Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
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

The molecular pharmacologic basis of epileptogenesis in cortical tubers in the tuberous sclerosis complex is unknown. Altered transcription of genes encoding glutamatergic and gamma-aminobutyric acid (GABA)-ergic receptors and uptake sites may contribute to seizure initiation and may occur selectively in dysplastic neurons and giant cells. Arrays containing GABA A (GABAAR), GluR, NMDA receptor (NR) subunits, GAD65, the vesicular GABA transporter (VGAT), and the neuronal glutamate transporter (EAAC1) cDNAs were probed with amplified poly (A) mRNA from tubers or normal neocortex to identify changes in gene expression. Increased levels of EAAC1, and NR2B and 2D subunit mRNAs and diminished levels of GAD65, VGAT, GluR1, and GABAAR alpha1 and alpha2 were observed in tubers. Ligand-binding experiments in frozen tuber homogenates demonstrated an increase in functional NR2B-containing receptors. Arrays were then probed with poly (A) mRNA from single, microdissected dysplastic neurons, giant cells, or normal neurons (n = 30 each). Enhanced expression of GluR 3, 4, and 6 and NR2B and 2C subunit mRNAs was noted in the dysplastic neurons, whereas only the NR2D mRNA was upregulated in giant cells. GABAAR alpha1 and alpha2 mRNA levels were reduced in both dysplastic neurons and giant cells compared to control neurons. Differential expression of GluR, NR, and GABAAR mRNAs in tubers reflects cell-specific changes in gene transcription that argue for a distinct molecular phenotype of dysplastic neurons and giant cells and suggests that dysplastic neurons and giant cells make differential contributions to epileptogenesis in the tuberous sclerosis complex.
 ...
PMID:Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers. 1119 98

Systemic administration of kainic acid (KA) induces status epilepticus (SE) that causes neurodegeneration and may subsequently lead to spontaneous recurrent seizures. We investigated the effects of KA-induced SE on tyrosine phosphorylation and solubility properties of the NMDA receptor. Following 1 h of SE, total protein tyrosine phosphorylation was elevated in both the hippocampus and frontal cortex relative to controls. Tyrosine phosphorylation of the NMDA receptor subunits NR2A and NR2B was also enhanced following SE. Animals that received KA but did not develop SE, did not exhibit increased tyrosine phosphorylation. SE resulted in a decrease in the solubility of NMDA receptor subunits and of PSD-95 in 1% deoxycholate. In contrast, the detergent solubility of AMPA and kainate receptors was not affected. These findings demonstrate that SE alters tyrosine phosphorylation of the NMDA receptor, and indicate that the interaction of the NMDA receptor with other components of the NMDA receptor complex are altered as a consequence of seizure activity.
 ...
PMID:Seizure activity results in increased tyrosine phosphorylation of the N-methyl-D-aspartate receptor in the hippocampus. 1168 75

Ro 63-1908, 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol, is a novel subtype-selective N-methyl-D-aspartate (NMDA) antagonist that has been characterized in vitro and in vivo. Ro 63-1908 inhibited [(3)H]dizocilpine ((3)H-MK-801) binding in a biphasic manner with IC(50) values of 0.002 and 97 microM for the high- and low-affinity sites, respectively. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopus oocytes containing NR1C + NR2B subunits with an IC(50) of 0.003 microM and those containing NR1C + NR2A subunits with an IC(50) of >100 microM, thus demonstrating greater than 20,000-fold selectivity for the recombinant receptors expressing NR1C + NR2B. Ro 63-1908 blocked these NMDA NR2B-subtype receptors in an activity-dependent manner. Ro 63-1908 was neuroprotective against glutamate-induced toxicity and against oxygen/glucose deprivation-induced toxicity in vitro with IC(50) values of 0.68 and 0.06 microM, respectively. Thus, the in vitro pharmacological characterization demonstrated that Ro 63-1908 was a potent and highly selective antagonist of the NR2B subtype of NMDA receptors. Ro 63-1908 was active against sound-induced seizures (ED(50) = 4.5 mg/kg i.p. when administered 30 min beforehand) in DBA/2 mice. The dose required to give a full anticonvulsant effect did not produce a deficit in the Rotarod test. NMDA-induced seizures were also inhibited by Ro 63-1908 with an ED(50) of 2.31 mg/kg i.v. when administered 15 min before testing. Ro 63-1908 gave a dose-related neuroprotective effect against cortical damage in a model of permanent focal ischemia. Maximum protection of 39% was seen at a plasma concentration of 450 ng/ml. There were, however, no adverse cardiovascular or CNS side-effects seen at this dosing level.
 ...
PMID:Pharmacological characterization of Ro 63-1908 (1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a novel subtype-selective N-methyl-D-aspartate antagonist. 1218 50

Kainic acid (KA)-induced experimental epilepsy, a model of excitotoxicity, leads to selective neuronal death and synaptic restructuring. We used this model to investigate the effects of neuronal hyperactivation on palmitoyl-protein thioesterase 1 (PPT1), the deficiency of which causes drastic neurodegeneration. Immunological stainings showed that epileptic seizures in adult rats led to a progressive and remarkable increase of PPT1 in limbic areas of the brain. Within 1 week, the maximal expression was observed in CA3 and CA1 pyramidal neurons of the hippocampus. In the surviving pyramidal neurons, PPT1 localized in vesicular structures in cell soma and neuritic extensions. After seizures, colocalization of PPT1 with synaptic membrane marker (NMDAR2B) was enhanced. Further, synaptic fractionation revealed that after seizures PPT1 was readily observed on the presynaptic side of synaptic junction. These data suggest that PPT1 may protect neurons from excitotoxicity and have a role in synaptic plasticity.
 ...
PMID:Status epilepticus induces changes in the expression and localization of endogenous palmitoyl-protein thioesterase 1. 1227 Jun 87

Overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors is closely related to epilepsy and excitotoxicity, and the phosphorylation of these receptors may facilitate glutamate-mediated synaptic transmission. Here we show that in awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases. Two hours after okadaic acid, when the EEG seizures were intense, an increased serine phosphorylation of some hippocampal proteins, including an enhancement of the serine phosphorylation of the NMDA receptor subunit NR2B, was detected by immunoblotting. Twenty-four hours after okadaic acid a marked destruction of hippocampal CA1 region was observed, which was not prevented by the receptor antagonists. These findings suggest that hyperphosphorylation of glutamate receptors in vivo may result in an increased sensitivity to the endogenous transmitter and therefore induce neuronal hyperexcitability and epilepsy.
 ...
PMID:Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B subunit of the NMDA receptor in rat hippocampus in vivo. 1242 30

We have previously shown that the intrahippocampal microinjection of okadaic acid (OKA), a potent inhibitor of serine/threonine protein phosphatases, induces epileptic seizures, neuronal death, and the hyperphosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. We administered OKA by reverse microdialysis in the hippocampus of awake and halothane-anesthetized rats, with simultaneous collection of microdialysis fractions and recording of the EEG activity, and subsequent histological analysis. OKA produced intense behavioral and persistent EEG seizure activity in the awake rats but not in the anesthetized animals, and did not significantly alter the extracellular concentration of glutamate and aspartate detected in the microdialysis fractions. One day after the experiment a remarkable neurodegeneration of CA1 hippocampal region was observed in both the awake and the anesthetized rats. We conclude that the OKA-induced epilepsy cannot be ascribed to increased extracellular glutamate, but to an increased sensitivity of NMDA receptor. We propose that halothane protected against the epilepsy because it blocks NMDA receptor overactivation, and that the neurodegeneration of CA1 region is independent of this overactivation and due probably to alterations of cytoskeletal proteins consequent to the OKA-induced hyperphosphorylation.
 ...
PMID:Epilepsy, neurodegeneration, and extracellular glutamate in the hippocampus of awake and anesthetized rats treated with okadaic acid. 1457 Mar 96

X11 alpha or Mint1 is a protein containing an N-terminal sequence, which binds to Munc-18 protein, a middle phosphotyrosine-binding domain (PTB) and two C-terminal PDZ (Post-synaptic density/Discs large/Zone Occludens-1) domains. The PDZ domains, which mediate protein-protein interactions have been shown to be involved in the organization of synaptic signaling pathways. Mint1 plays an important role in vesicle synaptic transport toward the active zone at the pre-synaptic site, and also participates in the transport of NR2B subunit of the NMDA receptor, to the post-synaptic site. To investigate the participation and distribution of this protein in the hippocampal subfield of rats submitted to the pilocarpine model of epilepsy, Mint1 was analyzed using Western blotting and immunohistochemistry. Animals of 5 h of status epilepticus showed decreased levels of this protein in the hippocampus when compared to the control animals. In contrast, animals from seizure-free period (silent group) and during spontaneous seizures phase (chronic group) showed increased Mint1 immunostaining in all hippocampal subfields, mainly in the dentate gyrus, when compared to the control group. The blotting confirmed the results obtained by immunohistochemistry. The present work suggests that Mint1 may be related to hippocampal plasticity during epileptogenesis in the pilocarpine model of temporal lobe epilepsy.
 ...
PMID:Levels of the synaptic protein X11 alpha/mint1 are increased in hippocampus of rats with epilepsy. 1470 32

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.
 ...
PMID:Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. 1474

CGX-1007, a 17-amino acid polypeptide isolated from the venom of Conus geographus, is a novel NMDA receptor antagonist that is selective for the NR2B subunit. CI-1041 (PD 196860; Co 200461) is a novel, orally available NR2B selective antagonist. Both compounds possess anticonvulsant activity in a variety of well-established animal seizure models. The present study was designed to assess the effects of CGX-1007 and CI-1041 on the acquisition and expression of kindled seizures. In the corneal kindled rat, CGX-1007 [Epilepsia 36 (1998) 39] and CI-1041, administered p.o., 2h prior to the kindling stimulation displayed time- and dose-dependent block of fully expressed corneal kindled seizures (ED50 = 300 pmol and 2.5mg/kg for CGX-1007 and CI-1041, respectively). In amygdala kindled rats, acute treatment with CGX-1007 blocked the secondarily generalized kindled seizure in a dose-dependent manner. Complete protection against the secondarily generalized seizure was only observed at a dose that produced behavioral impairment (4 nmol). Acute treatment with CI-1041 did not provide any notable protection against secondarily generalized seizures. Neither compound provided protection against the focal kindled seizure. Chronic i.c.v. infusion of CGX-1007 or chronic oral administration of CI-1041 did not delay the acquisition of amygdala kindling. The results from these studies suggest that NMDA receptors containing the NR2B subunit may contribute to the expression of fully kindled secondarily generalized seizures; however, they appear less important for the development of kindling. The differential results obtained with CGX-1007 and CI-1041 suggest that several classes of mechanistically distinct NR2B antagonists may exist and that CGX-1007 may be less specific as a NR2B receptor antagonist than initially reported.
 ...
PMID:The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression. 1513 62


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>