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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differential effects of metabotropic glutamate receptor antagonists on bursting activity in the amygdala. Metabotropic glutamate receptors (mGluRs) are implicated in both the activation and inhibition of epileptiform bursting activity in seizure models. We examined the role of mGluR agonists and antagonists on bursting in vitro with whole cell recordings from neurons in the basolateral amygdala (BLA) of amygdala-kindled rats. The broad-spectrum mGluR agonist 1S,3R-1-aminocyclopentane dicarboxylate (1S,3R-ACPD, 100 microM) and the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG, 20 microM) evoked bursting in BLA neurons from amygdala-kindled rats but not in control neurons. Neither the group II agonist (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG-I, 10 microM) nor the group III agonist L-2-amino-4-phosphonobutyrate (L-AP4, 100 microM) evoked bursting. The agonist-induced bursting was inhibited by the mGluR1 antagonists (+)-alpha-methyl-4-carboxyphenylglycine [(+)-MCPG, 500 microM] and (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG, 300 microM]. Kindling enhanced synaptic strength from the lateral amygdala (LA) to the BLA, resulting in synaptically driven bursts at low stimulus intensity. Bursting was abolished by (S)-4C3HPG. Further increasing stimulus intensity in the presence of (S)-4C3HPG (300 microM) evoked action potential firing similar to control neurons but did not induce epileptiform bursting. In kindled rats, the same threshold stimulation that evoked epileptiform bursting in the absence of drugs elicited excitatory postsynaptic potentials in (S)-4C3HPG. In contrast (+)-MCPG had no effect on afferent-evoked bursting in kindled neurons. Because (+)-MCPG is a mGluR2 antagonist, whereas (S)-4C3HPG is a mGluR2 agonist, the different effects of these compounds suggest that mGluR2 activation decreases excitability. Together these data suggest that group I mGluRs may facilitate and group II mGluRs may attenuate epileptiform bursting observed in kindled rats. The mixed agonist-antagonist (S)-4C3HPG restored synaptic transmission to control levels at the LA-BLA synapse in kindled animals. The different actions of (S)-4C3HPG and (+)-MCPG on LA-evoked bursting suggests that the mGluR1 antagonist-mGluR2 agonist properties may be the distinctive pharmacology necessary for future anticonvulsant compounds.
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PMID:Differential effects of metabotropic glutamate receptor antagonists on bursting activity in the amygdala. 1032 47

Convulsions were induced in rats by a single injection of pentylenetetrazol (PTZ) and [3H]L-2-amino-4-phosphonobutyrate ([3H]L-AP4) in vitro receptor autoradiography was used to evaluate the effects on the expression of group III metabotropic glutamate receptors. Significant increases by 60-80% in [3H]L-AP4 binding was observed in the frontal parts of cortex (sensory, motor and cingulate cortex) and by 28% in the molecular layer of the cerebellar cortex 24 h after PTZ-induced seizures. Since group III metabotropic glutamate receptors has an inhibitory effect on glutamatergic transmission, the observed increases in binding may indicate that these receptors serve as a mechanism for preventing further seizure activity.
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PMID:Pentylenetetrazol-induced seizures increase [3H]L-2-amino-4-phosphonobutyrate binding in discrete regions of the rat brain. 1033 70

Neuropeptide Y (NPY) has been shown to depress hyperexcitable activity that has been acutely induced in the normal rat brain. To test the hypothesis that NPY can also reduce excitability in the chronically epileptic human brain, we recorded intracellularly from dentate granule cells in hippocampal slices from patients with hippocampal seizure onset. NPY had a potent and long-lasting inhibitory action on perforant path-evoked excitatory responses. In comparison, the group 3 metabotropic glutamate receptor agonist L-2-amino-4-phosphonobutyric acid (L-AP4) evoked a mild and transient decrease. NPY-containing axons were found throughout the hippocampus, and in many epileptic patients were reorganized, particularly in the dentate molecular layer. NPY may therefore play a beneficial role in reducing granule cell excitability in chronically epileptic human tissue, and subsequently limit seizure severity.
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PMID:NPY inhibits glutamatergic excitation in the epileptic human dentate gyrus. 1040 Sep 74

Monosynaptic and polysynaptic responses of CA3 pyramidal cells (PC) to stimulation of the dentate gyrus (DG) are normally blocked by glutamate receptor antagonists (GluRAs). However, after kindled seizures, GluRAs block the monosynaptic excitatory postsynaptic potential (EPSP) and isolate a monosynaptic inhibitory postsynaptic potential (IPSP), suggesting that mossy fibers release GABA. However, kindling epilepsy induces neuronal sprouting, which can underlie this fast inhibitory response. To explore this possibility, the synaptic responses of PC to DG stimulation were analyzed in kindled epileptic rats, with and without seizures, and in nonepileptic rats, immediately after a single pentylenetetrazol (PTZ)-induced seizure, in which sprouting is unlikely to have occurred. Excitatory and inhibitory synaptic responses of PC to DG stimulation were blocked by GluRAs in control cells and in cells from kindled nonseizing rats, confirming that inhibitory potentials are disynaptically mediated. However, a fast IPSP could be evoked in kindled epileptic rats and in nonepileptic rats after a single PTZ-induced seizure. The same response was induced after rekindling the epileptic nonseizing rats. This IPSP has an onset latency that parallels that of the control EPSP and is not altered under low Ca(2+) medium or halothane perfusion. In addition, it was reversibly depressed by L(+)-2-amino-4-phosphonobutyric acid (L-AP4), which is known to inhibit transmitter release from mossy fibers. These results demonstrate that seizures, and not the synaptic rearrangement due to an underlying epileptic state, induce the emergence of fast inhibition in the DG-CA3 system, and suggest that the mossy fibers underlie this plastic change.
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PMID:Seizures induce simultaneous GABAergic and glutamatergic transmission in the dentate gyrus-CA3 system. 1111 Aug 37

GABAergic transmission in the mossy fiber (MF) projection of the hippocampus is not normally detected in the rat. However, seizures induce simultaneous glutamatergic and GABAergic transmission in this projection, which coincides with an overexpression of GAD(67) and vesicular GABA transporter (VGAT) mRNA in the dentate gyrus (DG) and MF. To test whether this plastic change could be induced in an activity-dependent fashion in the absence of seizures, I recorded intracellularly from slices/cells that served as their own control, before and after direct or synaptic kindling of the DG in vitro. As expected, synaptic responses of CA3 pyramidal cells to test pulse DG stimulation were blocked by perfusion of N-methyl-D-aspartate (NMDA) and non-NMDA receptors' antagonists. However, after kindling the perforant path (3 1-s trains of 0.1-ms pulses at 100 Hz, 1 min apart from each other every 15 min for 3 h), which potentiated synaptic responses without inducing epileptiform activity, the perfusion of glutamatergic antagonists blocked the excitatory synaptic potential and isolated a fast bicuculline-sensitive inhibitory synaptic potential. Immunohistochemical experiments confirmed the overexpression of GAD(67) in the kindled slices. If kindling stimulation was provided just for 1 h or if it was completed in the presence of the protein synthesis inhibitor, cycloheximide, the expression of the GABAergic potential was prevented. Alternatively, when control synaptic responses of a given cell were first blocked, the direct kindling stimulation over the same site during perfusion of glutamatergic antagonists resulted in the induction of fast GABAergic potentials after 16.6 +/- 0.9 kindling trials. Furthermore, a high spacial specificity of this phenomenon was evidenced by recording synaptic responses of a given pyramidal cell to two different MF inputs. After blockade of all synaptic responses with the perfusion of glutamatergic antagonists, one of the inputs was kindled, while synaptic responses between the kindling trials were monitored by applying test pulse stimulation to both inputs. After 17 +/- 1 trials, test pulse stimulation provided over the kindled site evoked GABAergic potentials, whereas test pulse stimulation delivered to the alternative nonkindled parallel MF input remained ineffective. The DG-evoked GABAergic responses were inhibited by the activation of GABA(B)R and mGluR, whereby activation of group III mGluR with L-2-amino-4-phosphonobutyric acid (L-AP4) was significantly more effective than the activation of group II mGluR with DCG-IV. These data demonstrate that GABAergic transmission from the MF projection has distinctive features in the adult rat, and that its induction is dependent on protein synthesis responding in an activity-dependent fashion.
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PMID:Activity-dependent expression of simultaneous glutamatergic and GABAergic neurotransmission from the mossy fibers in vitro. 1197 92

Activation of presynaptic metabotropic glutamate receptors (mGluRs) leads to a powerful inhibition of glutamate release from many synaptic terminals throughout the CNS. mGluRs as autoreceptors are believed to provide a negative feedback system that prevents potentially toxic accumulation of glutamate in the extracellular space during synchronous synaptic activity such as epileptic seizures. In this study we analyzed the function of presynaptic mGluR8 on terminals of the lateral perforant pathway in the pilocarpine model of limbic epilepsy. Field excitatory postsynaptic potentials (fEPSPs) recorded in hippocampal slices of rats that developed spontaneous recurrent seizures after pilocarpine-induced status epilepticus (SRS group) showed a significantly reduced sensitivity to Group III mGluR agonists and severe mossy fiber sprouting. The Group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 10 microM) depressed fEPSPs in the SRS group only by 26 +/- 21% compared to 50 +/- 18% in untreated rats. Similarly, the mGluR8 preferring agonist (R,S)-4-phosphonophenylglycine (PPG, 5 microM) was significantly less effective in slices from SRS rats (43 +/- 4% vs. 83 +/- 5%). Concentration-response curves for L-AP4 revealed that the EC(50) values were not different between the control and SRS group (13 +/- 7 microM vs. 9 +/- 9 microM), while the maximal depressing effect was significantly reduced. The remaining depressing effect of L-AP4 in the SRS group could be blocked by the Group III specific antagonists (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) and alpha-methyl-L-AP4 (MAP4). Rats that did not develop SRS following pilocarpine-induced status epilepticus were indistinguishable from control rats: fEPSPs were highly sensitive to L-AP4 and there was no mossy fiber sprouting. The results show that pilocarpine-induced status epilepticus can lead to a downregulation of mGluR8 and suggest that the condition of SRS is associated with a deteriorated autoregulation of glutamate release.
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PMID:Down-regulation of mGluR8 in pilocarpine epileptic rats. 1253 1

Glutamatergic ionotropic and metabotropic receptor modulators have been shown to produce anticonvulsant activity in a number of animal seizure models, e.g. maximal electroshock (MES) and DBA/2 sensory-induced seizures. The 6 Hz model of partial seizures is an alternative low frequency, long duration stimulation paradigm resulting in a seizure characterized by jaw and forelimb clonus, immobility, and an elevated tail (Straub-tail). A unique aspect of this model is that it is the only acute electrically-induced seizure model in which levetiracetam has displayed anticonvulsant activity, suggesting that the 6 Hz seizure model may be useful in identifying compounds with unique anticonvulsant profiles. The purpose of the present study was to examine the role of glutamate receptors in the MES and 6 Hz seizure models using a number of NMDA, AMPA/KA, and mGlu receptor modulators. The pharmacological profile of the 6 Hz seizure model was compared to that of the MES model using eight ionotropic glutamate receptor antagonists and eight mGlu receptor modulators. The ionotropic receptor antagonists MK-801, LY235959, NBQX, LY293558, GYKI 52466, LY300168, and LY377770 produced complete protection from tonic extension in the MES model. Furthermore, the noncompetitive mGlu1 (LY456236) and mGlu5 (MPEP) metabotropic receptor antagonists and the mGlu8 metabotropic receptor agonist (PPG) were also effective in the MES model whereas the competitive mGlu1 (LY367385) receptor antagonist, the mGlu2/3 (LY379268 and LY389795) and Group III (L-AP4) metabotropic receptor agonists were ineffective. In contrast, all of the compounds tested, produced dose-dependent protection in the 6 Hz model with an increase in potency as compared to the MES model. The largest protective indices (P.I.=TD50/ED50) observed were associated with the iGlu5 antagonist LY382884 and the mGlu2/3 receptor agonists LY379268 and LY389795 (P.I.=>14, 14, and 4.9, respectively) in the 6 Hz model. The results from the present study support the continued search for glutamate receptor modulators as potential antiepileptic agents. Furthermore these results illustrate the importance of using several different animal seizure models in the search for novel AEDs and the potential utility of the 6 Hz seizure model in identifying novel AEDs.
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PMID:Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models. 1452 50

The piriform cortex (PC) is the primary terminal zone of projections from the olfactory bulb, termed the lateral olfactory tract (LOT). The PC plays a critical role in processing of olfactory stimuli and is also a highly seizure prone area thought to be involved in some forms of temporal lobe epilepsy. Pharmacological and immunohistochemical studies provide evidence for the localization of various metabotropic glutamate receptors (GluRs) in the PC. We employed whole-cell patch clamp recordings from PC pyramidal cells to determine the roles of group III mGluRs in modulating synaptic transmission at the LOT-PC synapse. The group III mGluR agonist, L-AP4, induced a concentration-dependent inhibition of synaptic transmission at the LOT-PC synapse at concentrations that activate mGluR4 and mGluR8, but not mGluR7 or other mGluR subtypes (EC50=473nM). In addition, the selective mGluR8 agonist, DCPG (300nM), also suppressed synaptic transmission at the LOT synapse. Furthermore, the inhibitory actions of L-AP4 and Z-cyclopentyl-AP4, a selective mGluR4 agonist, were potentiated by the mGluR4 positive allosteric modulator, PHCCC (30microM). The high potency of L-AP4, combined with the observed effects of DCPG and PHCCC, suggests that both mGluR4 and mGluR8 play a role in the l-AP4-induced inhibition of synaptic transmission at the LOT-PC synapse.
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PMID:Metabotropic glutamate receptors mGluR4 and mGluR8 regulate transmission in the lateral olfactory tract-piriform cortex synapse. 1862 54

Considering the contribution of hippocampal formation and glutamate-mediated signalling to epileptogenesis, we investigated the effects of group III metabotropic glutamate receptor (mGluR)-selective ligands on the kindling of seizures. We also examined the concentration of the amino acid glutamate, GABA, alanine and taurine in the hippocampus of rats using a microdialysis technique. Pentylenetetrazol (PTZ), a non-competitive antagonist of the GABA(A) receptor, was administered intraperitoneally at 35 mg/kg body weight to induce seizures. It was determined that the kindling of PTZ-induced seizures could be attenuated by post intracerebroventricular administration of 100 nmol of the group III mGluR antagonist CPPG [(RS)-a-cyclopropyl-4-phosphonophenylglycine]. There were significant differences in tested parameters during the final stages of the kindling procedure. The group III mGluR agonist L-AP4 [L-(+)-2-amino-4-phosphonobutyric acid at 100 nmol, i.c.v.] did not significantly affect the kindling of seizures in comparison to control rats, although there was acceleration of the process as compared to CPPG treated animals. We demonstrated that the baseline concentrations of glutamate, GABA, alanine, taurine, and the glutamine/GABA ratio were elevated in the hippocampus of fully kindled rats. Intracerebroventricular administration of a single dose of CPPG increased the concentrations of glutamate in the hippocampus of control, non-kindled rats. Intracerebroventricular administration of L-AP4 did not affect the hippocampal amino acid concentration in either animal group. Overall, these data suggest that there is a shift in the balance between neurotransmitters towards increased production of excitatory amino acids, and this may be mediated by group III mGluRs during seizure kindling.
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PMID:The effects of group III mGluR ligands on pentylenetetrazol-induced kindling of seizures and hippocampal amino acids concentration. 1948 36

Vascular endothelial growth factor (VEGF) was first described as an angiogenic agent, but has recently also been shown to exert various neurotrophic and neuroprotective effects in the nervous system. These effects of VEGF are mainly mediated by its receptor, VEGFR-2, which is also referred to as the fetal liver kinase receptor 1 (Flk-1). VEGF is up-regulated in neurons and glial cells after epileptic seizures and counteracts seizure-induced neurodegeneration. In vitro, VEGF administration suppresses ictal and interictal epileptiform activity caused by AP4 and 0 Mg(2+) via Flk-1 receptor. We therefore explored whether increased VEGF signaling through Flk-1 overexpression may regulate epileptogenesis and ictogenesis in vivo. To this extent, we used transgenic mice overexpressing Flk-1 postnatally in neurons. Intriguingly, Flk-1 overexpressing mice were characterized by an elevated threshold for seizure induction and a decreased duration of focal afterdischarges, indicating anti-ictal action. On the other hand, the kindling progression in these mice was similar to wild-type controls. No significant effects on blood vessels or glia cells, as assessed by Glut1 and GFAP immunohistochemistry, were detected. These results suggest that increased VEGF signaling via overexpression of Flk-1 receptors may directly affect seizure activity even without altering angiogenesis. Thus, Flk-1 could be considered as a novel target for developing future gene therapy strategies against ictal epileptic activity.
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PMID:VEGF receptor-2 (Flk-1) overexpression in mice counteracts focal epileptic seizures. 2280 85


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