UMLS:C0036572 - FACTA Search

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

Various genes for transcription factors are induced in neurons involving long-lasting synaptic plasticity that is accompanied by de novo protein synthesis. In this study, we analyzed the gene expression of NeuroD-related factor (NDRF/neuroD2), a neural basic helix-loop-helix transcription factor, in the mouse hippocampus following pentylenetetrazol (PTZ)-induced seizures. Both the levels of mRNA and protein of NDRF were elevated by PTZ injection. In contrast to c-fos, a representative neuronal activation-related immediate-early gene that was induced within 1 h after PTZ administration, induction of the NDRF gene expression reached a maximum level at 7-8 h after PTZ injection and was inhibited by pretreatment with cycloheximide and MK801. In situ hybridization of the mouse hippocampus revealed that NDRF mRNA was significantly induced in the dentate gyrus. During hippocampal development, NDRF transcripts were found to be highly expressed in a juvenile period, when extensive synaptogenesis occurs. Our present results demonstrate that NDRF is a new member of the family of activation-induced transcription factors, whose expression is probably regulated by immediate-early transcription factors. NDRF is thought to be involved in long-lasting neuronal activation.
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PMID:Stimulation of gene expression of NeuroD-related factor in the mouse brain following pentylenetetrazol-induced seizures. 1175 69

The study was designed to investigate the effect of ketamine on convulsive behaviour using maximal electroshock (MES) test. An attempt was also made to study the possible receptor mechanisms involved. MES seizures were induced in mice via transauricular electrodes (60 mA, 0.2sec). Seizure severity was assessed by the duration of tonic hindlimb extensor phase and mortality due to convulsions. Intraperitoneal administration of ketamine produced a dose-dependent (5-50 mg/kg) protection against hindlimb extensor phase. The anticonvulsant effect of ketamine was antagonized neither by naloxone (low as well as high doses) nor sulpiride, but was attenuated by haloperidol, a dopamine (D2)/sigma receptor antagonist. Co-administration of gamma-aminobutyric acid (GABA)-ergic drugs (GABA, muscimol, diazepam and baclofen) and N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801) with ketamine facilitated the anticonvulsant action of the latter drug. In contrast, flumazenil, a benzodiazepine (BZD)-GABAA receptor antagonist, reversed the facilitatory effect of diazepam on the anti-MES effect of ketamine. Similarly, delta-aminovaleric acid (DAVA), antagonized the facilitatory effect of baclofen on anti-MES action of ketamine. These BZD-GABAergic antagonists, flumazenil or DAVA per se also attenuated the anti-MES effect of ketamine given alone. The results suggest that besides its known antagonistic effect on NMDA channel, other neurotransmitter systems i.e. sigma, GABAA-BZD-chloride channel complex and GABAB receptors may also be involved in the anti-MES action of ketamine.
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PMID:Possible mechanism of anticonvulsant effect of ketamine in mice. 1188 7

The study was designed to examine the effect of butorphanol, a classical opioid on convulsive behaviour using maximal electroshock (MES) test. An attempt was also made to investigate the role of possible receptor mechanisms involved. MES seizures were induced in mice via transauricular electrodes (60 mA, 0.2 s). Seizure severity was assessed by the duration of tonic hindlimb extensor phase and mortality due to convulsions. Intraperitoneal administration of butorphanol produced a dose-dependent (0.25-2 mg/kg) protection against hindlimb extensor phase. The anticonvulsant effect of butorphanol was antagonized by all the three opioid receptor antagonists (i.e., naloxone [mu], MR2266 [kappa], and naltrindole [delta], respectively). Coadministration of gamma-aminobutyric acid (GABA)-ergic drugs (diazepam, GABA, muscimol, and baclofen) and N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with butorphanol augmented the anticonvulsant action of the latter drug. In contrast, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the facilitatory effect of diazepam on the anti-MES effect of butorphanol. Similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, antagonized the facilitatory effect of baclofen, a GABA(B) agonist on anti-MES action of butorphanol. These BZD-GABAergic antagonists, flumazenil or DAVA, per se also counteracted the anti-MES effect of butorphanol given alone. These data exemplify the benefits of using the MES test, which is sensitive to opioidergic compounds and distinguished convulsive behavioural changes associated with GABAergic and NMDAergic effects. Taken together, the results implicate a role for multitude of neurotransmitter systems, i.e., opioid (mu, kappa, delta), NMDA channel, BZD-GABA(A) chloride channel complex, and GABA(B) receptors in the anti-MES action of butorphanol.
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PMID:Possible mechanism involved in the anticonvulsant action of butorphanol in mice. 1247 53

Various transcriptional activators are induced in neurons concomitantly with long-lasting neural activity, whereas only a few transcription factors are known to act as neural activity-inducible transcription repressors. In this study, mRNA of DREAM (DRE-antagonizing modulator), a Ca(2+)-modulated transcriptional repressor, was demonstrated to accumulate in the mouse brain after pentylenetetrazol (PTZ)-induced seizures. Accumulation in the mouse hippocampus reached maximal level in the late phase (at 7-8 h) after PTZ injection. Kainic acid induced the same response. Interestingly, the late induction of DREAM expression required new protein synthesis and was blocked by MK801 suggesting that Ca(2+)-influx via NMDA receptors is necessary for the PTZ-mediated DREAM expression. In situ hybridization revealed that PTZ-induced DREAM mRNA accumulation was observed particularly in the dentate gyrus, cerebral cortex, and piriform cortex. The results of the present study demonstrate that DREAM is a neural activity-stimulated late gene and suggest its involvement in adaptation to long-lasting neuronal activity.
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PMID:Seizure-mediated neuronal activation induces DREAM gene expression in the mouse brain. 1253 29

In the hippocampus, chelatable zinc is accumulated in vesicles of glutamatergic presynaptic terminals, abounding specially in the mossy fibers, from where it is released with activity and can exert a powerful inhibitory action upon N-methyl-D-aspartate receptors. Zinc is therefore in a strategic situation to control overexcitation at the zinc-rich excitatory synapses, and consequently zinc removal during high activity might result in excitotoxic neuronal damage. We analyzed the effect of zinc chelation with sodium dietyldithiocarbamate under overexcitation conditions induced by non-lesioning doses of kainic acid in the mouse hippocampus, to get insight into the role of zinc under overexcitation. Swiss male mice were injected with kainic acid (15 mg/kg, i.p.) 15 min prior to sodium dietyldithiocarbamate (150 mg/kg, i.p.), and left to survive for 6 h, 1 day, 4 days, or 7 days after the treatment. Cell damage was analyzed with the hematoxylin-eosin and acid fuchsin stainings. Neither control animals treated only with kainic acid nor those treated only with sodium dietyldithiocarbamate suffered seizures or neuronal damage. By contrast, the kainic acid+sodium dietyldithiocarbamate-treated animals showed convulsive behavior and cell death involving the hilus, CA3, and CA1 regions. Pretreatment with the N-methyl-D-aspartate receptor antagonist MK801 (1 mg/kg, i.p.) completely prevented neuronal damage. Experiments combining different doses of sodium dietyldithiocarbamate and kainic acid with different administration schedules demonstrated that the overlap of zinc chelation and overexcitation is necessary to trigger the observed effects. Moreover, the treatment with a high dose of sodium dietyldithiocarbamate (1000 mg/kg), which produced a complete bleaching of the Timm staining for approximately 12 h, highly increased the sensitivity of animals to kainic acid. Altogether, our results indicate that the actions of sodium dietyldithiocarbamate are based on a reduction of zinc levels, which under overexcitation conditions induce seizures and neuronal damage. These findings fully support a protective role for synaptically released zinc during high neuronal activity, most probably mediated by its inhibitory actions on N-methyl-D-aspartate receptors, and argue against a direct action of synaptic zinc on the observed neuronal damage.
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PMID:Zinc chelation during non-lesioning overexcitation results in neuronal death in the mouse hippocampus. 1257 20

Seizure-induced neuronal death may involve engagement of the BCL-2 family of apoptosis-regulating proteins. In the present study we examined the activation of proapoptotic BAD in cultured hippocampal neurons following seizures induced by removal of chronic glutamatergic transmission blockade. Kynurenic acid withdrawal elicited an increase in seizure-like electrical activity, which was inhibited by blockers of AMPA (CNQX) and NMDA (MK801 and AP5) receptor function. However, only NMDA receptor antagonists inhibited calcium entry as assessed by fura-2, and cell death of hippocampal neurons. Seizures increased proteolysis of caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) of cells. Seizure-like activity induced dephosphorylation of BAD and the disruption of its constitutive interaction with 14-3-3 proteins. In turn, BAD dimerized with antiapoptotic BCL-Xl after seizures. However, the absence of neuroprotective effects of pathway intervention suggests that BAD may perform a reinforcement rather than instigator role in cell death following seizures in vitro.
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PMID:Seizure-like activity leads to the release of BAD from 14-3-3 protein and cell death in hippocampal neurons in vitro. 1272 52

(1) Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. (2) CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly -80% of the NMDA-evoked current, with EC(50) of approximately 5 micro M. This effect was selective, reversible, use-dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. (3) CHF3381 also inhibited voltage-gated Na(+) currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 micro M). (4) Consistent with the mild effects on voltage-gated Na(+) channels, CHF3381 (100 micro M) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anti-convulsant agent and Na(+) channel blocker lamotrigine (100 micro M) inhibited stimulation-evoked glutamate overflow by approximately 50%. (5) CHF3381 reduced kindled seizure-induced c-fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo. (6) The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation.
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PMID:Mechanisms of action of CHF3381 in the forebrain. 1289 Jul 13

The present study was designed to investigate the effect of U50488H, a prototype non-peptide kappa opioid agonist on convulsive behaviour using a maximal electroshock (MES) seizure test in mice. An attempt was also made to explore the role of possible receptors involved. MES seizures were induced via transauricular electrodes (60 mA, 0.2 s). Seizure severity was evaluated by means of two parameters, i.e., (1). duration of tonic hindlimb extensor phase and (2). mortality due to convulsions. Intraperitoneal (i.p.) administration of U50488H dose dependently (5-20 mg/kg) decreased the hindlimb extensor phase of MES. The anticonvulsant effect of U50488H was attenuated by the general opioid antagonist, naloxone at a high dose, and by MR2266, a selective kappa antagonist, but not by naltrindole, a delta antagonist. Coadministration of gamma-aminobutyric acid (GABA)ergic drugs (diazepam, GABA, muscimol, and baclofen) and the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801), with U50488H augmented the anticonvulsant effect of the latter drug in mice. On the other hand, flumazenil, a central benzodiazepine (BZD) receptor antagonist, reversed the protective effect of diazepam and similarly, delta-aminovaleric acid (DAVA), a GABA(B) receptor antagonist, blocked the protective effect of baclofen, a GABA(B) agonist on the anti-MES action of U50488H. These BZD-GABAergic antagonists, namely, flumazenil or DAVA, on their own also counteracted the anti-electroshock seizure effect of U50488H given alone. However, mortality was not significantly altered in any of the above animal groups. Taken together, the findings have shown a possible role for multitude of important neurotransmitter systems, i.e., opioid (kappa), NMDA channel, GABA(A)-BZD-chloride channel complex, and GABA(B) receptors in the anticonvulsant action of U50488H.
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PMID:Studies on the anticonvulsant effect of U50488H on maximal electroshock seizure in mice. 1367 23

Experimental models of traumatic cortical brain injury in rodents reveal that specific regions of the hippocampus (e.g., CA3 and hilar subfields) are severely injured despite their distance from the initial insult. Hippocampal neurons may be intrinsically more vulnerable to mechanical insult than cortical neurons due to increased NMDA receptor densities and lower energy capacities, as evidenced by increased susceptibility to ischemic insults. The selective vulnerability of hippocampal neurons was evaluated using an in vitro model of TBI in which either primary rat cortical or hippocampal neurons (E17) seeded onto silicone substrates were subjected to graded levels of mechanical stretch. Although cortical neurons exhibited significantly longer increases in stretch-induced membrane permeability, injury of hippocampal neurons resulted in larger increases in intracellular free calcium concentration [Ca(2+)](i) and cell death. [ATP](i) deficits due to stretch were apparent by 60 min after injury in cortical neurons but recovered by 24 h, whereas significant deficits in [ATP](i) were not observed in hippocampal neurons until 24 h after injury. MK801 pretreatment decreased the stretch-induced [Ca(2+)](i) transients in both hippocampal and cortical cultures, thereby negating the regional specificity. However, MK801 pretreatment did not improve hippocampal viability and paradoxically, significantly increased cell death among cortical neurons. As the hippocampus is the primary brain region responsible for the memory deficits and epileptic seizures associated with TBI, understanding why this region is selectively damaged could lead to the development of more accurate mechanical tolerances as well as effective pharmaceutical agents.
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PMID:Susceptibility of hippocampal neurons to mechanically induced injury. 1463 77

Dendritic targeting of mRNA and local protein synthesis are mechanisms that enable neurons to deliver proteins to specific postsynaptic sites. Here, we demonstrate that epileptogenic stimuli induce a dramatic accumulation of BDNF mRNA and protein in the dendrites of hippocampal neurons in vivo. BDNF mRNA and protein accumulate in dendrites in all hippocampal subfields after pilocarpine seizures and in selected subfields after other epileptogenic stimuli (kainate and kindling). BDNF accumulates selectively in discrete dendritic laminas, suggesting targeting to synapses that are active during seizures. Dendritic targeting of BDNF mRNA occurs during the time when the cellular changes that underlie epilepsy are occurring and is not seen after intense stimuli that are non-epileptogenic, including electroconvulsive seizures and high-frequency stimulation. MK801, an NMDA receptor antagonist that can prevent epileptogenesis but not acute seizures, prevents the dendritic accumulation of BDNF mRNA, indicating that dendritic targeting is mediated via NMDA receptor activation. Together, these results suggest that dendritic accumulation of BDNF mRNA and protein plays a critical role in the cellular changes leading to epilepsy.
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PMID:Brain-derived neurotrophic factor mRNA and protein are targeted to discrete dendritic laminas by events that trigger epileptogenesis. 1528 90

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