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)

Previously we have demonstrated that mature inbred strains of mice differ significantly in their response to kainate-induced cell death. While both C57BL/6 and FVB/N mice exhibit similar seizure activity in response to kainate, only C57BL/6 mice can be characterized as resistant to kainate-induced cell death. To examine further the molecular pharmacological basis for this strain difference in hippocampal sensitivity, we assessed the ability of the ionotropic glutamate receptor agonists, kainic acid (KA), N-methyl-D-aspartate (NMDA), ibotenic acid (IBO), and quinolinic acid (QUIN), to promote excitotoxic damage. We examined seizure-related behavior and subsequent neurotoxicity in C57BL/6 and FVB/N mice following intrahippocampal administration of the kainate receptor agonist, KA, the NMDA receptor agonists NMDA or QUIN, or the NMDA and metabotropic glutamate receptor agonist, IBO. The time course and extent of cell death in mice were evaluated using Nissl and selective silver stains, and Fluoro-Jade, a fluorescent marker for dying neurons. In the present study, FVB/N mice were exquisitely sensitive to injection of KA at all doses, while susceptibility in C57BL/6 mice was dose dependent. In contrast, while hippocampal damage was present in both strains at all doses of QUIN, the extent of cell damage was significantly less in C57BL/6 mice at low doses (30 and 60 mM). Similarly, IBO administration resulted in differences in the extent of cell death when administered at the highest dose (126 mM). No strain-dependent differences in cell loss were observed following NMDA lesions. These results provide further evidence that susceptibility to excitotoxin-induced cell death is highly strain dependent and is kainate and NMDA receptor dependent.
 ...
PMID:Modulation of cell death by mouse genotype: differential vulnerability to excitatory amino acid-induced lesions. 1250 81

The granule cells of the dentate gyrus (DG) are considered to be glutamatergic, but they contain glutamic acid decarboxylase, gamma-amino butyric acid (GABA), and the vesicular GABA transporter mRNA. Their expression is regulated in an activity-dependent manner and coincides with the appearance of GABAergic transmission from the mossy fibers (MF) to pyramidal cells in area CA3. These data support the hypothesis that MF are able to release glutamate and GABA. Following the principle that a given neuron releases the same neurotransmitter(s) onto all its targets, we here demonstrate the emergence, after a generalized convulsive seizure, of MF GABAergic signaling sensitive to activation mGluR-III onto pyramidal cells and interneurons of CA3. Despite this, excitation overrides inhibition in interneurons, preventing disinhibition. Furthermore, on blockade of GABA and glutamate ionotropic receptors, an M1-cholinergic depolarizing signal is also revealed in both targets, which postsynaptically modulates the glutamatergic and GABAergic fast neurotransmission. The emergence of these nonglutamatergic signals depends on protein synthesis. In contrast to cholinergic responses evoked by associational/commissural fibers activation, cholinergic transmission evoked by DG stimulation is only observed after seizures and is strongly depressed by the activation of mGluR-II, whereas both are depressed by M2-AChR activation. With immunohistological experiments, we show that this cholinergic pathway runs parallel to the MF. Thus seizures compromise a delicate balance of excitation and inhibition, on which a complex interaction of different neurotransmitters emerges to counteract excitation at pre- and postsynaptic sites. Particularly, MF GABAergic inhibition emerges to exert an overall inhibitory action on CA3.
 ...
PMID:Activity-dependent induction of multitransmitter signaling onto pyramidal cells and interneurons of hippocampal area CA3. 1261 45

Systemic administration of kainic acid in C57BL/6 and FVB/N mice induces a comparable level of seizure induction yet results in differential susceptibility to seizure-induced cell death. While kainate administration causes severe hippocampal damage in mice of the FVB/N strain, C57BL/6 mice display no demonstrable cell loss or damage. At present, while the cellular mechanisms underlying strain-dependent differences in susceptibility remain unclear, some of this variation is assumed to have a genetic basis. As glutamate receptors are thought to participate in seizure induction and the subsequent neuronal degeneration that ensues, previous studies have proposed that variation in the precise subunit composition of glutamate receptors may result in differential susceptibility to excitotoxic cell death. Thus, we chose to examine the relationship between the cellular distribution and expression of glutamate receptor subunit proteins and cell loss within the hippocampus in mouse strains resistant and susceptible to kainate-induced excitotoxicity. Using semi-quantitative Western blot techniques and immunohistochemistry with the use of antibodies that recognize subunits of the KA (GluR5,6,7), AMPA (GluR1, GluR2, and GluR4), and NMDA (NMDAR1 and NMDAR2A/2B) receptors, we found no significant strain-dependent differences in the expression or distribution of these glutamate receptor subunits in the intact hippocampus. Following kainate administration, expression changes in ionotropic glutamate receptor subunits paralleled the development of susceptibility to cell death in the FVB/N strain only. Strain differences in hippocampal vulnerability to kainate-induced status epilepticus are not due to glutamate receptor protein expression.
 ...
PMID:Differences in ionotropic glutamate receptor subunit expression are not responsible for strain-dependent susceptibility to excitotoxin-induced injury. 1267 Jul 4

T cells may encounter glutamate, the major excitatory neurotransmitter in the nervous system, when patrolling the brain and in glutamate-rich peripheral organs. Moreover, glutamate levels increase in the CNS in many pathological conditions in which T cells exert either beneficial or detrimental effects. We discovered that normal human T cells, human T leukemia cells, and mouse anti-myelin basic protein T cells express high levels of glutamate ion channel receptor (ionotropic) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3). The evidence for GluR3 on T cells includes GluR3-specific RT-PCR, Western blot, immunocytochemical staining and flow cytometry. Sequencing showed that the T cell-expressed GluR3 is identical with the brain GluR3. Glutamate (10 nM), in the absence of any additional molecule, triggered T cell function: integrin-mediated T cell adhesion to laminin and fibronectin, a function normally performed by activated T cells only. The effect of glutamate was mimicked by AMPA receptor-agonists and blocked specifically by the selective receptor-antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-dione (NBQX), and by relevant anti-integrin mAbs. Glutamate also increased the CXCR4-mediated T cell chemotactic migration toward the key chemokine CXCL12/stromal cell-derived factor-1. GluR3 expression on normal, cancer and autoimmune-associated T cells and the ability of glutamate to directly activate T cell function could be of substantial scientific and clinical importance to normal neuroimmune dialogues and to CNS diseases and injury, and especially to: 1) T cell transmigration to the CNS and patrolling in the brain, 2) T cell-mediated multiple sclerosis, and 3) autoimmune epilepsy, as neurotoxic anti-GluR3 Abs are found and suspected to cause/potentiate seizures and neuropathology in several types of human epilepsies. Thus far, GluR3 was found only on neurons and glia cells; our results reveal a novel peripheral source of this antigenic receptor.
 ...
PMID:Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. 1268 73

The amygdala is a critical brain region for limbic seizure activity, but the mechanisms underlying its epileptic susceptibility are obscure. Several lines of evidence implicate GluR5 (GLU(K5)) kainate receptors, a type of ionotropic glutamate receptor, in the amygdala's vulnerability to seizures and epileptogenesis. GluR5 mRNA is abundant in temporal lobe structures including the amygdala. Brain slice recordings indicate that GluR5 kainate receptors mediate a portion of the synaptic excitation of neurons in the rat basolateral amygdala. Whole-cell voltage-clamp studies demonstrate that GluR5 kainate receptor-mediated synaptic currents are inwardly rectifying and are likely to be calcium permeable. Prolonged activation of basolateral amygdala GluR5 kainate receptors results in enduring synaptic facilitation through a calcium-dependent process. The selective GluR5 kainate receptor agonist ATPA induces spontaneous epileptiform bursting that is sensitive to the GluR5 kainate receptor antagonist LY293558. Intra-amygdala infusion of ATPA in the rat induces limbic status epilepticus; in some animals, recurrent spontaneous seizures occur for months after the ATPA treatment. Together, these observations indicate that GluR5 kainate receptors have a unique role in triggering epileptiform activity in the amygdala and could participate in long-term plasticity mechanisms that underlie some forms of epileptogenesis. Accordingly, GluR5 kainate receptors represent a potential target for antiepileptic and antiepileptogenic drug treatments. Most antiepileptic drugs do not act through effects on glutamate receptors. However, topiramate at low concentrations causes slow inhibition of GluR5 kainate receptor-mediated synaptic currents in the basolateral amygdala, indicating that it may protect against seizures, at least in part, through suppression of GluR5 kainate receptor responses.
 ...
PMID:GluR5 kainate receptors, seizures, and the amygdala. 1272 56

Epilepsy is closely related to an altered transmission of GABA, the major inhibitory transmitter in the brain. GABA acts through two classes of receptors, ionotropic GABA(A) receptors and metabotropic GABA(B) receptors. Using in situ hybridization, receptor autoradiography and immunocytochemistry, we now investigated temporal changes in the expression the GABA(B)-1 and GABA(B)-2 subunits (GABA(B)-1R and GABA(B)-1R, respectively) in the hippocampus following kainic-acid-induced seizures. Significant decreases (by about 40%) in mRNA levels of both splice variants (a and b) of GABA(B)-1R and of GABA(B)-2R were observed in the principal cell layer of the hippocampus 6-12 h after kainic acid injection in the rat. Whereas mRNA levels in the granule cell layer returned to basal after 24 h, the decreases persisted in sectors CA1 and CA3, presumably due to progressing neurodegeneration. In the sector CA3, GABA(B)-R mRNA levels and GABA(B)-R1 immunoreactivity partially recovered 30 days after the initial kainic acid seizures indicating receptor upregulation in surviving neurons.
 ...
PMID:Altered expression of GABAB receptors in the hippocampus after kainic-acid-induced seizures in rats. 1275 12

GABA, which generally mediates inhibitory synaptic transmissions, occasionally acts as an excitatory transmitter through intense GABA(A) receptor activation even in adult animals. The excitatory effect results from alterations in the gradients of chloride, bicarbonate, and potassium ions, but its functional role still remains a mystery. Here we show that such GABAergic excitation participates in the expression of seizure-like rhythmic synchronization (afterdischarge) in the mature hippocampal CA1 region. Seizure-like afterdischarge was induced by high-frequency synaptic stimulation in the rat hippocampal CA1-isolated slice preparations. The hippocampal afterdischarge was completely blocked by selective antagonists of ionotropic glutamate receptors or of GABA(A) receptor, and also by gap-junction inhibitors. In the CA1 pyramidal cells, oscillatory depolarizing responses during the afterdischarge were largely dependent on chloride conductance, and their reversal potentials (average -38 mV) were very close to those of exogenously applied GABAergic responses. Moreover, intracellular loading of the GABA(A) receptor blocker fluoride abolished the oscillatory responses in the pyramidal cells. Finally, the GABAergic excitation-driven afterdischarge has not been inducible until the second postnatal week. Thus, excitatory GABAergic transmission seems to play an active functional role in the generation of adult hippocampal afterdischarge, in cooperation with glutamatergic transmissions and possible gap junctional communications. Our findings may elucidate the cellular mechanism of neuronal synchronization during seizure activity in temporal lobe epilepsy.
 ...
PMID:Excitatory GABA input directly drives seizure-like rhythmic synchronization in mature hippocampal CA1 pyramidal cells. 1276 87

The 3,4-dicarboxyphenylglycines (3,4-DCPGs) have recently been shown to be effective new anticonvulsant agents in a rodent model of epilepsy, with the racemic mixture showing significantly greater potency than either isomer alone. The (R)-isomer has been identified as a competitive AMPA-type ionotropic glutamate receptor antagonist, whilst (S)-3,4-DCPG is a highly potent and selective metabotropic glutamate receptor 8 (mGlu8 receptor) agonist. We now report the inhibitory activity of (R)- and (RS)-3,4-DCPG, but not (S)-3,4-DCPG, against both 35 mM and 50 mM KCl-evoked glutamate release in the rat cerebral cortex in vitro. In contrast to the anticonvulsant actions of the 3,4-DCPGs, no evidence was obtained for a synergistic inhibitory interaction between the separate isomers. We conclude that whilst inhibition of cortical excitatory amino acid release may contribute to the anticonvulsant actions of (RS)-3,4-DCPG, it does not represent the sole mechanism of action. Synergistic interactions between ligands acting at different subtypes of ionotropic and metabotropic glutamate receptors remains a promising new strategy for the treatment of currently drug-refractory seizure states.
 ...
PMID:Anticonvulsant dicarboxyphenylglycines differentially modulate excitatory amino acid release in the rat cerebral cortex. 1278 21

The present experiments aimed to compare the length of seizure activity with the time-related increase of transmitter release and the induction of c-fos gene expression in the striatum of the rat. Anesthetized Wistar rats were intraperitoneally treated with 7 mg/kg 4-aminopyridine, and the transmitter levels in the striatum were measured by means of in vivo microdialysis, 30, 60, 90, 120, and 150 min following the treatment. Striatal and neocortical electric activity was monitored with depth and surface electrodes, respectively. The expression level of the c-fos gene was estimated by counting the striatal c-fos-immunostained cell nuclei at the time intervals of the microdialysis. 4-aminopyridine elicited high-frequency seizure discharges in the EEG and significantly increased glutamate, aspartate, GABA, serotonin, noradrenaline, and dopamine levels in the extracellular dialysates. The number of c-fos-stained cell nuclei in the striatum displayed a prolonged increase, showing significantly elevated numbers throughout the experiment. The increase of c-fos expression in time correlated best with the increase of glutamate release, which was also significantly elevated at every sampling time. The GABA release, culminating at 60 min after the seizure onset, correlated best with the cessation of the electrographic seizure. Aspartate, norepinephrine, serotonin, and dopamine displayed transient but significant elevations. We conclude that glutamate plays the essential role (most probably through ionotropic and metabotropic receptors) in the extracellular signaling, which eventually leads to intracellular cascades and c-fos gene expression in the striatum during convulsions.
 ...
PMID:Seizure, neurotransmitter release, and gene expression are closely related in the striatum of 4-aminopyridine-treated rats. 1294 21

Neuropathic pain and epileptic seizures bear several similarities, among them is the response to anticonvulsant drugs. It has therefore been hypothesized that epileptiform activity of nociceptive spinal dorsal horn neurons may contribute to paroxysmal forms of neuropathic pain. We used patch-clamp and field potential recordings from young rat spinal cord slices to test if nociceptive dorsal horn structures are indeed able to sustain epileptiform activity. Application of the convulsant 4-aminopyridine (100 microM) evoked epileptiform activity that was most pronounced in superficial dorsal horn and involved nociceptive lamina I neurons with a projection to the brain. The epileptiform activity was dependent on fast excitatory and inhibitory synaptic transmission through ionotropic glutamate receptors and GABA(A) receptors. During epileptiform activity, previously silent polysynaptic pathways from primary afferent C-fibers to superficial dorsal horn neurons were opened. Stimulation of primary afferents at Adelta- and C-fiber intensity interfered with the epileptiform rhythm, suggesting that both affect the same dorsal horn structures. Similar to neuropathic pain, spinal dorsal horn epileptiform activity was much less reduced by classical analgesics than by anticonvulsant agents.
 ...
PMID:Epileptiform activity in rat spinal dorsal horn in vitro has common features with neuropathic pain. 1449 51


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