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)

Some non-DBA2 Albino Swiss mice exhibit noise induced epileptic seizures during a short period of postnatal development. Because N-methyl-D-aspartate (NMDA) glutamate ionotropic receptors are involved in the occurrence of audiogenic seizures, we investigated by in situ hybridization methods, the expression of the different subunits (NR1, NR2A, NR2B, NR2C) of this receptor in the central nucleus of the inferior colliculus (IC), a main relay of the auditory pathways. At postnatal day 20, the NR2C subunit is highly expressed in the IC of convulsive mice, while in non-convulsive mice a slight signal is only found for NR1, NR2A, and NR2B. In adult mice, the NR1 and NR2A signals are observed while the NR2B signal is almost undetectable. The audiogenic susceptibility may be related to the transient expression of the NR2C subunit during a brief neonatal period during which synaptic reorganization happens.
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PMID:N-Methyl-D-aspartate receptor subunits NR1 and NR2C are overexpressed in the inferior colliculus of audiogenic mice. 762 42

Kindling refers to a phenomenon in which repeated application of initially subconvulsive electrical stimulations produces limbic and clonic motor seizures of progressively increasing severity. Once established, the increased excitability is lifelong. Enhanced function of synapses using the NMDA subtype of glutamate receptor could contribute to the expression of the increased excitability. We previously found that CA3 pyramidal cells of hippocampus of kindled animals exhibit a selective and long-lasting (1 month) increased sensitivity to NMDA-evoked depolarization. The goal of this study was to develop a molecular explanation of the enhanced sensitivity to NMDA. We used radioligand binding studies of membranes isolated from microdissected regions of hippocampus including fascia dentata, CA3, and CA1. We also used quantitative in situ hybridization with subtype-specific riboprobes or oligonucleotides to determine whether increased expression of one or more of the genes encoding NMDA receptors was present in hippocampal granule and pyramidal cells of kindled animals. When studied 28 d after the last evoked seizure, we found that kindling induced a 2.8-fold increase in the number of binding sites for the competitive NMDA receptor antagonist 3-[(+/-)-2-(carboxypiperazine-4-yl)][1,2-3H-]propyl-1-phosphonic acid (3H-CPP). This increase was confined to region CA3 within the hippocampus. Similar, though much smaller, changes were detected 24 hr after the last evoked seizure. Surprisingly, no changes in the binding of another competitive NMDA receptor antagonist, cis-4-(phosphonomethyl)-2-3H-piperidinecarboxylate (3H-CGS-19755), were detected at either time point in any hippocampal region. Transcript levels of the NMDA receptor genes NMDAR1, NR2A, NR2B, NR2C, and NR2D and a glutamate-binding protein (GBP) were not altered by kindling. These findings demonstrate that kindling induces the expression of an NMDA receptor that is novel in that it is recognized by 3H-CPP but not by 3H-CGS-19755. The molecular basis of this novel NMDA receptor is not determined by differential expression of mRNA transcripts of known NMDA receptor genes. The direction, time course, and location of the kindling-induced increase in 3H-CPP binding suggest that this novel receptor may underlie the increased sensitivity of CA3 neurons to NMDA observed in kindled animals.
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PMID:Kindling induces the long-lasting expression of a novel population of NMDA receptors in hippocampal region CA3. 802 71

Intense electrical activity throughout the brain which results from generalized epileptic or kindled seizures is thought to cause persistent and widespread neuronal plastic changes. We have previously reported that stage 5 kindled seizures cause an increase in vasopressin messenger RNA content and nitric oxide synthase activity in neuroendocrine cells of the supraoptic nucleus which lasts for at least four months after the last seizure. To evaluate whether changes in the expression of N-methyl-D-aspartate receptor subunits might contribute to these effects, the expression of NR1, NR2A, NR2B. NR2C and NR2D subunit messenger RNAs was examined by in situ hybridization in neuroendocrine cells of the supraoptic nucleus one month after amygdala kindling to stage 5 seizures. No change in NR1 subunit messenger RNA expression was seen. In contrast, NR2B subunit messenger RNA was significantly increased. by about 63%, and NR2D subunit messenger RNA was significantly decreased, by about 22%. indicating a shift in NR2 subunit messenger RNA expression. NR2B subunit messenger RNA was also significantly increased in adjacent limbic structures. The long-lasting shift towards increased NR2B and decreased NR2D messenger RNA expression after kindling suggests that N-methyl-D-aspartate receptor NR2 composition may be an important factor in the maintenance of pathological plasticity following generalized seizures. If these changes in messenger RNA are translated into increased NR2B and decreased NR2D subunits in the N-methyl-D-aspartate receptors in vivo, both a decrease in sensitivity due to a strong magnesium block and an increase in channel ion gating might be predicted.
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PMID:Amygdala kindling alters N-methyl-D-aspartate receptor subunit messenger RNA expression in the rat supraoptic nucleus. 913 Jul 80

Chronic ethanol exposure and subsequent withdrawal are known to change NMDA receptor activity. This study examined the effects of chronic ethanol administration and withdrawal on the expression of several NMDA receptor subunit and splice variant mRNAs in the rat cerebral cortex. Ethanol dependence was induced by ethanol vapour exposure. To delineate between seizure-induced changes in expression during withdrawal and those due to withdrawal per se, another group of naive rats was treated with pentylenetetrazol (PTZ) injection (30 mg/kg, i.p.). RNA samples from the cortices of chronically treated and withdrawing animals were compared to those from pair-fed controls. Changes in NMDA receptor mRNA expression were determined using ribonuclease protection assays targetting the NR2A, -2B, -2C and NR1-pan subunits as well as the three alternatively spliced NR1 inserts (NR1-pan describes all the known NR1 splice variants generated from the 5' insert and the two 3' inserts). The ratio of NR1 mRNA incorporating the 5' insert vs. that lacking it was decreased during ethanol exposure and up to 48 h after withdrawal. NR2B mRNA expression was elevated during exposure, but returned to control levels 18 h after withdrawal. Levels of NR2A, NR2C, NR1-pan and both 3' NR1 insert mRNAs from the ethanol-treated groups did not alter compared with the pair-fed control group. No changes in the level of any NMDA receptor subunit mRNA was detected in the PTZ-treated animals. These data support the hypothesis that changes in NMDA receptor subunit composition may underlie a neuronal adaptation to the chronic ethanol-inhibition and may therefore be important in the precipitation of withdrawal hyperactivity.
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PMID:Chronic ethanol exposure and withdrawal influence NMDA receptor subunit and splice variant mRNA expression in the rat cerebral cortex. 1008 58

Transcriptional and translational regulation of glutamate receptor expression determines one of the key phenotypic features of neurons in the brain--the properties of their excitatory synaptic receptors. Up- and down-regulation of various glutamate receptor subunits occur throughout development, following ischemia, seizures, repetitive activation of afferents, or chronic administration of a variety of drugs. The promoters of the genes that encode the NR1, NR2B, NR2C, GluR1, GluR2, and KA2 subunits share several characteristics that include multiple transcriptional start sites within a CpG island, lack of TATA and CAAT boxes, and neuronal-selective expression. In most cases, the promoter regions include overlapping Sp1 and GSG motifs near the major initiation sites, and a silencer element, to guide expression in neurons. Manipulating the levels of glutamate receptors in vivo by generating transgenic and knockout mice has enhanced understanding of the role of specific glutamate receptor subunits in long-term potentiation and depression, learning, seizures, neural pattern formation, and survival. Neuron-specific glutamate receptor promoter fragments may be employed in the design of novel gene-targeting constructs to deliver future experimental transgene and therapeutic agents to selected neurons in the brain.
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PMID:Genetic regulation of glutamate receptor ion channels. 1033 Oct 83

The purification, characterization, and synthesis of conantokin-R (Con-R), an N-methyl-D-aspartate (NMDA) receptor peptide antagonist from the venom of Conus radiatus, are described. With the use of well defined animal seizure models, Con-R was found to possess an anticonvulsant profile superior to that of ifenprodil and dizocilpine (MK-801). With voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs, Con-R exhibited the following order of preference for NR2 subunits: NR2B approximately NR2A > NR2C >> NR2D. Con-R was without effect on oocytes expressing the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 or the kainate receptor subunit GluR6. In mouse cortical neurons voltage-clamped at -60 mV, Con-R application produced a slowly developing block of inward currents evoked by 10 microM NMDA and 1 microM glycine (IC(50) = 350 nM). At 3 microM, Con-R did not affect gamma-aminobutyric acid- or kainate-evoked currents. Con-R prevented sound-induced tonic extension seizures in the Frings audiogenic seizure-susceptible mice at i.c.v. doses below toxic levels. It was also effective at nontoxic doses in CF#1 mice against tonic extension seizures induced by threshold (15 mA) and maximal (50 mA) stimulation, and it partially blocked clonic seizures induced by s.c. pentylenetetrazol. In contrast, MK-801 and ifenprodil were effective only at doses approaching (audiogenic seizures) or exceeding (electrical and pentylenetetrazol seizures) those required to produce significant behavioral impairment. These results indicate that the subtype selectivity and other properties of Con-R afford a distinct advantage over the noncompetitive NMDA antagonists MK-801 and ifenprodil. Con-R is a useful new pharmacological agent for differentiation between the anticonvulsant and toxic effects of NMDA antagonists.
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PMID:In vitro and in vivo characterization of conantokin-R, a selective NMDA receptor antagonist isolated from the venom of the fish-hunting snail Conus radiatus. 1060 79

Changes in mRNA levels of N-methyl-D-aspartate receptor (NR) subunits were studied in a rat model of withdrawal from forced ethanol ingestion over a period of 8 days. In part, this model may reflect the epsilon-type of human alcoholism according to Jellinek (College University Press, New Haven; 1972). The epsilon-type is characterized by dipsomania over a period of several days, recurring every few months and often followed by ethanol-induced seizures. Seizures may be modulated by an increased glutamatergic neurotransmission to excitatory or inhibitory neurons on the basis of a changed gene expression of NR subunits. This hypothesis promoted the present study. Film autoradiograms and emulsion-coated brain sections following labeling of cholinergic and GABAergic neuron populations were evaluated. NR subunit 1 (NR1) expression, studied with a probe recognizing all NR1 transcripts, was unchanged after withdrawal from chronic ethanol treatment compared to control animals. Using probes specific for different splice segments of NR1, however, we found that, in ethanol-treated rats, the expression of NR1-2 was decreased in all, and that of NR1-4 in all but one, areas investigated (only single label experiments were performed with NR1 splice variants). Withdrawing rats revealed a higher expression of NR subunit 2A (NR2A) mRNA in GABAergic neurons. No changes could be observed at the regional level. Conversely, NR2B mRNA was not substantially altered in cholinergic and GABAergic neurons, but showed a decrease over brain areas. For both, NR2C and NR2D, no ethanol-related changes of mRNA expression were observed. A link between such differential alterations in NR mRNA subunit expression and ethanol-induced seizures in withdrawing alcoholics of the epsilon-type seems possible.
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PMID:Changes in NMDA receptor subunit gene expression in the rat brain following withdrawal from forced long-term ethanol intake. 1068 78

Although serine proteases and their receptors are best known for their role in blood coagulation and fibrinolysis, the CNS expresses many components of an extracellular protease signaling system including the protease-activated receptor-1 (PAR1), for which thrombin is the most effective activator. In this report we show that activation of PAR1 potentiates hippocampal NMDA receptor responses in CA1 pyramidal cells by 2.07 +/- 0.27-fold (mean +/- SEM). Potentiation of neuronal NMDA receptor responses by thrombin can be blocked by thrombin and a protein kinase inhibitor, and the effects of thrombin can be mimicked by a peptide agonist (SFLLRN) that activates PAR1. Potentiation of the NMDA receptor by thrombin in hippocampal neurons is significantly attenuated in mice lacking PAR1. Although high concentrations of thrombin can directly cleave both native and recombinant NR1 subunits, the thrombin-induced potentiation we observe is independent of NMDA receptor cleavage. Activation of recombinant PAR1 also potentiates recombinant NR1/NR2A (1.7 +/- 0.06-fold) and NR1/NR2B (1.41 +/- 0.11-fold) receptor function but not NR1/NR2C or NR1/NR2D receptor responses. PAR1-mediated potentiation of recombinant NR1/NR2A receptors occurred after activation with as little as 300 pm thrombin. These data raise the intriguing possibility that potentiation of neuronal NMDA receptor function after entry of thrombin or other serine proteases into brain parenchyma during intracerebral hemorrhage or extravasation of plasma proteins during blood-brain barrier breakdown may exacerbate glutamate-mediated cell death and possibly participate in post-traumatic seizure. Furthermore, the ability of neuronal protease signaling to control NMDA receptor function may also have roles in normal brain development.
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PMID:Potentiation of NMDA receptor function by the serine protease thrombin. 1084 28

For the purpose of investigating the long-term effects of seizures in neonatal rats on spatial learning ability and N-methyl-D-aspartate (NMDA) receptor expression in adult rat brain, a seizure was induced by inhalant flurothyl daily in neonatal Wistar rats from postnatal day 6 (P6). The authors assigned six rats each averagely into the single-seizure group, the recurrent-seizure group (seizures induced in six consecutive days), and the control group. During P60 to P65, the rats were tested for spatial learning ability with the Morris water maze task. On P75, the authors examined protein expression of the NMDA receptor (NR) subunits, NR1, 2A, 2B, 2C, and 2D, in the cerebral cortex and hippocampus by Western blotting analysis. On P65, the escape latencies from the water maze of the rats in the recurrent-seizure group were significantly longer than those of the control rats, but there was no difference between the single-seizure group and the control group. NR subunit expression in the cerebral cortex and hippocampus of the rats with single seizure was similar to those in the control rats. Compared with the control rats, the protein expressions of NR1, NR2A and NR2B in the cerebral cortex and NR2A in the hippocampus of the recurrent-seizure group was significantly decreased, but NR2C protein expression in the cerebral cortex and hippocampus significantly increased. Recurrent seizures induced in neonatal rats might cause long-term spatial learning ability deficit and modify NR expression in the cerebral cortex and hippocampus of adult rats. The results suggest that abnormal NR expression might play an important role in long-term spatial learning ability deficit induced by recurrent seizures in early life.
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PMID:Long-term effects of seizures in neonatal rats on spatial learning ability and N-methyl-D-aspartate receptor expression in the brain. 1535 1

To evaluate the long-term effects of single or recurrent prolonged neonatal seizures on seizure threshold and neuronal activity in the brain, a novel "twist" seizure was induced by coupling early-life flurothyl-induced seizures with later exposure to pentylenetetrazol. The authors assigned six neonatal rats for each group: the single-seizure group (SS), the recurrent-seizure group (RS) and the control group. At postnatal day 46, seizure threshold was examined using pentylenetetrazol, and then the brain slices were evaluated with thionine staining, in situ end labeling and immunohistochemical studies. The Results showed that the rats in SS and RS groups all had reduced latencies to develop generalized tonic seizures induced by PTZ compared with controls (P<0.01). Morphologic changes, cell loss and apoptotic cells were observed only in those of RS group. Significant fos and NR2C-immunoreactive positive cells were seen in hippocampus of rats in both SS and RS groups compared with controls (P<0.01). A significant decrease in the number of GABA-A-alpha1 immunoreactive positive neurons was detected in hippocampus in rats of SS and RS groups compared with the controls (P<0.01). We conclude that neonatal rats subjected to prolonged seizures have pronounced long-term effects on seizure threshold and neuronal neurophysiological activity in the brain. Obvious neuronal injury, however, was only seen in rat with recurrent-seizures. Subtle brain damage might occur in rats experiencing single prolonged neonatal seizures.
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PMID:c-Fos, N-methyl-d-aspartate receptor 2C, GABA-A-alpha1 immonoreactivity, seizure latency and neuronal injury following single or recurrent neonatal seizures in hippocampus of Wistar rat. 1585 68


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