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 intracellular accumulation of PAF following cell stimulation suggests an intracellular signal transduction pathway. High affinity binding sites for PAF in microsomal membranes and displacement of PAF from these sites by structurally distinct PAF antagonists suggests the existence of an intracellular receptor. Suppression of primary genomic responses by a PAF antagonist selective for the intracellular Ca2+ and arachidonic acid metabolites, is linking the intracellular generation of PAF to immediate-early transcription. Several of the metabolites that transiently accumulate after injury may elicit beneficial effects on regenerative processes. The membrane metabolite PAF, which accumulates after seizure and ischemia, may initiate reparative processes by promoting transcriptional activation of immediate-early transcription factors. The long-term effects of these immediate-early gene transcription factors may provide a synthetic mechanism to replenish and rebuild cells following traumatic events.
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PMID:Second messengers derived from excitable membranes are involved in ischemic and seizure-related brain damage. 130 97

Each time he stood up a 60-year old man experienced myoclonic jerks, quickly followed by a syncope due to major postural hypotension. Progressive autonomic failure was associated with pyramidal, extrapyramidal and cerebellar features in a pattern characteristic of Shy-Drager disease. Myoclonic jerks suggested seizures, but no electroencephalographic epileptiform activity was found. This case together with data from the literature suggest, that such involuntary movements may result from cerebral anoxia.
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PMID:[Postural hypotension with myoclonia in multisystemic atrophy]. 143 54

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), undetectable in resting neural tissue, accumulates in brain during seizures. A hetrazepine, BN-50730, is shown here to displace [3H]PAF-specific binding from microsomal, but not from synaptosomal membranes, indicating selectivity for a high affinity intracellular binding site. Rats pretreated with BN-50730 by intraperitoneal or intracerebroventricular injection exhibited an inhibition of the electroconvulsive shock (ECS)-induced expression of c-fos and zif-268 in hippocampus. A much more pronounced, dose-dependent inhibition of ECS-induced zif-268 mRNA in hippocampus by intracerebroventricular injection of BN-50730 was observed. It is concluded that, in the hippocampus, PAF is a mediator of the expression of zif-268 and, to a lesser extent, c-fos through an intracellular specific binding site. Thus, PAF may be a messenger in signal regulated zinc-finger transcription factors, and in other immediate-early genes involved in long-term synaptic plasticity changes.
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PMID:Platelet-activating factor is a messenger in the electroconvulsive shock-induced transcriptional activation of c-fos and zif-268 in hippocampus. 814 3

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

Long-term potentiation (LTP), a model of activity-dependent synaptic plasticity and of certain forms of memory, comprises the persistent enhancement of excitatory neurotransmission that results from high-frequency activation. A presynaptic component of LTP is thought to be modulated by a retrograde messenger generated by the postsynaptic neuron. Arachidonic acid, nitric oxide, carbon monoxide and PAF have each been proposed as retrograde messengers in LTP, but arachidonic acid, unlike PAF, requires NMDA receptor activation. A PAF antagonist (BN 52021) that provides neuroprotection in ischemia-reperfusion displaces [3H] PAF bound to presynaptic membranes, blocks PAF-induced glutamate exocytosis and inhibits LTP. An antagonist selective for the intracellular PAF binding site (BN 50730) did not affect LTP, nor did BN 52021 modify NMDA currents. LTP was induced with weak synaptic stimulation coupled with postsynaptically administered enzyme resistant mcPAF. Theta-burst stimulation (10 min) after bath applications of mcPAF (1 microM) induced APV-independent LTP that was blocked by 5 microM BN 52021. When this antagonist was infused into the hippocampus before or immediately after training, it impaired memory of inhibitory avoidance training in the rat. Memory was not altered if the antagonist is infused 30 or 60 min after training. Moreover, mcPAF enhances memory on retention test performance of step-down inhibitory avoidance habituation and learning in rats. Also, memory was studied using a caudate nucleus-dependent cued water maze task. Rats received an 8 trial (30 s intertrial interval) training session in which a visible cued escape platform was located in a different quadrant of the maze of each trial. Following trial 8, the rats received a unilateral post-training intra-caudate injection of mcPAF (1 microgram/0.5 microliter), BN 52021 (0.5 microgram/0.5 microliter) or vehicle. On a retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. The retention test escape latencies of rats given mcPAF were significantly lower than those of the vehicle-injected controls, indicating a memory enhancing effect of mcPAF. Injection of mcPAF did not affect retention when administered 2 h post-training, indicating a time-dependent effect of mcPAF on memory. The latencies for animals injected with BN 52021 were significantly higher than those of the controls, indicating that antagonism of endogenous PAF impairs memory. The findings show that PAF plays a role in memory formation in a caudate-mediated cued discrimination task. Administration of BN 52021 2 h post-training had no affect on retention, indicating a time-dependent effect of endogenous PAF on memory formation. PAF, the most potent bioactive lipid known, modulates excitatory synaptic transmission, neuronal plasticity and memory. When PAF production is overstimulated as in seizures or ischemia, it becomes neurotoxic.
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PMID:Bioactive lipids in excitatory neurotransmission and neuronal plasticity. 901 70

A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test.
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PMID:Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties. 959 13

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

Lissencephaly patients are born with severe brain malformations and suffer from recurrent seizures. LIS1, the gene mutated in isolated lissencephaly patients, is a subunit of the heterotrimeric cytosolic enzyme platelet-activating factor acetylhydrolase (PAF-AH), interacts with tubulin, and affects microtubule dynamics. In order to gain molecular insights into the possible involvement of LIS1 in seizures in lissencephaly patients, we induced seizures in rats by injection of kainate. PAF-AH activity was markedly reduced as early as 30 min following initiation of seizures, making this parameter a sensitive indicator of seizure events. PAF-AH activity returned to and surpassed control values 1 week following initiation of seizures. Expression of LIS1 in the dentate gyrus changed significantly in a manner similar to that of PAF-AH enzymatic activity. This is the first correlation found between LIS1 expression and PAF-AH activity. Furthermore, the expression of the alpha2 catalytic subunit, which is the major PAF-AH catalytic subunit in rat adult brain, changed in a dramatic fashion. An additional higher-mobility LIS1 cross-reactive band was detected in samples isolated a week following seizure occurrence. This LIS1 isoform was enriched in the microtubule-associated fraction. We propose that LIS1 expression is an important factor in regulation of PAF-AH activity. We postulate that reductions in LIS1 protein levels found in lissencephaly patients may render them more susceptible to seizures.
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PMID:Platelet-activating factor (PAF) acetylhydrolase activity, LIS1 expression, and seizures. 1039 95

Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.
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PMID:Overexpression of the alpha1B-adrenergic receptor causes apoptotic neurodegeneration: multiple system atrophy. 1117 18