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)

Understanding the molecular basis of altered neuronal excitability in epilepsy is a major challenge in neuroscience research. The present study suggests an inverse correlation between changes in neuronal excitability in status epilepticus and the activity of type II multifunctional calcium/calmodulin-dependent kinase II (CaM kinase II), a major Ca(2+)-signal transducing system in brain. 'Continuous' hippocampal stimulation (CHS), a new model of non-convulsive limbic status epilepticus (SE), mimics the progression of electrographic changes characteristic in human SE and allows for quantitation of post-stimulus seizure severity. In the present study, hippocampus and anterior neocortex from CHS-stimulated rats and paired surgical controls were assayed for CaM kinase II activity by incorporation of radiolabeled phosphate from [gamma-32P]ATP into the 50-kDa subunit of the kinase itself (autophosphorylation). In all instances, CHS induced sustained interictal bursting and/or electrographic seizures. Decreased CaM kinase II activity was seen in all preparations from electrically stimulated hippocampus. CaM kinase II activity in CHS animals was diminished by 37% relative to controls (P less than 0.01; Student's paired t-test). The progressive intensity of the EEG discharges correlated directly with the decrement of CaM kinase II activity (P less than 0.05; Spearman's rank correlation test, n = 5). This is the first report of a dynamic modulation of a biochemical system that has been implicated in neuronal excitability in coordination with the characterized developmental stages of SE.
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PMID:Loss of type II calcium/calmodulin-dependent kinase activity correlates with stages of development of electrographic seizures in status epilepticus in rat. 131 99

Electrographic and clinical observations were made for 6 months after the injection of kainic acid (KA) solution (1 microgram in 1 microliter of phosphate buffer solution) through a chronically implanted cannula into a unilateral amygdala of freely moving and non-anesthetized cats. The control group (phosphate buffer group) showed no change during the observation period. After the injection of kainic acid, focal status epilepticus in the limbic system was observed for 3 days. Cats recovered clinically but persistent IIDs were observed at the injected site of the amygdala. These IIDs increased in amplitude and frequency and began to trigger spontaneous amygdaloid seizures. Secondary epileptogenic foci were then established in the contralateral amygdala, and amygdaloid seizures began to occur alternatively on both sides and finally trigger frequent limbic seizures from 20 to 40 days after KA injection. Spontaneous secondarily generalized seizures developed about 30 days after KA injection and occurred once or twice a week thereafter. The animals were completely normal in their behavior during the interictal phase. This is an excellent model of experimental epilepsy for the investigation of the mechanism of limbic seizure development and further study using this model will provide informations useful for the therapy of temporal lobe epilepsy in man.
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PMID:Spontaneous secondarily generalized seizures induced by a single microinjection of kainic acid into unilateral amygdala in cats. 241 95

The cerebral metabolic response to bicuculline (BC)-induced status epilepticus (SE) was studied in two-week-old ketamine-anesthetized marmoset monkeys. During 30-min clonic seizures, mean blood pressure, plasma glucose and paO2 did not decrease and plasma lactate doubled. Brains were funnel-frozen and punch biopsies of frontoparietal cortex, temporal cortex and thalamus were analyzed for ATP, phosphocreatine (PCr), glucose and lactate. There were marked reductions of ATP (to 56-77% of controls), PCr (to 23-28% of controls) and glucose (to 1-4% of controls), and lactate increased 3- to 6-fold in seizure animals. NADH fluorescence increased during seizures in cerebral cortex, thalamus, amygdaloid nuclei, hippocampus, posterior striatum and hemispheric white matter. This suggests a reduced tissue redox state in these regions and is correlated with the high energy phosphate depletion and elevated lactate in cortex and thalamus. Our results demonstrate a significant depletion of energy reserves and glucose in cerebral cortex and thalamus during neonatal seizures in the absence of adverse systemic factors. These seizure-induced metabolic changes in brain could have adverse long-term effects on brain development and function.
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PMID:Generalized seizures deplete brain energy reserves in normoxemic newborn monkeys. 313 58

Prepubescent male rats with an amygdaloid electrode in place were administered kainic acid (KA) intraperitoneally (i.p.) while controls received phosphate-buffered saline (PBS). All KA-treated animals developed status epilepticus with bilateral forelimb clonus and ictal discharges on the EEG. The rats were then tested as adults for learning, memory, emotionality, social interaction, and activity level using the T maze, water maze, handling test, home cage intruder test, and open field test. KA-treated rats learned at a slower rate in the water maze and T maze than the controls. In addition, KA-treated rats had evidence of impaired memory during spatial bias testing in the water maze. In the home cage intruder test, KA-treated animals were more submissive and less aggressive than control animals. Finally, KA-treated animals were significantly more active than control animals in the open field test. This study demonstrates that KA administration to the immature brain, in a convulsant dose, results in permanent changes in behavior, learning, and memory.
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PMID:Behavioral effects of kainic acid administration on the immature brain. 319 87

NMR spectroscopic methods have recently been developed for measurement of several concentrated cerebral metabolites in vivo. At present, 31P spectra from the brain permit detection of ATP, PCr, Pi, and certain sugar and lipid phosphates. The resonant frequency of Pi also provides a measure of cerebral pHi, and under some conditions ADP concentration can be calculated from information available in the 31P spectrum. The 1H spectrum of brain provides measurements of lactate, creatine, and several amino acids and choline-containing compounds. Both kinds of spectra can be obtained from the same subject. Our group at Yale used combined 31P and 1H methods to demonstrate that loss and recovery of phosphate energy stores and concomitant changes in cerebral amino acids during hypoglycemic coma in rodents could be observed in vivo. We then used the same methods to show that cerebral pHi can be normal while lactate is elevated in status epilepticus. NMR spectroscopy performed in vivo provides an array of chemically specific measurements unavailable by any other non-invasive method. It is thought to be entirely free of deleterious biological effects; hence, its potential for use in humans is considerable.
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PMID:Combined 1H and 31P NMR studies of cerebral metabolism in vivo. 357 13

Electrographic and clinical observations were made after the injection of kainic acid into the unilateral hippocampus of freely moving cats. Vehicle solution (phosphate buffer solution) for control study and kainic acid(1, 4 and 12 micrograms) were administered via a chronically implanted cannula. The control group showed no modification during the observation period. After the injection of 1 microgram of kainic acid, focal status epilepticus was observed for 2-3 days and then cats became normal afterwards. In the group of 4 micrograms kainic acid infection, cats demonstrated limbic status for 3 days, and persistent inter-ictal discharges continued during the observation period. Independent amygdaloid seizures and secondary generalized convulsions developed in the cats administered 12 micrograms of kainic acid. The cats died in the status epilepticus. The dose-dependent and substantial effect of KA without the influences of anesthesia and surgery was demonstrated. The results were discussed in relation to the human medial temporal sclerosis and the effects on the emotional mechanism of the limbic system. We suggest this model to be useful in the study of various types of temporal lobe epilepsy and the emotional mechanisms of the limbic system.
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PMID:Electroclinical features of kainic acid-induced status epilepticus in freely moving cats. Microinjection into the dorsal hippocampus. 617 56

Neuronal loss and gliosis were detected in the rat hippocampus soon after unilateral intra-amygdala injection of kainate (KA) (2.5 nmol) while solid mossy fiber sprouting could be seen only fourteen days after this injection. Using this experimental model, we examined the metabotropic glutamate receptor (mGluR)-induced inositol phosphate (IP) formation in hippocampal synaptoneurosomes and slices. In synaptoneurosomes prepared from ipsilateral hippocampi fourteen days following injection, there were no significant changes in mGluR- and carbachol(CARB)-stimulated IPs syntheses when sham-operated and KA-injected animals were compared. In the corresponding hippocampal slices, significant increases of the mGluR responses mediated by ibotenate (IBO) and aminocyclopentane-trans-1,3-dicarboxylate (t-ACPD) were noted after KA application. The net stimulation values respectively expressed in a pair-wise fashion for buffer-injected control and KA-treated animals were IBO: 1,947 +/- 457 and 10,553 +/- 1,242; t-ACPD: 1,557 +/- 662 and 9,449 +/- 2,251 dpm/mg protein respectively. Significantly augmented mGluR responses in hippocampal slices were also measured at 7, 42 and 92 days after KA injection. There were, however, no significant increases in CARB-stimulated phosphoinositide hydrolysis in the hippocampal slices at all time-intervals after KA administration. These findings show that there are differences between the mGluR responses in hippocampal synaptoneurosome and slice preparations, suggesting the presence of two distinct populations of mGluR in each of these two models. The large specific increases in certain mGluR activities after KA-induced status epilepticus in hippocampal slices could represent one of the molecular mechanisms which underlie the profound morphological changes, in particular gliosis or mossy fiber sprouting, which follow the KA-induced status epilepticus.
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PMID:Kainate-induced status epilepticus leads to a delayed increase in various specific glutamate metabotropic receptor responses in the hippocampus. 806 81

The effect of domoic acid-induced seizure activity on energy metabolism and on brain pH in mice was studied by continuous EEG recording and in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. Mice were divided into ventilated (n = 6) and nonventilated (n = 7) groups. Baseline EEG was 0.1-mV amplitude with frequence of > 30-Hz and of 4-5 Hz. After intraperitoneal (i.p.) administration of domoic acid (6 mg/kg), electrographic spikes appeared at increasing frequency, progressing to high-amplitude (0.1-0.8 mV) continuous seizure activity (status epilepticus). In ventilated mice, the [31P]NMR spectra showed that high-energy phosphate levels and tissue pH did not change after domoic acid administration or during the intervals of spiking or status epilepticus. Nonventilated mice showed periods of EEG suppression accompanied by decreases in the levels of high-energy phosphate metabolites and in pH, corresponding to episodic respiratory suppression during the spiking interval. In all animals, status epilepticus was followed by a marked decrease in EEG amplitude that progressed rapidly to isoelectric silence. [31P]NMR spectra obtained after this were indicative of total energy failure and tissue acidosis. In a separate group of ventilated mice (n = 4), domoic acid-induced status epilepticus was accompanied initially by an increase in mean arterial blood pressure (MAP) that slowly returned to baseline level. Isoelectric silence was accompanied by a decrease in MAP to 75 +/- 8 mm Hg. These experiments suggest that domoic acid-induced seizures are not accompanied by an increase in substrate demand that exceeds supply.
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PMID:Phosphate energy metabolism during domoic acid-induced seizures. 824 72

Status epilepticus occurs in more than 50,000 people in the United States each year and should be considered a neurologic emergency. A variety of drugs are used to treat status epilepticus, including i.v. benzodiazepines, phenytoin, and barbiturates. They are all short of being ideal, primarily because of difficulties with administration or associated toxicity. Fosphenytoin, a prodrug and phosphate ester of phenytoin, was developed to overcome the drawbacks associated with i.v. phenytoin. With its efficacy, safety, and ease of administration, fosphenytoin is a valuable option for the treatment of status epilepticus.
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PMID:Emergency treatment of status epilepticus. 864 10

Fosphenytoin is a phosphate ester prodrug of phenytoin developed as a replacement for standard injectable sodium phenytoin. After absorption, phenytoin is cleaved (conversion half-life 8-15 min) from fosphenytoin. Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions (including standard intravenous solutions) and rapidly absorbed by the intramuscular route. Fosphenytoin has been tested successfully for three indications in humans: intramuscular maintenance dosing, intramuscular loading dose administration, and intravenous treatment of status epilepticus. Local toxicity (pain, burning, itching) is less by the intramuscular or intravenous route for fosphenytoin than for standard injectable sodium phenytoin. Systemic toxicity is similar with both preparations except that hypotension is less common and paresthesias are more common with fosphenytoin.
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PMID:Fosphenytoin (Cerebyx). 903 68


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