipoxygenase pathway in the regulation of proenkephalin (proENK) and prodynorphin (proDYN) gene expression induced by kainic acid (KA) in rat hippocampus, the effects of esculetin, aspirin, or phenidone on the seizure activity, proENK and proDYN mRNA levels, and the level of fos-related antigene (Fra) protein induced by KA in rat hippocampus were studied. Esculetin (5 mg/kg), aspirin (15 mg/kg), or phenidone (50 mg/kg) was administered orally five times every 12 h before the injection of KA (10 mg/kg, i.p.). Seizure activity induced by KA was significantly attenuated by phenidone. However, neither esculetin nor aspirin affected KA-induced seizure activity. The proENK and proDYN mRNA levels were markedly increased 4 and 24 h after KA administration. The elevations of both proENK and proDYN mRNA levels induced by KA were inhibited by pre-administration with phenidone, but not with esculetin and aspirin. ProENK-like protein level increased by KA administration was also inhibited by pre-administration with phenidone, but not with esculetin and aspirin. The increases of proENK and proDYN mRNA levels induced by KA were well correlated with the increases of Fra protein level. Additionally, the induction of Fra protein was inhibited by pre-administration with phenidone, but not with esculetin and aspirin. The results suggest that blockade of both cyclooxygenase and lipoxygenase pathways appears to be responsible for increases of proENK and proDYN mRNA levels induced by KA via inhibiting the induction of Fra protein in rat hippocampus.
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PMID:Phenidone blocks the increases of proenkephalin and prodynorphin gene expression induced by kainic acid in rat hippocampus: involvement of Fos-related antigene protein. 951 84

Cerebral hypoxia in the fetus and newborn results in neonatal morbidity and mortality as well as long-term sequelae such as mental retardation, seizure disorders, and cerebral palsy. In the developing brain, determinants of susceptibility to hypoxia should include the lipid composition of the brain cell membrane, the rate of lipid peroxidation, the presence of antioxidant defenses, and the development and modulation of excitatory amino acid neurotransmitter receptors such as the N-methyl-D-aspartate (NMDA) receptor, the intracellular Ca2+, and the intranuclear Ca(2+)-dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. Using electron spin resonance spectroscopy of alpha-phenyl-N-tert-butyl-nitrone spin adducts, studies from our laboratory demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. Pretreatment with MgSO4 significantly decreased the hypoxia-induced increase in free radical generation in the term fetal brain. We also showed that brain tissue hypoxia modifies the NMDA receptor ion-channel recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist-dependent Ca2+ in synaptosomes was demonstrated. The increase in intracellular Ca2+ may activate several enzymatic pathways such as phospholipase A2 and metabolism of archidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases, and activation of nitric oxide synthase. Using inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol), and nitric oxide synthase (N-nitro-L-arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane peroxidation, and cell membrane dysfunction in the hypoxic brain. Specifically, generation of nitric oxide free radicals during hypoxia may lead to nitration and nitrosylation of specific membrane proteins and receptors, resulting in dysfunction of receptors and enzymes. We conclude that hypoxia-induced modification of the NMDA receptor leading to increased intracellular Ca2+ results in free radical generation and cell injury. We suggest that during hypoxia the increased intracellular Ca2+ may lead to increased intranuclear Ca2+ concentration and alter nuclear events including transcription of specific apoptotic genes and activation of endonucleases, resulting in programmed cell death.
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PMID:Mechanisms of perinatal cerebral injury in fetus and newborn. 1081 2


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