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)

Nitric oxide has been postulated as a retrograde intercellular messenger for long-term potentiation, a form of synaptic plasticity that is associated with learning and memory processes. In the present study we investigated whether the loss or survival of nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-containing neurons, which are known to synthesize nitric oxide, would be an useful indicator for evaluating the structural and functional state of the rat hippocampus after status epilepticus that is induced by intraperitoneal injection of kainic acid. Besides NADPH diaphorase histochemistry, two other histological parameters were studied: the grade of cell damage evaluated from silver-impregnated sections, and the number of somatostatin-containing neurons in different hippocampal subfields. We found that the number of NADPH diaphorase-containing neurons in the hilus and granule cell layer correlated well with spatial learning and memory performance as assessed by the Morris water-maze test. The extent of cell damage in the CA1 subfield analysed in silver-impregnated sections and the number of hilar somatostatin-containing neurons also significantly correlated with latencies in the water-maze test. Furthermore, linear regression analysis revealed that the number of somatostatin-containing neurons in the hilus explains about 50% of the variation in water-maze learning. These findings emphasize that although general structural preservation is of crucial importance for the function of the hippocampus also interneurons, such as somatostatin- and NADPH diaphorase-containing neurons, may play an important role during the acquisition phase and processing of information in hippocampal circuitry. Therefore, in addition to evaluating general cell damage, analysis of the cell loss that occurs in the interneuron subpopulations will be beneficial in verifying structural and functional deficits of the hippocampus after status epilepticus.
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PMID:Comparison of NADPH diaphorase histochemistry, somatostatin immunohistochemistry, and silver impregnation in detecting structural and functional impairment in experimental status epilepticus. 925 25

The distribution and time course of changes of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) positivity were studied in immature rats (12 and 25 days old) surviving motor status epilepticus (SE) induced by a high dose of pilocarpine. Motor SE characterized by continuous convulsions was interrupted after 2 h by an injection of clonazepam (0.5 mg/kg or 1 mg/kg in 12- and 25-day-old rats, respectively) in order to reduce mortality. Correlation between electroencephalographic and behavioral seizure activity was confirmed using animals with electrodes implanted bilaterally in the hippocampus and sensorimotor cortex. Brains were examined 2, 6, 13, and 21 days after motor SE using NADPH-diaphorase histochemistry. Two types of changes were found in both age groups: (a) decrease of NADPH-d positivity occurred in both neuropil and cell bodies in piriform, periamygdalar, and entorhinal cortices; and (b) NADPH-d positivity was induced in the cell bodies in the hippocampal fields CA1/2, CA3, and dentate gyrus. These changes were more intense in animals surviving SE at postnatal day 25 than in younger age group, and they peaked 2 days after SE. The changes observed after SE disappeared quickly in 12-day-old rat pups, where only moderate changes could be observed in piriform, periamygdalar, and entorhinal cortices 6 days after SE, whereas the changes in the histochemical positivity persisted in older animals even 21 days after SE.
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PMID:Changes in NADPH-diaphorase positivity induced by status epilepticus in allocortical structures of the immature rat brain. 1021 Jan 66

Changes in residual ATP concentrations were investigated following subcellular fractionation of rat brain cortex after a prolonged period of status epilepticus induced by sequential administration of lithium and pilocarpine. After 2 h of continuous high-amplitude rapid spiking on EEG, we found significantly decreased levels of residual ATP in the homogenate and mitochondria fractions from status epilepticus rat brains compared to matched controls. No difference in residual ATP level was observed in the synaptosomal preparations of status epilepticus animals compared to controls. Inorganic phosphate concentration in the status animals was higher than controls in the cytosolic fraction only. F1-ATPase activity, an enzymatic indicator of mitochondrial ATP synthesis rate, was significantly higher in the status brains, whereas other mitochondrial enzymes were not different in the status and control rat groups. These findings, together with our earlier report of reduced synaptosomal ecto-ATPase activity, suggest that either the corresponding in vivo ATP concentrations were reduced as a result of status epilepticus or other biochemical changes had occurred that facilitated the hydrolysis of ATP following decapitation. Controls for and measurement of such other changes failed to provide an explanation for the observed changes in residual ATP.
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PMID:Altered residual ATP content in rat brain cortex subcellular fractions following status epilepticus induced by lithium and pilocarpine. 1034 93

Aspirin (acetylsalicylic acid), and its main metabolite sodium salicylate, have been shown to protect neurons from excitotoxic cell death in vitro. The objective of our study was to investigate the possible neuroprotective effects of sodium salicylate in vivo in rats with kainic acid-induced seizures, a model for temporal lobe epilepsy in human patients. Male Sprague-Dawley rats received intraperitoneal injections of kainic acid either alone, or with sodium salicylate given before and for 40h after kainic acid injections. The control group received either phosphate-buffered saline or sodium salicylate without co-administration of kainic acid. Animals developed status epilepticus, which was aborted 1.5-2h later with diazepam. On day 3 following kainic acid-induced seizures, animals received bromodeoxyuridine to measure cellular proliferation, and were killed under anesthesia 24h later. Brains were removed, sectioned, and analysed for gross histological changes, evidence of hemorrhage, DNA fragmentation, cellular proliferation, and microglial immunohistochemistry. We report that sodium salicylate did not protect neurons from seizure-induced cell death, and to the contrary, it caused focal hemorrhage and cell death in the hippocampal formation and the entorhinal/piriform cortex of rats with kainic acid-induced seizures. Hemorrhage was never observed in animals that received vehicle, kainic acid or sodium salicylate only, which indicated that sodium salicylate exerted its effect only in animals with seizures, and was confined to select regions of the brain that undergo seizure activity. Large numbers of cells displaying DNA fragmentation were detected in the hippocampal formation, entorhinal/piriform cortex and the dorsomedial thalamic nucleus of rats that received kainic acid or kainic acid in combination with sodium salicylate. Bromodeoxyuridine immunohistochemistry revealed large numbers of proliferating cells in and around the areas with most severe neural injury induced by kainic acid or kainic acid co-administered with sodium salicylate. These same brain regions displayed intense staining with a microglia-specific marker, an indication of microglial activation in response to brain damage. In all cases, the degree of cell death, cell proliferation and microglia staining was more severe in animals that received the combination of kainic acid and sodium salicylate when compared to animals that received kainic acid alone. We hypothesize that our findings are attributable to sodium salicylate-induced blockade of cellular mechanisms that protect cells from calcium-mediated injury. These initial observations may have important clinical implications for patients with epilepsy who take aspirin while affected by these conditions, and should promote further investigation of this relationship.
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PMID:The aspirin metabolite sodium salicylate causes focal cerebral hemorrhage and cell death in rats with kainic acid-induced seizures. 1092 56

Several lines of evidence suggest that the binding affinity of glutamate decarboxylase (GAD) to the active form of pyridoxine is low in cases of pyridoxine-dependent seizures (PDS) and that a quantitative imbalance between excitatory (i.e. glutamate) and inhibitory (i.e. gamma-aminobutyric acid, GABA) neurotransmitters could cause refractory seizures. However, inconsistent findings with GAD insufficiency have been reported in PDS. We report a case of PDS that is not accompanied by an elevated cerebrospinal fluid (CSF) glutamate concentration. Intravenous pyridoxine phosphate terminated generalized seizures which were otherwise refractory to conventional anti-epileptic medicines. No seizure occurred once oral pyridoxine (13.5 mg/kg per day) was started in combination with phenobarbital sodium (PB, 3.7 mg/kg per day). The electroencephalogram (EEG) normalized approximately 8 months after pyridoxine was started. The patient is gradually acquiring developmental milestones during the 15 months follow-up period. The CSF glutamate and GABA concentrations were determined on three separate occasions: (1) during status epilepticus; (2) during a seizure-free period with administration of pyridoxine and PB; and (3) 6 days after suspension of pyridoxine and PB and immediately before a convulsion. The CSF glutamate level was below the sensitivity of detection (<1.0 microM) on each of the three occasions; the CSF GABA level was within the normal range or moderately elevated. The CSF and serum concentrations of vitamin B6-related substances, before pyridoxine supplementation, were within the normal range. We suggest that (1) PDS is not a discrete disease of single etiology in that insufficient activation of GAD may not account for seizure susceptibility in all cases and (2) mechanism(s) of anti-convulsive effect of pyridoxine, at least in some cases, may be independent of GAD activation.
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PMID:CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine action in seizure control. 1122 25

Since the dorsal and ventral hippocampus in the rat may act differently from one another in limbic seizures, we studied effects of orthogonal transection between the dorsal and ventral hippocampus upon kainic acid-induced amygdalar seizures. A total of 26 rats were divided into three groups. Ten rats underwent transection using a modified wire knife (transection group); 16 others were untransection group (n=10) and controls (n=6). All the rats then underwent stereotactic implantation of electrodes in the left amygdala (LA), left dorsal hippocampus (LdH), left ventral hippocampus (LvH), and the left sensorimotor cortex (LCx). A stainless steel cannula also was introduced into the LA. Rats except controls later received 1.0 microg of kainic acid (KA) via the cannula. Controls received phosphate buffer solution alone. In the untransection group, multiple spike discharges in the LA immediately propagated concurrently to the LvH and LdH. Propagation involved the LCx to become status epilepticus 1 to 2 h after KA injection. Seizures, characterized by mastication, salivation, facial twitching, forelimb clonus, and sometimes rearing and falling, lasted 1 to 2 days. Microscopic examination revealed severe neuronal cell damage in the LA, LvH, and LdH. In the transection group, multiple spike discharges initiated from the LA and were propagated to LvH, but LdH as well as LCx involvement was slight. Status epilepticus involved only the LA and LvH 1 to 2 h following KA injection. Seizures subsided within 24 h, showing no ictal manifestations except for aggressiveness. Overall, seizures were weak and transient compared with those in controls. Histologically, hippocampal neuronal damage was slight, but damage to amygdalar neurons was similar to that in untransection group. No electroclinical and histological changes were seen in controls. These results indicated that connections between the dorsal and ventral hippocampus are important for full development of KA-induced amygdalar seizures.
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PMID:Hippocampal transection attenuates kainic acid-induced amygdalar seizures in rats. 1128 62

This study focused on the effects of status epilepticus on the activity of calcineurin, a neuronally enriched, calcium-dependent phosphatase. Calcineurin is an important modulator of many neuronal processes, including learning and memory, induction of apoptosis, receptor function and neuronal excitability. Therefore, a status epilepticus-induced alteration of the activity of this important phosphatase would have significant physiological implications. Status epilepticus was induced by pilocarpine injection and allowed to continue for 60 min. Brain region homogenates were then assayed for calcineurin activity by dephosphorylation of p-nitrophenol phosphate. A significant status epilepticus-dependent increase in both basal and Mn(2+)-dependent calcineurin activity was observed in homogenates isolated from the cortex and hippocampus, but not the cerebellum. This increase was resistant to 150 nM okadaic acid, but sensitive to 50 microM okadaic acid. The increase in basal activity was also resistant to 100 microM sodium orthovanadate. Both maximal dephosphorylation rate and substrate affinity were increased following status epilepticus. However, the increase in calcineurin activity was not found to be due to an increase in calcineurin enzyme levels. Finally, increase in calcineurin activity was found to be NMDA-receptor activation dependent. The data demonstrate that status epilepticus resulted in a significant increase in both basal and maximal calcineurin activity.
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PMID:A significant increase in both basal and maximal calcineurin activity in the rat pilocarpine model of status epilepticus. 1146 66

The results of several studies have contributed to the hypothesis that BDNF promotes seizure activity, particularly in adult hippocampus. To test this hypothesis, BDNF, vehicle (phosphate-buffered saline, PBS), or albumin was infused directly into the hippocampus for 2 weeks using osmotic minipumps. Rats were examined behaviorally, electrophysiologically, and anatomically. An additional group was tested for sensitivity to the convulsant pilocarpine. Spontaneous behavioral seizures were observed in BDNF-infused rats (8/32; 25%) but not in controls (0/20; 0%). In a subset of six animals (three BDNF, three albumin), blind electrophysiological analysis of scalp recordings contralateral to the infused hippocampus demonstrated abnormalities in all BDNF rats; but not controls. Neuronal loss in BDNF-treated rats was not detected relative to PBS- or albumin-treated animals, but immunocytochemical markers showed a pattern of expression in BDNF-treated rats that was similar to rats with experimentally induced seizures. Thus, BDNF-infused rats had increased expression of NPY in hilar neurons of the dentate gyrus relative to control rats. NPY and BDNF expression was increased in the mossy fiber axons of dentate gyrus granule cells relative to controls. The increase in NPY and BDNF expression in BDNF-treated rats was bilateral and occurred throughout the septotemporal axis of the hippocampus. Mossy fiber sprouting occurred in five BDNF-treated rats but no controls. In another group of infused rats that was tested for seizure sensitivity to the convulsant pilocarpine, BDNF-infused rats had a shorter latency to status epilepticus than PBS-infused rats. In addition, the progression from normal behavior to severe seizures was faster in BDNF-treated rats. These data support the hypothesis that intrahippocampal BDNF infusion can facilitate, and potentially initiate, seizure activity in adult hippocampus.
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PMID:Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. 1192 62

Fosphenytoin is a phosphate ester prodrug developed as an alternative to intravenous phenytoin for acute treatment of seizures. Advantages include more convenient and rapid intravenous administration, availability for intramuscular injection, and low potential for adverse local reactions at injection sites. Drawbacks include the occurrence of transient paraesthesias and pruritus at rapid infusion rates, and cost. Fosphenytoin is highly bound (93-98%) to plasma proteins. Saturable binding at higher plasma concentrations accounts for an increase in its distribution volume and clearance with increasing dose and infusion rate. Fosphenytoin is entirely eliminated through metabolism to phenytoin by blood and tissue phosphatases. The bioavailability of the derived phenytoin relative to intravenous phenytoin is approximately 100% following intravenous or intramuscular administration. The half-life for conversion of fosphenytoin to phenytoin ranges from 7-15 minutes. Faster intravenous infusion rates and competitive displacement of derived phenytoin from plasma protein binding sites by fosphenytoin compensate for the expected conversion-related delay in appearance of phenytoin in the plasma. Unbound phenytoin plasma concentrations achieved with intravenous fosphenytoin loading doses of 100-150 or 50-100mg phenytoin sodium equivalents/min are comparable, and achieved at similar times, to those with equimolar doses of intravenous phenytoin at 50 (maximum recommended rate) or 20-40 mg/min, respectively. The rapid achievement of effective concentrations permits the use of fosphenytoin in emergency situations, such as status epilepticus. Following intramuscular administration, therapeutic phenytoin plasma concentrations are observed within 30 minutes and maximum plasma concentrations occur at approximately 30 minutes for fosphenytoin and at 2-4 hours for derived phenytoin. Plasma concentration profiles for fosphenytoin and total and unbound phenytoin in infants and children closely approximate those in adults following intravenous or intramuscular fosphenytoin at comparable doses and infusion rates. Earlier and higher unbound phenytoin plasma concentrations, and thus an increase in systemic adverse effects, may occur following intravenous fosphenytoin loading doses in patients with a decreased ability to bind fosphenytoin and phenytoin (renal or hepatic disease, hypoalbuminaemia, the elderly). Close monitoring and reduction in the infusion rate by 25-50% are recommended when intravenous loading doses of fosphenytoin are administered in these patients. The potential exists for clinically significant interactions when fosphenytoin is coadministered with other highly protein bound drugs. The pharmacokinetic properties of fosphenytoin permit the drug to serve as a well tolerated and effective alternative to parenteral phenytoin in the emergency and non-emergency management of acute seizures in children and adults.
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PMID:Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. 1248 78

There is evidence that BDNF influences the birth of granule cells in the dentate gyrus, which is one of the few areas of the brain that demonstrates neurogenesis throughout life. However, studies to date have not examined this issue directly. To do so, we compared the effects of BDNF, phosphate-buffered saline (PBS), or bovine serum albumin (BSA) on neurogenesis after infusion into the hippocampus of the normal adult rat, using osmotic pumps that were implanted unilaterally in the dorsal hilus. BDNF, PBS, and BSA were infused for 2 weeks. The mitotic marker bromodeoxyuridine (BrdU) was administered twice daily during the 2-week infusion period. At least 1 month after infusion ended, brains were processed immunocytochemically using antibodies to BrdU, a neuronal nuclear protein (NeuN), or calbindin D28K (CaBP), which labels mature granule cells. Stereology was used to quantify BrdU-labeled cells in the dorsal hippocampus that were double-labeled with NeuN or CaBP. There was a statistically significant increase in BrdU(+)/NeuN(+) double-labeled cells in the granule cell layer after BDNF infusion relative to controls. The values for BrdU(+)/NeuN(+) cells were similar to BrdU(+)/CaBP(+) cells, indicating that most new neurons were likely to be granule cells. In addition, BrdU(+)/NeuN(+)-labeled cells developed in the hilar region after BDNF infusion, which have previously only been identified after severe continuous seizures (status epilepticus) and associated pathological changes. Remarkably, neurogenesis was also increased contralaterally, but BDNF did not appear to spread to the opposite hemisphere. Thus, infusion of BDNF to a local area can have widespread effects on hippocampal neurogenesis. The results demonstrate that BDNF administration to the dentate gyrus leads to increased neurogenesis of granule cells. They also show that ectopic granule cells develop after BDNF infusion, which suggests that ectopic migration is not necessarily confined to pathological conditions. These results are discussed in light of the evidence that BDNF increases neuronal activity in hippocampus. Thus, the mechanisms underlying neurogenesis following BDNF infusion could be due to altered activity as well as direct effects of BDNF itself, and this is relevant to studies of other growth factors because many of them have effects on neuronal excitability that are often not considered.
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PMID:Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. 1637 58


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