Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guanidinosuccinic acid (GSA) is a guanidino compound found in mammalian central nervous system and physiological fluids. Its level has been found to be greatly increased in serum and cerebrospinal fluid of patients with renal failure, and the compound is suggested to play a role in uremic encephalopathy. In this report we examined the behavioral, electrographic and morphological effects of intrahippocampal GSA injection in unanesthetized rats. Intrahippocampal administration of 2 microliters GSA solution (3.5 nM) was followed by behavior observation, and electrohippocampographic and electrocorticographic recording. GSA-injected animals showed partial clonic seizures leading to generalized clonic seizures, and eventually status epilepticus. These were accompanied by epileptiform electrographic discharges. During generalized clonic seizures, the electrohippocampogram showed arythmic bursting spikes. Epileptiform electric activity persisted even after the generalized clonic convulsions had stopped, and lasted until the animals were killed, 5 days following injection. Microscopic examination of brain slices of these rats revealed severe neural damage in CA1 area of hippocampus. Treatment of rats with the non-competitive NMDA receptor antagonist ketamine prevented both partial and generalized clonic seizures, epileptiform electrographic discharges, and GSA-induced hippocampal damage.
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PMID:Epileptiform activity and hippocampal damage produced by intrahippocampal injection of guanidinosuccinic acid in rat. 876 97

The messenger RNAs (mRNAs) for the neurotrophins, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF), are upregulated during epileptic seizure activity, as visualized by in situ hybridization techniques. Neurotrophins might be protective against excitotoxic cell stress, and the upregulation during seizures might provide such cell protection. In this study, a high dose of pilocarpine (300 mg/kg) was used to induce long-lasting, limbic motor status epilepticus and a selective pattern of brain damage. The regulation of BDNF, trkB, and NGF mRNA was studied by in situ hybridization at 1, 3, 6, and 24 h after induction of limbic motor status epilepticus. BDNF immunoreactivity was examined with an anti-peptide antibody and the neuropathological process studied in parallel. BDNF mRNA increased in hippocampus, neocortex, piriform cortex, striatum, and thalamus with a maximum at 3-6 h. Hybridization levels increased earlier in the resistant granule and CA1 cells as compared to the vulnerable CA3 neurons. BDNF immunoreactivity was elevated in dentate gyrus at 3-6 h. trkB mRNA increased in the entire hippocampus. NGF mRNA in hippocampus appeared in dentate gyrus at 3-6 h and declined in hilar neurons at 6-24 h. Cell damage was found in the CA3 area, entire basal cortex, and layers II/III of neocortex. Endogenous neurotrophins are upregulated during status epilepticus caused by pilocarpine, which is related to the coupling between neuronal excitation and trophic factor expression. This upregulation of neurotrophic factors may serve endogenous protective effects; however, the excessive levels of neuronal hyperexcitation resulting from pilocarpine seizures lead to cell damage which cannot be prevented by endogenous neurotrophins.
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PMID:Cellular hybridization for BDNF, trkB, and NGF mRNAs and BDNF-immunoreactivity in rat forebrain after pilocarpine-induced status epilepticus. 882 76

The temporal evolution of irreversible neuronal damage from pilocarpine-induced seizures was studied by light microscopy. Neuronal cell death was judged on a 0-3 scale by estimating the percentage of acidophilic neurons in each of 23 brain regions. In addition, in the dorsal dentate hilus (CA4), quantitative cell counts of normal and acidophilic neurons were also performed. A few dead neurons (grade 0.5 damage) appeared in ventral hippocampal CA1 and CA3 regions after 20-min status epilepticus (SE). Slight-to-mild damage (grades 0.5-1.5) occurred in 14 and 12 brain regions after 40-min and 1-h SE respectively, and slight-to-moderate damage (grades 0.5-2.0) was found in 15 regions after 3-h SE. Twenty-four h and 72 h after 3-h SE, there was slight-to-severe damage (grade 0.5-3.0) in 22 and 21 regions respectively. Three-h SE produced more severe damage to 7 brain regions compared to 1-h SE, and 16 regions had more pronounced neuronal injury 24 h after rather than 0-4 h after 3-h SE. Eight brain regions had less damage 72 h compared to 24 h after SE, probably because of progressive neuronal lysis and dropout, but in mediodorsal and lateroposterior thalamic nuclei damage worsened from 24 to 72 h after SE. Neuronal cell counting revealed 20% acidophilic neurons in dorsal dentate hilus after 40-min SE and no difference between the 1-h and 3-h seizure groups (31% vs. 43% acidophilic neurons respectively). Among the 3 groups of rats with 3-h SE and varying recovery periods, the 24-h and 72-h recovery groups had higher percentages of acidophilic neurons (65% and 54% respectively) than the 0-4-h group (43%). Finally, the hippocampal CA2 region and dentate granule cell layer and the caudate-putamen, considered resistant to seizure-induced cell injury, were all damaged from SE lasting 40 min or more.
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PMID:The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. 882 81

Pilocarpine injection into rodents leads to the development of chronic limbic seizures that follow an initial status epilepticus and a seizure-free interval. It has been proposed that a decreased efficacy of the mechanisms that buffer the extracellular concentration of K+ ([K+]o) leads to an increase in seizure susceptibility. Therefore, we analyzed the changes in [K+]o associated with the synchronous activity induced by 4-aminopyridine (4AP) in hippocampal slices obtained from control and pilocarpine-treated rats. At all recording sites (i.e. stratum radiatum of the CA1 and CA3 subfields, and hilus of the dentate gyrus), the amplitude of GABA-mediated synchronous field potentials induced by 4AP, as well as the associated [K+]o increases, were significantly reduced in slices obtained from the pilocarpine-treated rats. In the control group, the field-potential amplitudes reached 1 mV (i.e. 1.7 +/- 0.3 mV in CA1, 0.93 +/- 0.2 mV in CA3, and 1.03 +/- 0.12 mV in the hilus; mean +/- SEM), while the accompanying rises in [K+]o exceeded 4 mM (i.e. 4.17 +/- 0.15 mM in CA1, 4.04 +/- 0.12 mM in CA3, 4.04 +/- 0.11 mM in the hilus) from a baseline of 3.25 mM. The corresponding values in slices from the pilocarpine-treated group were rarely greater than 0.4 mV (i.e. 0.3 +/- 0.09 mV in CA1, 0.27 +/- 0.03 mV in CA3 and 0.38 +/- 0.06 mV in the hilus), and larger than 3.6 mM (i.e. 3.63 +/- 0.04 mM in CA1, 3.64 +/- 0.03 mM in CA3 and 3.60 +/- 0.04 mM in the hilus) from a similar baseline value. With pilocarpine, the rate of occurrence of the GABA-mediated potential significantly decreased from 0.035 to 0.016 s-1. Since the rises in [K+]o decreased rather than increased and their overall duration was unchanged (possibly reflecting cell loss), we conclude that a modification of [K+]o buffering capacity is unlikely to account for the appearance of in vivo seizures in the pilocarpine model of epilepsy.
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PMID:Extracellular potassium elevations in the hippocampus of rats with long-term pilocarpine seizures. 883 Mar 21

1. This report examines alterations in presynaptic and postsynaptic processes mediated by gamma-aminobutyric acid-B (GABAB) receptors within hippocampal region CA1 in a model of chronic temporal lobe epilepsy (TLE). Intracellular recordings were obtained in pyramidal cells from combined hippocampal/parahippocampal control slices and slices obtained > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. 2. Monosynaptic inhibitory postsynaptic potentials (IPSPs) were evoked by placement of the stimulating electrode in stratum pyramidale within 500 microns of the recording electrode in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and D(-)-2-amino-5-phosphonovaleric acid. Control IPSPs exhibited early (GABAA-receptor-mediated) and late (GABAB-receptor-mediated) components. In contrast, post-SSLSE IPSPs displayed only a GABAA-receptor-mediated IPSP. Post-SSLSE IPSPs were completely eliminated by antagonists of the GABAA receptor (bicuculline methiodide and picrotoxin). In control tissue, GABAB receptor antagonists P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid (CGP 55845A), 3-N[1-(S)-(3,4-dichlorophenyl) ethyl]amino-2-(S)- hydroxypropyl-P-benzyl-phosphinic acid (CGP 35348), and 2-hydroxysaclofen eliminated the late component of the biphasic IPSP but had no discernible effect on IPSPs evoked in post-SSLSE CA1 pyramidal cells. 3. A paired pulse paradigm was employed to investigate the integrity of presynaptic GABAB-receptor-mediated inhibition of GABA release. To isolate pure GABAA-receptor-mediated responses, and thus facilitate comparison with post-SSLSE tissue, control neurons were penetrated with intracellular electrodes containing Cs2SO4/lidocaine, N-ethyl bromide (QX-314), and IPSPs were evoked employing the monosynaptic IPSP protocol. In controls, paired pulses [interpulse intervals (IPIs) of 70-1,500 ms] resulted in a diminution of the second early, GABAA-receptor-mediated chloride IPSP (IPSPA) relative to the first; maximum paired pulse depression (PPD) occurred at an IPI of 100 ms. GABAB receptor antagonists reduced PPD without affecting the amplitude of IPSPAs; the GABAB receptor agonist baclofen reduced the amplitude of both the first and second IPSPA and largely alleviated PPD. In contrast, no PPD was evident at any IPI in post-SSLSE neurons. Neither antagonists nor agonists of GABAB-receptor-mediated processes had an effect on either the degree of PPD or the amplitude of IPSPs. 4. To better approximate the pattern of CA1 pyramidal cell activation occurring during epileptiform activity. IPSPAs were evoked by trains of stimuli. In controls, mean monosynaptic IPSPA amplitude decreased by approximately 60% during a 3-Hz, 5-s train, with more than half the decline coming between the first and second IPSPs. In post-SSLSE, no significant IPSPA depression resulted from delivery of stimulus trains. Baclofen reduced the amplitude of control IPSPAs evoked during stimulus trains; both agonist and antagonists significantly lessened the degree of IPSP depression. These same agents altered neither IPSP amplitude nor the degree of use-dependent IPSP depression produced in post-SSLSE tissue during stimulus trains. 5. We conclude that a dysfunction of both presynaptic and postsynaptic GABAB-receptor-mediated processes occurs in hippocampal area CA1 in the post-SSLSE model of TLE. GABAB receptor agonists and antagonists had no effect on post-SSLSE CA1 pyramidal cell synaptic responses, whereas antagonists of the GABAA receptor completely eliminated IPSPs. Repetitive activation produced no use-dependent synaptic depression. The implications of these findings for the epileptogenic potential of post-SSLSE CA1 and the "dormant basket cell" hypothesis are discussed.
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PMID:Profound disturbances of pre- and postsynaptic GABAB-receptor-mediated processes in region CA1 in a chronic model of temporal lobe epilepsy. 887 Dec 36

1. Kainate treatment preferentially kills dentate hilar neurons and CA3 pyramidal cells and ultimately leads to a chronic epileptic state. Bicuculline-induced epileptiform bursts were studied to test the hypothesis that multiple kainate injections and consequent status epilepticus would lead-after weeks to months of recovery-to prolonged synchronous afterdischarges in the isolated CA1 area of rat hippocampal slices, as would be expected if new recurrent excitatory circuits had formed. 2. Synaptic responses evoked in CA1 pyramidal cells of rats injected subcutaneously with kainate (10 hourly injections, 5 mg/kg each) 24-316 days before the slice experiment were compared with responses in slices from untreated and saline-injected controls. The maximal response to stratum radiatum stimulation in normal solution consisted of two to eight population spikes. 3. When gamma-aminobutyric acid-A receptor-mediated inhibition was reduced with bicuculline, synchronized burst afterdischarges after the initial stimulation-evoked burst, similar to the type of activity described in area CA3 under conditions where inhibition is impaired, occurred in 23% of slices. 4. The prolonged synchronized burst afterdischarges in the isolated CA1 area of kainate-treated rats were associated with large excitatory postsynaptic potentials (EPSPs). These prolonged bursts were not graded with the stimulus intensity; rather, they were triggered in an all-or-none manner, even though there was some variability across bursts. The bursts of population spikes also were correlated with subthreshold EPSPs. 5. Slices that had synchronized burst afterdischarges had significantly more damage in area CA3 than slices without afterdischarges. 6. The data indicate that kainate-induced damage in CA3 can lead to prolonged synchronous afterdischarges, even after CA1 is surgically isolated from the CA3 area. Because the repetitive bursts during the prolonged and synchronous afterdischarges were associated with large EPSPs, these data suggest that kainate-induced damage to CA3 and subsequent degeneration of synaptic terminals in the CA1 area causes the formation of new recurrent excitatory circuits that could be involved in the development of chronic epilepsy.
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PMID:Spontaneous and stimulation-induced synchronized burst afterdischarges in the isolated CA1 of kainate-treated rats. 889 98

A novel antiepileptic drug, tiagabine ((R)-N-[4,4-di-(3-methylthien-2-yl) but-3-enyl] nipecotic acid hydrochloride), was studied in rats in order to determine its efficacy in preventing seizures, seizure-induced neuronal damage and impairment of spatial memory in the perforant pathway stimulation model of status epilepticus. In pilot experiments, administration of tiagabine (50, 100 or 200 mg/kg/day) with subcutaneously implanted Alzet osmotic pumps led to a dose-dependent increase in tiagabine concentrations in the serum and brain. Two days of tiagabine treatment at a dose range of 50-200 mg/kg/day did not change the levels of gamma-aminobutyric acid (GABA), glutamate or aspartate in cisternal cerebrospinal fluid (CSF) compared to the controls. In the pentylenetetrazol test, the maximal anticonvulsive effect of tiagabine administered via osmotic pumps was achieved already with a dose of 50 mg/kg/day. In the perforant pathway model of status epilepticus, subchronic treatment with tiagabine (Alzet pumps, 50 mg/kg/day) completely prevented the appearance of generalized clonic seizures during stimulation (P < 0.001). In the same rats, tiagabine treatment reduced the loss of pyramidal cells in the CA3c and CA1 fields of the hippocampus (P < 0.05) but not the loss of somatostatin immunoreactive neurons in the hilus. Two weeks after perforant pathway stimulation, the tiagabine-treated rats performed better in the Morris water-maze test than the vehicle-treated rats did (P < 0.001). Our results show that tiagabine treatment reduces the severity of seizures in the perforant pathway stimulation model of status epilepticus. Possibly associated with the reduction in seizure number and severity, tiagabine treatment also reduced seizure-induced damage to pyramidal cells in the hippocampus as well as the impairment of the spatial memory associated with hippocampal damage.
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PMID:Tiagabine prevents seizures, neuronal damage and memory impairment in experimental status epilepticus. 890 Oct 9

We studied the time course and possible mechanisms of the development of chronic epilepsy following unilateral stimulation of the perforant path. After 24 h of perforant path stimulation by a modified Sloviter method, lesions were restricted to the hippocampus, except for 2 of 24 rats with minimal entorhinal neuronal injury in layer 3. Lesions were exclusively ipsilateral in the polymorph layer of the hilus and in CA4-CA3C, predominantly ipsilateral in CA3, in CA1 and in the granule cell layer. Feedforward and feedback inhibition were studied by paired pulse stimulation. In the week following inhibition, there was complete loss of GABAA-mediated, short interstimulus interval (ISI)-dependent inhibition and frequency-dependent inhibition, and also of GABAB-mediated long ISI-dependent inhibition. Yet no spontaneous seizures were observed at that time. In the next four weeks, we saw no evidence of increasing excitatory drive such as would be expected from recurrent mossy fiber sprouting. On the contrary, there was progressive return of inhibition. By four weeks post-lesion, the majority of animals had developed spontaneous recurrent seizures, and/or seizures on 2 Hz stimulation (never seen in controls), in spite of complete or near-complete recovery of short ISI-dependent, GABAA-mediated inhibition. A small but significant loss of frequency-dependent inhibition persisted, but individual animals with complete recovery of frequency-dependent inhibition showed spontaneous seizures, suggesting that loss of GABAA-mediated inhibition was not the direct cause of chronic epilepsy. GABAB-mediated, long ISI-dependent inhibition continued to show a significant loss. The ratio of the population spike amplitude at 250 microA to the maximal population spike amplitude, a measure of granule cell excitability, was unchanged immediately after stimulation, but increased in the next few weeks in a manner identical to that seen in kindling, suggesting the possibility that during the transient loss of inhibition, spontaneous kindling had occurred. Intracellular recordings from granule cells in hippocampal slices prepared from these animals showed a significant loss of GABAB-mediated slow inhibitory postsynaptic potentials (IPSPs). These data show that the sequellae of unilateral status epilepticus with damage restricted to the hippocampus are sufficient to cause chronic recurrent seizures. There is a possibility that chronic epilepsy is not the direct result of the loss of inhibitory drive or of a sprouting-induced increase in excitatory drive, but represents plastic changes akin to spontaneous kindling, possibly facilitated by loss of GABAB-mediated inhibition.
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PMID:Chronic epilepsy with damage restricted to the hippocampus: possible mechanisms. 898 5

This study determined whether there were differences in hippocampal neuron loss and synaptic plasticity by comparing rats with spontaneous epilepsy after limbic status epilepticus and animals with a similar frequency of kindled seizures. At the University of Virginia, Sprague-Dawley rats were implanted with bilateral ventral hippocampal electrodes and treated as follows; no stimulation (electrode controls; n=5): hippocampal stimulation without status (stimulation controls; n=5); and limbic status from continuous hippocampal stimulation (n=12). The limbic status group were electrographically monitored for a minimum of four weeks. Four rats had no recorded chronic seizures (status controls), and all three control groups showed no differences in hippocampal pathology and were therefore incorporated into a single group (controls). Eight limbic status animals eventually developed chronic epilepsy (spontaneous seizures) and an additional eight rats were kindled to a similar number and frequency of stage 5 seizures (kindled) as the spontaneous seizures group. At the University of California (UCLA) the hippocampi were processed for: (i) Niss1 stain for densitometric neuron counts; (ii) neo-Timm's histochemistry for mossy fiber sprouting; and (iii) immunocytochemical staining for glutamate decarboxylase, N-methyl-D-aspartate receptor subunit 2, AMPA receptor subunit 1 and the GABA(A) receptor. In the fascia dentata inner and outer molecular layers the neo-Timm's stain and immunoreactivity was quantified as gray values using computer image analysis techniques. Statistically significant results (P<0.05) showed the following. Compared to controls and kindled animals, rats with spontaneous seizures had: (i) lower neuron counts for the fascia dentata hilus, CA3 and CA1 stratum pyramidale; (ii) greater supragranular inner molecular layer mossy fiber staining; and (iii) greater glutamate decarboxylase immunoreactivity in both molecular layers. Greater supragranular excitatory mossy fiber and GABAergic axon sprouting correlated with: (i) increases in N-methyl-D-aspartate receptor subunit 2 inner molecular layer staining; (ii) more AMPA receptor subunit 1 immunoreactivity in both molecular layers; and (iii) greater outer than inner molecular layer GABA(A) immunoreactivity. Furthermore, in contrast to kindled animals, rats with spontaneous seizures showed that increasing seizure frequency per week and the total number of natural seizures positively correlated with greater Timm's and GABAergic axon sprouting, and with increases in N-methyl-D-aspartate receptor subunit 2 and AMPA receptor subunit 1 receptor staining. In this rat limbic status model these findings indicate that chronic seizures are associated with hippocampal neuron loss, reactive axon sprouting and increases in excitatory receptor plasticity that differ from rats with an equal frequency of kindled seizures and controls. The hippocampal pathological findings in the limbic status model are similar to those in humans with hippocampal sclerosis and mesial temporal lobe epilepsy, and support the hypothesis that synaptic reorganization of both excitatory and inhibitory systems in the fascia dentata is an important pathophysiological mechanism that probably contributes to or generates chronic limbic seizures.
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PMID:In contrast to kindled seizures, the frequency of spontaneous epilepsy in the limbic status model correlates with greater aberrant fascia dentata excitatory and inhibitory axon sprouting, and increased staining for N-methyl-D-aspartate, AMPA and GABA(A) receptors. 913 Jul 82

Although status epilepticus in children is associated with neuronal pathologies, there are few developmental models of status epilepticus which produce damage in the immature brain. We have developed a new model of status epilepticus using systemically injected pilocarpine in immature rabbits pretreated with lithium. Injected animals demonstrated behavioral and electrographic seizures. Behavioral seizures were characterized by sustained or recurrent bouts of clonus in all limbs. The pilocarpine-induced seizures had a 40% mortality. All animals surviving the status epilepticus had hippocampal lesions when evaluated 48 h after the SE. Within the hippocampus, CA1 pyramidal cells were the most vulnerable cell population. Extrahippocampal damage was seen in the majority of animals. Our results show that severe seizures cause hippocampal lesions in the absence of hypoxemia and suggest that the presumed resistance of the immature brain to seizure-induced damage is not a general rule which can be applied to all models or species.
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PMID:Lithium-pilocarpine status epilepticus in the immature rabbit. 917 39


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