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 effects of arachidonic acid and its metabolites on gamma-aminobutyric acid (GABAA) receptor function were determined in rat cerebral cortical synaptoneurosomes. Incubation of synaptoneurosomes with phospholipase A2 decreased muscimol-induced 36Cl- uptake. Arachidonic acid, the major unsaturated fatty acid released by phospholipase A2, also inhibited muscimol-induced 36Cl uptake. Similar inhibition was obtained with other unsaturated fatty acids (docosahexaenoic, oleic) but not with saturated fatty acids (stearic, palmitic). The effect of arachidonic acid on muscimol responses was inhibited by bovine serum albumin (BSA), and BSA enhanced muscimol responses directly, indicating the generation of endogenous arachidonic acid in the synaptoneurosome preparation. The generation of endogenous arachidonic acid was also indicated by the ability of 2 inhibitors of arachidonic acid metabolism, indomethacin and nordihydroguaiaretic acid (NDGA), to inhibit muscimol-induced 36Cl uptake. We conclude that arachidonic acid probably has both direct and indirect actions on muscimol responses since both enzyme inhibitors inhibited muscimol responses but did not prevent the effect of exogenously added arachidonic acid. In additional experiments, arachidonic acid metabolites generated by cyclooxygenase, prostaglandins D2, E2 and F2 alpha, each decreased muscimol responses; prostaglandins F2 alpha was the most potent inhibitor. Since the unsaturated fatty acids and their metabolites are most susceptible to peroxidation, a generating system of superoxide radicals was tested on muscimol responses. A combination of xanthine and xanthine oxidase inhibited muscimol-induced 36Cl uptake in a concentration-dependent manner. We propose that the inhibition of GABAA neurotransmission by arachidonic acid and its metabolites can lead to increased neuronal excitability. This mechanism may play an important role in the development of neuronal damage following seizures or cerebral ischemia.
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PMID:Inhibition of GABA-gated chloride channel function by arachidonic acid. 132 73

Several model systems have been used to test the hypothesis that the release of FFA in the brain is regulated by depolarization of neurons. This FFA release is likely the result of the activation of phospholipase A2. The increased neuronal activity that occurs due to synchronous depolarization during seizures causes activation of phospholipase A2. Decreasing neuronal activity by administering the anxiolytic, diazepam, appears to decrease the activity of phospholipase A2. The GABA antagonist, bicuculline, which causes depolarization by negating the hyperpolarizing tone imposed on neurons by GABA, causes FFA release in synaptosomes and in neurons in tissue culture. Likewise, the glutamate agonist, kainic acid, which depolarizes neurons by opening sodium channels, increases the activity of phospholipase A2. PC-specific phospholipase C, another enzyme important in the generation of the second messenger, DG, is also activated by depolarization. Several important questions remain to be answered. The site of FFA release, in terms of the pre-vs. postsynaptic membrane, is not clear, although the experiments with synaptosomes support the hypothesis that activation of phospholipase A2 may be an important regulator of presynaptic events. This idea has also been suggested by studies on the phenomenon of long-term potentiation, where free 20:4 or its metabolites may be involved in presynaptic facilitation of neurotransmitter release (Freeman et al., 1990; Massicotte et al., 1990; Williams et al., 1989; also see Dorman, this volume). The activation of the PI cycle and subsequent stimulation of protein kinase C may be a postsynaptic event important in the integration of inputs at the dendrite and soma or a presynaptic event involved in the modulation of neurotransmitter release (Taniyama et al., 1990; El-Fakahany et al., 1990; also see Nishizuka, this volume). Therefore the stimulation of a PC-specific phospholipase C, which is capable of generating large amounts of DG over a prolonged period of time (Exton, 1990; Martinson et al., 1990; Diaz-Laviada et al., 1990), could occur at either site. Another important question is the role of FFA and DG in affecting cell-cell signaling events, particularly with regard to ion fluxes. Modulation of an acetylcholine-linked K+ channel in the heart by FFA and their oxygenation products has been reported (Kim and Clapham, 1989). The cardiac muscarinic receptor is linked to a hyperpolarizing K+ channel via a G protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Reciprocal regulation of fatty acid release in the brain by GABA and glutamate. 135 87

The N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptor, which gates Ca(2+)-permeable ion channels, is known for its role in learning and memory formation, in the induction of long-term potentiation, and also in seizure activity and neurotoxicity. In primary cultures of cerebellar neurons, agonists of NMDA receptors induce a dose-dependent release of [3H]arachidonic acid ([3H]AA), which is potentiated by activation of the glycine-positive modulatory site and inhibited by NMDA receptor antagonists. NMDA receptor-induced [3H]AA release is inhibited by quinacrine and partially depends on the presence of extracellular calcium. The [3H]AA release is not sensitive, however, to pretreatment with pertussis or cholera toxin, which suggests a Ca(2+)-dependent activation of phospholipase A2 not employing G proteins. Pretreatment of cultures with the natural and semisynthetic sphingolipids GT1b and PKS 3, respectively, inhibits NMDA receptor-mediated [3H]AA release. We also demonstrated glutamate-evoked [3H]AA release from rat hippocampal slices, which is NMDA receptor mediated, calcium dependent and sensitive to quinacrine. Arachidonic acid and its metabolites have been shown to play a role as second messengers and to modulate neuronal activity. Moreover, they are thought to act as transsynaptic modulators in the mechanism of NMDA receptor-induced long-term potentiation in the hippocampus. Their role in ischemic brain pathology has also been postulated. Our experiments on cultured cerebellar granule cells, incubated in a Mg(2+)-free medium deprived of glucose and oxygen, demonstrated a time-dependent stimulation of [3H]AA release. This release was inhibited by antagonists of NMDA receptors and by quinacrine. Stimulation of NMDA-sensitive glutamate receptors and the subsequent calcium-mediated activation of phospholipase A2 may play a role in the in vivo release of arachidonic acid during brain ischemia. This hypothesis is supported by the observation that the enhanced level of thromboxane B2 in the gerbil brain after 5 min of global ischemia is reduced by the systemic application of either the NMDA antagonist MK-801 or the ganglioside GM1.
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PMID:NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. 138 78

The effects of kainate (KA)-induced epileptic seizures on the binding properties of hippocampal glutamate receptors, on the modulation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/quisqualate receptor by phospholipase A2 (PLA2), and on the formation of long-term potentiation (LTP) were studied in hippocampal membranes and hippocampal slices. Systemic administration of KA (10 mg/kg; 15 hr survival) produced specific changes in the binding properties of the AMPA/quisqualate receptors and its regulation. Whereas the binding of various ligands to the N-methyl-D-aspartate receptors was not modified by KA treatment, there was a significant decrease in the maximal number of binding sites for [3H]AMPA. In addition, the increase in [3H]AMPA binding elicited by PLA2 treatment of hippocampal, but not cerebellar, membranes was markedly decreased after KA injection. LTP was also substantially reduced in area CA1 of hippocampal slices from KA-treated animals. The loss of LTP was not due to changes in postsynaptic responses elicited by the bursts that trigger the potentiation effect, thus suggesting that KA treatment disrupts processes that follow N-methyl-D-aspartate receptor activation. Systemic administration of KA was associated with calpain activation as the amount of spectrin breakdown products was increased severalfold in hippocampus but not in cerebellum. Pretreatment of telencephalic membranes with calpain greatly reduced the PLA2-induced increase in [3H]AMPA binding. The results provide evidence in favor of an essential role of PLA2 in the development of LTP and suggest that the order of activation of different calcium-dependent processes is critical for producing the final changes underlying LTP.
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PMID:Modulation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/quisqualate receptors by phospholipase A2: a necessary step in long-term potentiation? 184 14

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

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

This study addresses the question of whether the cyclooxygenase inhibitors indomethacin and diclofenac and the glucocorticosteroid dexamethasone ameliorate neuronal necrosis following cerebral ischemia. In addition, since these drugs inhibit the production of prostaglandins and depress phospholipase A2 activity, respectively, the importance of free fatty acids (FFAs) on the development of ischemic neuronal damage was assessed. Neuronal damage was determined in the rat brain at 1 week following 10 min of forebrain ischemia. The cyclooxygenase inhibitors, whether given before or after ischemia, failed to alter the brain damage incurred. Animals given dexamethasone were divided into three groups and the drug was administered at a constant dosage of 2 mg/kg: (a) 2 days, 1 day, and 3 h intraperitoneally before (chronic pretreatment), (b) 3 h intraperitoneally before (acute pretreatment), and (c) 5 min intravenously and 6 h and 1 day intraperitoneally after (chronic posttreatment) induction of ischemia. Acute pretreatment did not affect the histopathological outcome. Chronic posttreatment of animals with dexamethasone ameliorated the damage inflicted on the caudate nucleus, but had no effect on other brain areas investigated. Unexpectedly, the chronic pretreatment aggravated the brain damage and caused seizures following ischemia. Histopathological data showed massive neuronal damage in these brains. The accumulation of FFA levels during ischemia was markedly suppressed, and the decrease in the energy charge was curtailed by chronic pretreatment with dexamethasone. However, brain glucose levels in control animals and lactic acid concentrations following 10 min of ischemia were significantly higher both in the cerebral cortex and in the hippocampus of dexamethasone-treated animals. These results suggest that aggravation of neuronal necrosis by chronic dexamethasone pretreatment could be ascribed to lactic acidosis due to hyperglycemia in combination with an action of dexamethasone on glucocorticoid receptors in the brain.
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PMID:Chronic dexamethasone pretreatment aggravates ischemic neuronal necrosis. 309 61

In order to characterize the in vivo action of phospholipase A2 (PLA2) on opiate receptors and opiate-induced behaviors, the effects of injections of PLA2 into the periaqueductal gray region (PAG) of the rat were assessed on free fatty acid (FFA) release, opiate-binding levels, and morphine-induced behaviors. Rats received bilateral PAG injections of 2 micrograms of PLA2 while anesthetized. One hour later, regions around the cannulae tracts in PLA2-treated rats contained over 2.5 times more FFA than saline-injected controls, and 3H-dihydromorphine binding was reduced on average more than 70%. In another series of experiments, conscious rats were given 2 micrograms of PLA2 prior to 10 micrograms of morphine through cannulae chronically implanted into the PAG. PLA2 did not significantly attenuate morphine-induced analgesia as measured by the tail-flick test to radiant heat, but did prevent the explosive motor behavior observed following morphine injections alone. PLA2 by itself did not induce analgesia, but did cause explosive motor behavior 2 hr after the injections. Neither lysophosphatidylcholine nor trypsin resulted in motor seizures following PAG injections. It was concluded that the behavioral effects of PLA2 result from the unique properties of the enzyme, rather than generalized membrane damage, and that the opioid sites and mechanisms that mediate analgesia are different from those associated with explosive motor behavior.
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PMID:The biochemical and behavioral effects of phospholipase A2 and morphine microinjections in the periaqueductal gray of the rat. 396 75

Seizures promote PLA2 activation which is selectively detectable in isolated synaptosomes by an increased free arachidonic acid (AA) and docosahexaenoic acid (DHA) pool size. During long-term potentiation, a role of AA and its oxygenated metabolites has been explored in several laboratories. We have studied another PLA2 product, platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-glycerophosphocholine) that is also generated during intense synaptic activity such as seizures. We found specific PAF binding sites in both synaptic and intracellular membranes. Using rat postnatal hippocampal synaptic pairs we have shown that PAF specifically increases the release of excitatory neurotransmitter. This effect is elicited through the synaptic binding site since an antagonist selective for this site blocks the PAF-mediated increase in excitatory neurotransmitter release. Although PAF augments evoked excitatory synaptic currents, it does not alter GABA-mediated inhibitory currents. PAF increases the frequency but not the amplitude of spontaneous excitatory synaptic minis. At present it is not known if the phospholipase A2 that accumulates free polyunsaturated fatty acids is the same as the one that gives rise to PAF. This lipid mediator effect on excitatory synaptic transmission may be a critical step in long term potentiation, synaptic plasticity, memory formation and epileptogenesis.
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PMID:The activation of phospholipase A2 and release of arachidonic acid and other lipid mediators at the synapse: the role of platelet-activating factor. 839 52

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


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