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)

Systemic administration of kainic acid (KA) to rodents results in limbic seizures and subsequent neurodegeneration similar to that observed in certain types of human epilepsy, and it is a commonly used animal model for this disease. Oxidative stress has been suggested to play a role in the neuronal injury associated with KA administration. Based on this observation, chronic treatment with antioxidants has been proposed as a possible protective therapy against neuronal damage associated with epileptic seizures. Here we demonstrate by histochemical, electrophysiological, and biochemical means that knockout mice with decreased activity of the protective antioxidant enzyme glutathione peroxidase, which display elevated basal brain oxidative stress levels, are resistant to KA-induced seizure activity and neurodegeneration. This appears to be a result of decreased NMDA receptor function due to oxidation of its NR1 subunit. This suggests that the chronic use of antioxidants as antiepileptic agents to modulate NMDA-dependent seizure-induced neurodegeneration may be detrimental rather than protective and calls into question their use as a therapeutic agent in the treatment of epilepsy.
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PMID:Chronic brain oxidation in a glutathione peroxidase knockout mouse model results in increased resistance to induced epileptic seizures. 1091 65

Modulation of the N-methyl-d-aspartate (NMDA)-selective glutamate receptors by extracellular protons and Zn(2+) may play important roles during ischemia in the brain and during seizures. Recombinant NR1/NR2A receptors exhibit a much higher apparent affinity for voltage-independent Zn(2+) inhibition than receptors with other subunit combinations. Here, we show that the mechanism of this apparent high-affinity, voltage-independent Zn(2+) inhibition for NR2A-containing receptors results from the enhancement of proton inhibition. We also show that the N-terminal leucine/isoleucine/valine binding protein (LIVBP)-like domain of the NR2A subunit contains critical determinants of the apparent high-affinity, voltage-independent Zn(2+) inhibition. Mutations H42A, H44G, or H128A greatly increase the Zn(2+) IC(50) (by up to approximately 700-fold) with no effect on the potencies of glutamate and glycine or on voltage-dependent block by Mg(2+). Furthermore, the amino acid residue substitution H128A, which mediates the largest effect on the apparent high-affinity Zn(2+) inhibition among all histidine substitutions we tested, is also critical to the pH-dependency of Zn(2+) inhibition. Our data revealed a unique interaction between two important extracellular modulators of NMDA receptors.
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PMID:Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors. 1098 4

The present study was designed to clarify the role of the NR1, NR2A and NR2B subunits of N-methyl-D-aspartate receptors in the development of morphine-induced place preference using specific antibodies to N-methyl-D-aspartate receptor subunits in the mouse. An i.c.v. injection with specific antibodies against the carboxyl-terminal region of either NR1, NR2A or NR2B subunits caused the attenuation of seizures induced by i.v. infusion of N-methyl-D-aspartate in the mouse. Using western blotting, NR1, NR2A and NR2B subunits were found to be highly expressed in the cerebral cortex and hippocampus of the mouse brain, which are key areas in producing seizures regulated by N-methyl-D-aspartate receptors. These findings indicate that all three subunits of the N-methyl-D-aspartate receptor in these areas are likely to be critical for the seizure induced by i.v. infusion of N-methyl-D-aspartate. Furthermore, present data provide evidence that these antibodies when given into the brain specifically act on the target sites, resulting in the blockade of the respective N-methyl-D-aspartate receptor subunit. Under these conditions, i.c.v. treatment with the antibody against NR2B subunits abolished the morphine-induced place preference, whereas antibodies against NR1 and NR2A subunits did not affect the rewarding effect of morphine. Furthermore, the NR2B subunit protein was specifically up-regulated in the limbic forebrain of morphine-conditioned mice, whereas the protein levels of either NR1 or NR2A subunits were not altered.From these results, we suggest that the stimulation of the carboxyl-terminal region of NR2B subunits in the limbic forebrain may contribute to the development of morphine-induced rewarding effect.
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PMID:Molecular evidence for the involvement of NR2B subunit containing N-methyl-D-aspartate receptors in the development of morphine-induced place preference. 1111 9

Antiepileptic drugs (AEDs) cover a broad spectrum of pathological conditions ranging from seizures following congenital or acquired brain disorders to behavioural and psychiatric disorders and recently neuropathic pain. The need for novel antiepileptics raises from the expanding field of indications as well as from the fact, that special seizure types are refractory to common AEDs. In addition, many of the conventional antiepileptic drugs exhibit an unfavourable side-effect profile. Since there is growing evidence, that NMDA receptor activation might play a crucial role in epilepsy, NMDA receptor antagonists have become compounds of interest in preventing and treating seizures. This review focuses on NMDA receptor antagonistic compounds, which are already in use for the treatment of epileptic seizures (i. e. MgSO4, felbamate) and compounds in clinical trials (i. e. remacemide, ADCI). Further interest is put on NMDA antagonists in preclinical and biological testing (memantine, dizocilpine, conantokins, Co101244/PD174494, ifenprodil, arcaine, L-701,324, eliprodil, CGP40116, LY235959, LY233053, MRZ2/576, LU73068, 4-Cl-KYN). Some of the latter compounds are predominantely of academic interest (i. e. 4-Cl-KYN), others (i. e. dizocilpine, LY235959, LY233053) might be of therapeutical value when combined with conventional AEDs. In order to reduce adverse effects in antiepileptic medication using NMDA antagonists, special interest will be focused on subtype selective compounds. In this respect, Co101244, a novel potent and selective NR1/2B NMDA receptor antagonist might be a lead for therapeutically promising compounds.
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PMID:The NMDA receptor complex: a promising target for novel antiepileptic strategies. 1156 66

Ca2+ currents are thought to enhance glutamate excitotoxicity. To investigate whether reduced expression of the Ca2+ limiting GluR2(B) subunit enhances seizure-induced vulnerability to either CA1 or CA3 neurons, we delivered GluR2(B) oligodeoxynucleotides (AS-ODNs) to the dorsal hippocampus of adult rats before inducing kainate (KA) seizures. After knockdown, no changes in behavior, electrographic activity, or histology were observed. In contrast, GluR2(B) knockdown and KA-induced status epilepticus produced accelerated histological injury to the ipsilateral CA3a-b and hilar subregions. At 8 to 12 h, the CA3a was preferentially labeled by both silver and TUNEL methods. TUNEL staining revealed 2 types of nuclei. They were round with uniform label, features of necrosis, or had DNA clumping or speckled chromatin deposits within surrounding cytosol, features of apoptosis. At 16 to 24 h, many CA3a-c neurons were shrunken, eosinophilic, argyrophilic, or completely absent. Immunohistochemistry revealed marked decreases in GluR2(B) subunits throughout the hippocampus, NR1 immunoreactivity was also reduced but to a lesser extent. In contrast, GluR1 and NR2A/B immunohistochemistry was relatively uniform except in regions of cell loss or within close proximity to the CA1 infusion site. At 144 h, the CA3 was still preferentially injured although bilateral CA1 injury was also observed in some AS-ODN-, S-ODN-, and KA-only-treated animals. Glutamate receptor antibodies revealed generalized decreases in the CA3 with all probes tested at this delayed time. In contrast, GluR2(B) expression was increased within CA1 irregularly shaped, injured neurons. Therefore, hippocampal deprivation of GluR2(B) subunits is insufficient to induce cell death in mature animals but may accelerate the already known CA3/hilar lesion, possibly by triggering apoptosis within CA3 neurons. CA1 and DG survive the first week despite their loss of GluR2(B) subunits, suggesting that other intrinsic properties such as increased Na+ conductance and reduced ability of the GluR2(B) subunit to interact with certain cytoplasmic proteins may be responsible for the augmented cell death rather than changes in AMPA receptor-mediated Ca2+ permeability. Alternatively, changes in allosteric interactions that affect other receptor classes of high density at the mossy fiber synapse (e.g. KA receptors) may augment KA neurotoxicity. Latent GluR2(B) increases in CA1 injured neurons support a role for AMPA receptor subunit alterations in seizure-induced tolerance.
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PMID:GluR2(B) knockdown accelerates CA3 injury after kainate seizures. 1290

Differences in expression of N-methyl-D-aspartate (NMDA) receptor and voltage gated Ca2+ channels (VGCC) in the gerbil cerebellum were investigated to identify routes of Ca2+ influx that may be involved in Purkinje cell damage. Immunodensities of NR1 and NR2A/B were the same in seizure resistant (SR) and seizure sensitive (SS) gerbils. However, both P/Q type (alpha1A) and L2 type (alpha1D) VGCC levels were higher in the Purkinje cells of SS gerbils than in those of SR gerbils, whereas N type (alpha1B) and L1 type (alpha1C) VGCC levels were similar in the two groups. Our findings suggest that increases in P/Q type (alpha1A) and L2 type (alpha1D) VGCC are implicated in the degeneration of Purkinje cells in SS gerbils.
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PMID:Elevated P/Q type (alpha1A) and L2 type (alpha1D) Purkinje cell voltage-gated calcium channels in the cerebella of seizure prone gerbils. 1474 18

The aim of this study was to examine the expression profiles of N-methyl-D-aspartate (NMDA) receptor subunits in rats during seizure development and kindled process induced by pentylenetetrazole (PTZ). Using quantitative Western blotting, the levels of NR1, NR2A and NR2B subunits were measured in the cortex and hippocampus of rats at different times after PTZ injection. In the early seizure developmental process, both NR1 and NR2A were markedly increased in the cortex, and NR1 was significantly increased in the hippocampus. On the other hand, in the kindled process both NR1 and NR2A decreased in the cortex and hippocampus. However, the NR2B subunit had no appreciable change in both the seizure developmental and kindled process. Therefore, these results showed that expression of NMDA receptors undergoes subunit- and region-related changes in the developmental and kindled seizure of rats induced by PTZ.
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PMID:Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. 1474

The N-methyl-D-aspartate (NMDA) receptor-gated ion channel is comprised of at least one NR1 subunit and any of four NR2 subunits (NR2A-D). The NR2 subunit confers different pharmacological and kinetic properties to the receptor. CGX-1007 (Conantokin G), a 17-amino acid polypeptide isolated from the venom of Conus geographus, is a novel NMDA receptor antagonist that is thought to be selective for the NR2B subunit. CGX-1007 has been reported to have highly potent, broad-spectrum anticonvulsant activity in animal seizure models. CI-1041 is an investigational compound, which also possesses anticonvulsant activity and has been shown to be highly selective for NR2B containing NMDA receptors. Although both CI-1041 and CGX-1007 are reportedly NR2B specific antagonists, they differ in their ability to block amygdala-kindled seizures, suggesting that the mechanism of action of these compounds differs. The present study was designed to test the hypothesis that CI-1041 and CGX-1007 would differentially modulate the function of NMDA receptors at excitatory synapses. Using the whole cell patch clamp technique, CGX-1007 and CI-1041 were found to block CA1 pyramidal cell, NMDA receptor-mediated excitatory postsynaptic currents (N-EPSCs) in a concentration-dependent manner in hippocampal slices from P4-P6 animals. In contrast, only CGX-1007 decreased NMDA receptor-mediated EPSC peak amplitude in slices from adult animals. The CGX-1007 block of peak amplitude was accompanied by a similar concentration-dependent decrease in decay kinetics of NMDA receptor-mediated EPSCs. These results suggest that while CI-1041 may be selective for NMDA receptors containing the NR2B subunit, CGX-1007 appears to be less selective than previously reported.
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PMID:The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on NMDA receptor-mediated EPSCs. 1513 63

Neuronal migration disorders (NMDs) constitute the main pathologic substrate of medically intractable epilepsy in human. This study is designed to investigate the changes in expression of glutamate receptor subtypes on radiation-induced NMD in rats. The lesion was produced by intrauterine irradiation (240 cGy) on E17 rats, and then 10 weeks old rats were used for the study. The pathologic and immuno-histochemical findings for glutamate receptor subunit proteins on NMD cortex were correlated with development of behavioral seizures and EEG abnormality. Spontaneous seizures uncommonly occurred in NMD rats (5%); however, clinical stages of seizures were significantly increased in NMD rats by an administration of kainic acid. Brains taken from irradiated rats revealed gross and histopathologic features of NMD. Focal cortical dysplasia was identified by histopathology and immunohistochemistry with neurofilament protein (NF-M/H). Significantly strong NR1 and NR2A/B immunoreactivities were demonstrated in cytomegalic and heterotopic neurons of NMD rats. The results of the present study indicate that epileptogenesis of NMD might be caused by upregulation of glutamate receptor expression in dysplastic neurons of the rat cerebral cortex with NMDs.
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PMID:Upregulation of glutamate receptors in rat cerebral cortex with neuronal migration disorders. 1520 10

Seizures have been shown to promote the proliferation of granule cell precursors in the adult brain, but the underlying mechanisms remain largely unknown. Using systemic bromodeoxyuridine (BrdU) to label dividing cells, we examined the effects of selective ionotropic glutamate receptor antagonists on granule cell precursor proliferation in adult rats after pentylenetrazol (PTZ)-induced generalized clonic seizures. We found that the NMDA receptor antagonist MK-801 significantly inhibited behavioral and EEG seizures and completely blocked seizure-induced increase in the number of BrdU-labeled cells in the dentate gyrus. Although the AMPA/KA receptor antagonist DNQX was not observed to affect seizures, it significantly suppressed the number of BrdU-labeled cells in the dentate gyrus. Double immunohistochemical staining showed that both the mature granule cells and the majority of BrdU-labeled, mitotically active cells expressed the NMDA receptor subunit NR1 and the AMPA/KA receptor subunit GluR2. Because accumulated evidence showed that mild seizures are sufficient to promote precursor cell proliferation, the present findings that MK-801 inhibited seizures and completely blocked seizure-induced increase in precursor cell proliferation suggest that the direct blockade action of MK-801 on NMDA receptors on the granule cell precursors may play an important role in blocking seizure-induced precursor cell proliferation. The suppression of seizure-induced proliferation of granule cell precursors by DNQX may be achieved by the direct action of DNQX on AMPA/KA receptors on the granule cell precursors. Thus, our findings indicate that seizures may promote cell proliferation in the adult rat dentate gyrus through glutamatergic mechanisms acting on both NMDA and AMPA/KA receptors.
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PMID:Ionotropic glutamate receptor antagonists inhibit the proliferation of granule cell precursors in the adult brain after seizures induced by pentylenetrazol. 1531 97


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