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 aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethylimidazo[1,2a]quinoxal ine-2-carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). In comparison, the prototype non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose-dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED50 of 4.9 mg kg(-1). Up to 20 mg kg(-1), only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg(-1), and the glycine/NMDA site antagonist L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent.
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PMID:LU 73068, a new non-NMDA and glycine/NMDA receptor antagonist: pharmacological characterization and comparison with NBQX and L-701,324 in the kindling model of epilepsy. 986 55

The main excitatory neurotransmitter in the brain is glutamate, which exerts its effects through multiple ionotropic and metabotropic receptors. Pharmacological and electrophysiological data point to essential role of glutamate receptors in seizure phenomena. Agonists of these receptors depolarize neurons and induce convulsions in various animal species. In contrast, glutamate receptor antagonists suppress seizure activity and may prevent development of an experimental epileptogenesis. Unfortunately, some of these drugs may evoke severe adverse effects such as, psychosis, impairment of memory and disturbance of motor functions. It is, however, believed that better understanding of molecular biology of glutamate receptors may help to design new anticonvulsants with good efficacy and safety profiles. Some aspects of excitatory amino acid neurochemistry and their therapeutic potential are critically discussed in this paper.
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PMID:[Excitatory amino acids and perspectives of epilepsy treatment]. 1010 80

The NMDA receptor is one of the ionotropic glutamate receptors essential for excitatory neurotransmission. The NMDAR1 subunit is inactivated by direct interaction with calmodulin. The protein levels of calmodulin, NMDAR1 and their complex were quantified in tissue resected from epileptogenic and non-epileptogenic cortical areas as determined by chronic subdural electrode recordings from three patients (aged 6, 14 and 18 years) with focal epilepsy associated with cortical dysplasia. In all patients, the co-assembly of calmodulin and NMDAR1 was decreased in epileptogenic dysplastic cortex compared with normal appearing non-epileptogenic cortex, while there was no significant difference in the total protein levels of calmodulin or NMDAR1 between the two EEG groups. These results suggest that decreased calmodulin-NMDAR1 co-assembly is a cellular mechanism that contributes to hyperexcitability in dysplastic cortical neurons and in focal seizure onsets.
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PMID:Decreased calmodulin-NR1 co-assembly as a mechanism for focal epilepsy in cortical dysplasia. 1038 Sep 90

This manuscript summarizes mouse mutants for ionotropic glutamate receptors that were generated by different laboratories to analyze the function of the NMDA and AMPA receptors in the mouse. Thus, NMDA receptor mutant mice that were generated by the "knock-in" technology demonstrate that the NR1 and the NR2B subunits participate in the formation of NMDA receptors that are involved in vital functions like breathing and suckling of a newborn mouse. Mice that lack NR2A, -2C, and -2D subunits were described to be viable and have been used to study the role of NMDA receptors in adult mice. The depletion of the GluR-B subunit revealed an NMDA receptor-independent form of long-term potentiation (LTP). This AMPA receptor-mediated LTP at CA3/CA1 synapses was also observed in mice that carry an editing-deficient GluR-B allele even though these mice die prematurely after heavy epileptic seizures. In other mutants, the intracellular COOH-terminal domain of the NMDA receptor was truncated; and when compared to NMDA receptor "knock-out" mice, a functional knock-out of the NMDA receptor was observed. However, in the synapses of NR2AC/AC mutants, gatable NMDA receptors were synaptically activated, indicating that the knock-out phenotypes mediated by the COOH-terminally truncated NMDA receptors appear to reflect defective intracellular signaling.
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PMID:Mice with genetically modified NMDA and AMPA receptors. 1041 26

Picrotoxin, an antagonist of GABA(A) receptor-mediated activity, elicited 320- to 475-ms synchronized bursts from the CA3 region of the guinea pig hippocampal slice. The addition of the selective group I metabotropic glutamate receptor (mGluR) agonist (S)-3, 5-dihydroxyphenylglycine (DHPG, 50 microM; 20- to 45-min application) gradually increased the burst duration to 1-4 s; this effect persisted 2-3 h after agonist removal. To determine whether the induction of this long-lasting effect required ongoing synchronized activity during mGluR activation, DHPG application in a second set of experiments took place in the presence of CNQX and (R, S)-CPP, antagonists of AMPA/kainate and NMDA receptors, respectively. In these experiments, synchronized bursting was silenced during the mGluR agonist application, yet after wash out of the DHPG and the ionotropic glutamate receptor (iGluR) blockers, epileptiform discharges 1-10 s in duration appeared and persisted at least 2 h after wash out of the mGluR agonist. The potentiated bursts were reversibly shortened by application of 500-1,000 microM (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) or (S)-4-carboxyphenylglycine (4CPG), agents with group I mGluR antagonist activity. These data suggest that transient activation of group I mGluRs, even during silencing of synchronized epileptiform activity, may have an epileptogenic effect, converting brief interictal-length discharges into persistent seizure-length events. The induction process is iGluR independent, and the maintenance is largely mediated by the action of endogenous glutamate on group I mGluRs, suggesting that autopotentiation of the group I mGluR-mediated response may underlie the epileptogenesis seen here.
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PMID:Group I mGluR-mediated silent induction of long-lasting epileptiform discharges. 1044 1

Considerable information is available regarding the role of ionotropic glutamate receptors in the generation of interictal spikes. Progress in the study of metabotropic glutamate receptors (mGluRs) makes clear that activation of these receptors can contribute greatly to seizure discharges and epileptogenesis. The effects of activation of the different mGluR subgroups on neuronal hypersynchrony and the initiation and propagation of seizure discharges in hippocampal slices are discussed herein. To help one understand the mechanisms that underlie these effects, information regarding the action of mGluRs on cellular and synaptic properties is summarized. The data bring to the forefront the critical role of mGluRs in epilepsy and emphasize the anticonvulsant effects of group II and III mGluR activation as opposed to the convulsant action of group 1, which elicits seizure discharges and epileptogenesis in experimental models.
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PMID:Role of metabotropic glutamate receptors in epilepsy. 1051 55

Glutamate, the principal excitatory neurotransmitter in the brain, acts on three families of ionotropic receptor--AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid), kainate and NMDA (N-methyl-D-aspartate) receptors and three families of metabotropic receptor (Group I: mGlu1 and mGlu5; Group II: mGlu2 and mGlu3; Group III: mGlu4, mGlu6, mGlu7 and mGlu8). Glutamate is removed from the synaptic cleft and the extracellular space by Na+-dependent transporters (GLAST/EAAT1, GLT/EAAT2, EAAC/EAAT3, EAAT4, EAAT5). In rodents, genetic manipulations relating to the expression or function of glutamate receptor proteins can induce epilepsy syndromes or raise seizure threshold. Decreased expression of glutamate transporters (EAAC knockdown, GLT knockout) can lead to seizures. In acquired epilepsy syndromes, a wide variety of changes in receptors and transporters have been described. Electrically-induced kindling in the rat is associated with functional potentiation of NMDA receptor-mediated responses at various limbic sites. Group I metabotropic responses are enhanced in the amygdala. To date, no genetic epilepsy in man has been identified in which the primary genetic defect involves glutamate receptors or transporters. Changes are found in some acquired syndromes, including enhanced NMDA receptor responses in dentate granule cells in patients with hippocampal sclerosis.
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PMID:Glutamate receptors and transporters in genetic and acquired models of epilepsy. 1051 65

Acetylcholine functions as a neuromodulator in the mammalian brain by binding to specific receptors and thus bringing about profound changes in neuronal excitability. Activation of muscarinic receptors often results in an increased excitability of cortical cells. It is, however, unknown whether such an action is present in the subiculum, a limbic structure that may be involved in cognitive processes as well as in seizure propagation. Most rat subicular neurons are endowed of intrinsic membrane properties that make them fire action potential bursts. Using intracellular recordings from these bursting cells in a slice preparation, we report here that application of the cholinergic agonist carbachol (CCh, 30-100 microM) to medium containing ionotropic excitatory amino acid receptor antagonists reduces burst-afterhyperpolarizations (burst-AHPs) and discloses depolarizing plateau potentials that outlast the triggering current pulses by 140-2,800 ms. These plateau potentials appear with CCh concentrations >50 microM and are dependent on the resting membrane potential and on the intensity/duration of the triggering pulse; are recorded during application of tetrodotoxin (1 microM, n = 5 neurons); but are markedly reduced by replacing 82% of extracellular Na(+) with equimolar choline (n = 6). Plateau potentials also are abolished by Co(2+) (2 mM; n = 5) or Cd(2+) (1 mM; n = 2) application and by recording with electrodes containing the Ca(2+) chelator bis(2-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid (0.2 M; n = 6). CCh-induced burst-AHP reduction and plateau potentials are reversed by the muscarinic antagonist atropine (0.5 microM, n = 7). In conclusion, our findings demonstrate a powerful muscarinic modulation of the intrinsic excitability of subicular bursting cells that is predominated by the appearance of plateau potentials. These changes in excitability may contribute to physiological processes such as learning or memory and play a role in the generation of epileptiform depolarizations. We propose that, as in other limbic structures, muscarinic plateau potentials in the subiculum are mainly due to a Ca(2+)-dependent nonselective cationic conductance.
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PMID:Muscarinic receptor activation induces depolarizing plateau potentials in bursting neurons of the rat subiculum. 1056 29

The N-methyl-D-aspartate (NMDA) receptor is one of the ionotropic glutamate receptor subtypes and exhibits a voltage-dependent blockade of its channel function by extracellular magnesium. This magnesium block is known to be absent or weak early in development and is gradually acquired while the brain matures. Interestingly, in adult patients with temporal lobe epilepsy, the magnesium block appears to be altered allowing more current to flow at a negative membrane potential. We are interested whether a similar change might be observed in children's hippocampi that have frequently been involved in medically intractable seizures. In the present study, we grouped the patients into 2 categories based on the degree of brain maturity: (I) children under the age of 2 (immature, n = 2) and (II) children over the age of 2 (mature, n = 6). Dentate gyri were imaged in real time for intrinsic optical signals with the use of a transmitted light in hippocampal slice preparations. Light transmittance (LT), which reflects a neuronal synaptic depolarization and a concomitant change in cell volume, was calculated. In the immature hippocampus, LT increased significantly in response to NMDA in the presence of extracellular magnesium. However, the mature hippocampi showed little response to NMDA unless magnesium ions were removed from the extracellular artificial cerebrospinal fluid. LT increase was also induced in response to alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA); however, there were no age-dependent differences in the AMPA induced LT increase. Differential sensitivity of the NMDA receptor to extracellular magnesium between immature and mature hippocampi suggests the probable presence of developmental regulation of magnesium block for the NMDA receptor in the human hippocampus of children with medically intractable seizures.
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PMID:Developmental changes in NMDA-induced intrinsic optical signals in the hippocampal dentate gyrus of children with medically intractable seizures. 1057 45

Hepatic encephalopathy (HE) and portal-systemic encephalopathy (PSE) are the terms used interchangeably to describe a complex neuropsychiatric syndrome associated with acute or chronic hepatocellular failure, increased portal systemic shunting of blood, or both. Hepatic encephalopathy complicating acute liver failure is referred to as fulminant hepatic failure (FHF). The clinical manifestations of HE or PSE range from minimal changes in personality and motor activity, to overt deterioration of intellectual function, decreased consciousness and coma, and appear to reflect primarily a variable imbalance between excitatory and inhibitory neurotransmission. Pathogenic mechanisms that may be responsible for HE have been extensively investigated using animal models of HE, or cultures of CNS cells treated with neuroactive substances that have been implicated in HE. Of the many compounds that accumulate in the circulation as a consequence of impaired liver function, ammonia is considered to play an important role in the onset of HE. Acute ammonia neurotoxicity, which may be a cause of seizures in FHF, is excitotoxic in nature, being associated with increased synaptic release of glutamate (Glu), the major excitatory neurotransmitter of the brain, and subsequent overactivation of the ionotropic Glu receptors, mainly the N-methyl-D-aspartate (NMDA) receptors. Hepatic encephalopathy complicating chronic liver failure appears to be associated with a shift in the balance between inhibitory and excitatory neurotransmission towards a net increase of inhibitory neurotransmission, as a consequence of at least two factors. The first is down-regulation of Glu receptors resulting in decreased glutamatergic tone. The down-regulation follows excessive extrasynaptic accumulation of Glu resulting from its impaired re-uptake into nerve endings and astrocytes. Liver failure inactivates the Glu transporter GLT-1 in astrocytes. The second factor is an increase in inhibitory neurotransmission by gamma-aminobutyric acid (GABA) due to (a) increased brain levels of natural benzodiazepines; (b) increased availability of GABA at GABA-A receptors, due to enhanced synaptic release of the amino acid; (c) direct interaction of modestly increased levels of ammonia with the GABA-A-benzodiazepine receptor complex; and (d) ammonia-induced up-regulation of astrocytic peripheral benzodiazepine receptors (PBZR). Brain ammonia is metabolised in astrocytes to glutamine (Gln), an osmolyte, and increased Gln accumulation in these cells may contribute to cytotoxic brain edema, which often complicates FHF. Glutamine efflux from the brain is an event that facilitates plasma-to-brain transport of aromatic amino acids. Tryptophan and tyrosine are direct precursors of the aminergic inhibitory neurotransmitters, serotonin and dopamine, respectively. Changes in serotonin and dopamine and their receptors may contribute to some of the motor manifestations of HE. Finally, oxindole, a recently discovered tryptophan metabolite with strong sedative and hypotensive properties, has been shown to accumulate in cirrhotic patients and animal models of HE.
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PMID:Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. 1061 92


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