UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excitatory amino acids (EAAs) are critically involved in the initiation and propagation of seizures. N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors appear to be of special interest in this regard. Besides receptor binding by antagonists, the function of glutamatergic synapses can be altered via autoreceptor-mediated mechanisms or by receptor desensitisation. Therefore, the effect of AMPA (1, 10 or 100 pmol per animal, intracerebroventricular injection) was tested on acutely induced pentylenetetrazol (PTZ) seizures. The lowest dose exerted clear anticonvulsant effects. Furthermore, 1 and 10 pmol AMPA were tested for their efficacy to suppress PTZ kindling. The lower dose reduced seizure severity significantly but 10 pmol AMPA was ineffective. In reaction to a test dose of PTZ, the kindled groups pretreated with AMPA reached seizure scores similar to saline-pretreated kindled rats, suggesting that the kindled state was reached. In a further experiment, we tested the effect of cyclothiazide (CYC, which blocks AMPA receptor desensitisation) on the 1 pmol AMPA-mediated anticonvulsant effect. The AMPA response was not altered. These results suggest that autoreceptor-mediated mechanisms rather than desensitisation might contribute to the anticonvulsant effect found.
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PMID:Low doses of AMPA exert anticonvulsant effects on pentylenetetrazol-kindled seizures. 1170 Dec 15

The perinatal age window is characterized by vulnerability to age-specific patterns of injury. Hypoxia/ischemia occurs in a number of settings both in term and preterm neonates, yet the patterns of response appear dependent upon the age of the infant. In the preterm neonate, hypoxic/ischemic insults result in selective white matter injury, termed periventricular leukomalacia (PVL), with little or no cortical pathology. However, in term babies, hypoxic encephalopathy is the most common cause of seizures, and also can result in cortical infarction. Extracellular glutamate accumulates in the setting of hypoxia/ischemia, and excess activation of glutamate receptors has been implicated in hypoxic/ischemic cellular death. Glutamate receptors are developmentally regulated in both neuronal and glial cells within the brain. Using rodent models, we have shown that hypoxia/ischemia results in selective white matter injury in postnatal day (P) seven rat pups, while hypoxia causes seizures in P10-12 rats, but not at younger or older ages. We have further demonstrated that antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor subtype block white matter injury at P7 and seizures at P10. We have shown that AMPA receptors are relatively overexpressed in oligodendrocytes (OLs) within white matter at P7 and in neurons in cortex and hippocampus at P10. Hence maturational patterns of glutamate receptor expression correlate with age-specific regional susceptibility to injury to hypoxia/ischemia. While glutamate receptor blockade represents a rational strategy in the treatment of perinatal hypoxic/ischemic brain injury, it is unclear what role variations in their expression play in normal development and plasticity. Further investigation of patterns of glutamate receptor subunit expression in human brain and in experimental animal models is necessary to determine potential age specific strategies as well as adverse effects.
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PMID:The role of glutamate receptor maturation in perinatal seizures and brain injury. 1217 72

Knowledge of the neural mechanisms underlying the development of benzodiazepine (BZ) dependence remains incomplete. The gamma-aminobutyric acid (GABA(A)) receptor, being the main locus of BZ action, has been the main focus to date in studies performed to elucidate the neuroadaptive processes underlying BZ tolerance and withdrawal in preclinical studies. Despite this intensive effort, however, no clear consensus has been reached on the exact contribution of neuroadaptive processes at the level of the GABA(A) receptor to the development of BZ tolerance and withdrawal. It is likely that changes at the level of this receptor are inadequate in themselves as an explanation of these neuroadaptive processes and that neuroadaptations in other receptor systems are important in the development of BZ dependence. In particular, it has been hypothesised that as part of compensatory mechanisms to diazepam-induced chronic enhancement of GABAergic inhibition, excitatory mechanisms (including the glutamatergic system) become more sensitive [Behav. Pharmacol. 6 (1995) 425], conceivably contributing to BZ tolerance development and/or expression of withdrawal symptoms on cessation of treatment, including increased anxiety and seizure activity. Glutamate is a key candidate for changes in excitatory transmission mechanisms and BZ dependence, (1) since there are defined neuroanatomical relationships between glutamatergic and GABAergic neurons in the CNS and (2) because of the pivotal role of glutamatergic neurotransmission in mediating many forms of synaptic plasticity in the CNS, such as long-term potentiation and kindling events. Thus, it is highly possible that glutamatergic processes are also involved in the neuroadaptive processes in drug dependence, which can conceivably be considered as a form of synaptic plasticity. This review provides an overview of studies investigating changes in the GABAergic and glutamatergic systems in the brain associated with BZ dependence, with particular attention to the possible differential involvement of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in these processes.
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PMID:Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. 1272 68

Rasmussen's encephalitis is a childhood disease resulting in intractable seizures associated with hippocampal and neocortical inflammation. An autoantibody against the GluR3 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors is implicated in the pathophysiology of Rasmussen's encephalitis. AMPA receptors mediate excitatory neurotransmission in the brain and contain combinations of four subunits (GluR1-4). Although the distributions of GluR1, GluR2, and GluR4 are known in some detail, the cellular distribution of GluR3 in the mammalian brain remains to be described. We developed and characterized a GluR3-specific monoclonal antibody and quantified the cellular distribution of GluR3 in CA1 of the rat hippocampus. GluR3 immunoreactivity was detected in all pyramidal neurons and astrocytes and in most interneurons. We quantified the intensity of GluR3 immunoreactivity in interneuron subtypes defined by their calcium-binding protein content. GluR3 immunofluorescence, but not GluR1 or GluR2 immunofluorescence, was significantly elevated in somata of parvalbumin-containing interneurons compared to pyramidal somata. Strikingly, increased GluR3 immunofluorescence was not observed in calbindin- and calretinin-containing interneurons. Furthermore, 24% of parvalbumin-containing interneurons could be distinguished from surrounding neurons based on their intense GluR3 immunoreactivity. This subpopulation had significantly elevated GluR3 immunoreactivity compared to the rest of parvalbumin-containing interneurons. Electron microscopy revealed enriched GluR3 immunoreactivity in parvalbumin-containing perikarya at cytoplasmic and postsynaptic sites. Parvalbumin-containing interneurons, potent inhibitors of cortical pyramidal neurons, are vulnerable in the brains of epileptic patients. Our findings suggest that the somata of these interneurons are enriched in GluR3, which may render them vulnerable to pathological states such as epilepsy and Rasmussen's encephalitis.
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PMID:Glutamate receptor subunit 3 (GluR3) immunoreactivity delineates a subpopulation of parvalbumin-containing interneurons in the rat hippocampus. 1276 21

In the present study, the susceptibility of the mdx mouse, a dystrophin-deficient genetic model of Duchenne muscular dystrophy (DMD), to various convulsant stimuli has been evaluated and compared to three related mice strains (C57BL/6J, C57BL/10 and DBA/2 mice). Animals were treated with chemical convulsants impairing gamma-aminobutyric acid (GABA) neurotransmission [pentylenetetrazole, picrotoxin, bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), methyl-beta-carboline-3-carboxylate (beta-CCM)], enhancing glutamatergic neurotransmission [N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainic acid (KA)] or a K(+) channel blocker (4-aminopyridine). Occurrence of clonic and/or tonic seizures was evaluated to observe possible differences in seizure susceptibility. In addition, all strains of mice were repeatedly treated with a subconvulsant dose of pentylenetetrazole (PTZ) for possible differences in kindling development. The mdx mice exhibited no difference in seizure susceptibility for all convulsant drugs with the exception of a significantly lower sensitivity to AMPA and KA than the other mice strains. This study demonstrates that mdx mice possess a decreased susceptibility to some convulsant stimuli. However, mdx mice showed an enhanced seizure severity and a shorter latency in the development of chemical kindling produced by administration of PTZ. The present data suggests that the dystrophin deficiency in mdx mice affects the pathophysiology and pharmacology of acute and chronic epileptic seizures in an opposite manner.
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PMID:Seizure susceptibility to various convulsant stimuli in dystrophin-deficient mdx mice. 1528 97

Dopamine (DA) and other receptors physically interact in the plasma membrane of basal ganglia neurons forming receptor mosaics (RMs). Two types of RMs are discussed, homomers formed only by DA-receptor (DA-R) subtypes and heteromers formed by DA-R associated with other receptors, such as A2A, A1, mGluR5, N-methyl-D-aspartate (NMDA), gamma-aminobutryic acid (GABA)-A, and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. By being part of horizontal molecular networks, RMs tune multiple effector systems already at membrane level, such as G protein regulated inward rectifying potassium channels and dopamine transporter activity. Also, ligand-gated ion channels such as GABA-A and NMDA receptors are modulated by DA-R, e.g., in the striatal GABA output neurons through the formation of heteromeric complexes with these receptors. Thus, intramembrane DA-R-receptor interactions play an important role in the information handling in the basal ganglia. On this basis, functional implications of DA RM in physiological and pathological conditions are discussed. The effects of temperature on RM are discussed not only because receptor-decoding mechanisms are temperature sensitive, but also in view of the suggestion that possible ordering effects (i.e., changes in the entropy of a receptor complex) induced by a ligand are as a result of alterations in the receptor oligomerization (i.e., are related to rearrangements of the RM). Hence, brain temperature may have profound effects on brain integrative functions not only because its effects on the kinetics of biochemical reactions, but also for its effects on receptor geometry, building up of RM, and alterations in protein expression, as is the case of H-channels following febrile seizures.
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PMID:Existence and theoretical aspects of homomeric and heteromeric dopamine receptor complexes and their relevance for neurological diseases. 1605 39

The immature brain is intrinsically hyperexcitable, a feature that, despite being crucial for learning, synaptogenesis and neuronal plasticity, predisposes the neonate to seizures. Seizures represent the most common neurologic manifestation of impaired brain function in this age group. Importantly, although seizure-induced neuronal injury is minimal in the "healthy" neonatal brain, the "metabolically-compromised" brain appears more vulnerable. Even in the "healthy" brain, however, seizures result in impaired learning, enhanced susceptibility to further seizures, and increased risk of brain injury with seizures later in life, as a result of altered hippocampal circuitry. Given these findings, an aggressive approach to neonatal seizures appears warranted. However, our current conventional therapies (including phenobarbital, phenytoin, and benzodiazepines), even when used in combination, are often ineffective in controlling seizures. Lidocaine may yield better efficacy but requires more study. Recent animal data suggest that alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists such as topiramate may have a neuroprotective role. However, further work is needed to confirm the safety of excitatory amino acid antagonists in neonates because there remains a prevailing concern that such agents may impair normal neurodevelopmental processes.
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PMID:Neonatal seizures: to treat or not to treat? 1611 75

It is well documented that N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors play a pivotal role in ischaemic brain injury. Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6*PSD-95*MLK3 signalling module and subsequent c-Jun N-terminal kinase (JNK) activation. Here we investigate whether GluR6 mediated JNK activation is correlated with ischaemic brain injury. Our results show that cerebral ischaemia followed by reperfusion can enhance the assembly of the GluR6*PSD-95*MLK3 signalling module and JNK activation. As a result, activated JNK can not only phosphorylate the transcription factor c-Jun and up-regulate Fas L expression but can also phosphorylate 14-3-3 and promote Bax translocation to mitochondria, increase the release of cytochrome c and increase caspase-3 activation. These results indicate that GluR6 mediated JNK activation induced by ischaemia/reperfusion ultimately results in neuronal cell death via nuclear and non-nuclear pathways. Furthermore, the peptides we constructed, Tat-GluR6-9c, show a protective role against neuronal death induced by cerebral ischaemia/reperfusion through inhibiting the GluR6 mediated signal pathway. In summary, our results indicate that the KA receptor subunit GluR6 mediated JNK activation is involved in ischaemic brain injury and provides a new approach for stroke therapy.
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PMID:Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence. 1633 May 2

We examined antiepileptogenic and anticonvulsant effects of [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate (YM872), a potent and highly water-soluble alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor antagonist, in the rat amygdala kindling model of epilepsy. Administration of YM872 significantly suppressed fully kindled seizures. Daily pretreatment with YM872 markedly retarded development of kindling during drug sessions. We also used the rekindling method to investigate the antiepileptogenic effect of YM872 in an attempt to differentiate between true and false effects in the conventional method of daily administration. The results using the rekindling method suggested that the effect of YM872 was truly antiepileptogenic, indicating its possible clinical usefulness as an antiepileptogenic drug. We also affirmed the importance of AMPA receptors in the seizure expression mechanism and development of kindling-induced epileptogenesis.
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PMID:Effect of YM872, a selective and highly water-soluble AMPA receptor antagonist, in the rat kindling and rekindling model of epilepsy. 1640 98

This report is the second of a two-part evaluation of developmental differences in alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit expression in cell populations within white matter and cortex. In part I, we reported that, in rat, developmental expression of Ca2+-permeable (GluR2-lacking) AMPARs correlated at the regional and cellular level with increased susceptibility to hypoxia/ischemia (H/I), suggesting an age-specific role of these receptors in the pathogenesis of brain injury. Part II examines the regional and cellular progression of AMPAR subunits in human white matter and cortex from midgestation through early childhood. Similarly to the case in the rodent, there is a direct correlation between selective vulnerability to H/I and expression of GluR2-lacking AMPARs in human brain. For midgestational cases aged 20-24 postconceptional weeks (PCW) and for premature infants (25-37 PCW), we found that radial glia, premyelinating oligodendrocytes, and subplate neurons transiently expressed GluR2-lacking AMPARs. Notably, prematurity represents a developmental window of selective vulnerability for white matter injury, such as periventricular leukomalacia (PVL). During term (38-42 PCW) and postterm neonatal (43-46 PCW) periods, age windows characterized by increased susceptibility to cortical injury and seizures, GluR2 expression was low in the neocortex, specifically on cortical pyramidal and nonpyramidal neurons. This study indicates that Ca2+-permeable AMPAR blockade may represent an age-specific therapeutic strategy for potential use in humans. Furthermore, these data help to validate specific rodent maturational stages as appropriate models for evaluation of H/I pathophysiology.
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PMID:Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. II. Human cerebral white matter and cortex. 1668 Jul 61

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