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)

Synthesis of arachidonoyl CoA and docosahexaenoyl CoA in homogenates and microsomes from cerebrum, cerebellum, and brain stem and in synaptic plasma membranes from cerebrum of control rats and rats undergoing bicuculline-induced status epilepticus were studied. Arachidonoyl CoA synthesis was 3-5 times higher than docosahexaenoyl CoA in homogenates and microsomes. The synaptic plasma membranes showed only 1.5- to 2.5-fold higher activity. The presence of Triton X-100 (0.1%) in the incubation medium did not alter the activity of arachidonoyl CoA synthesis but did increase the synthesis of docosahexaenoyl CoA in homogenates, microsomes, and especially in synaptic plasma membranes. The synthesis of these polyenoic fatty acyl CoAs were 4-6 times higher in microsomes than in homogenates. Synaptic plasma membranes exhibited about the same amount of activity as homogenates in the synthesis of docosahexaenoyl CoA, but only half the activity of the latter in arachidonoyl CoA synthesis. The synthesis of arachidonyl CoA and docosahexaenoyl CoA in cerebral homogenates and microsomes was higher than that of cerebellum and brain stem. The apparent Km values for labeled arachidonic acid (17 microM) and docosahexaenoic acid (12 microM) in synaptic plasma membranes were lower than the values for microsomes isolated from different brain regions. The Vmax values were also 4-10 times lower. Microsomes from different regions did not differ in their apparent Km values, but did show variations in apparent Vmax values. Cerebellar microsomes showed lower Vmax values than the other two regions. The presence of Triton X-100 caused a significant decrease in the apparent Km values with little change in the Vmax values. Bicuculline-induced seizures did not alter the kinetic properties of arachidonoyl CoA and docosahexaenoyl CoA synthesis, except there was a significant decrease in the apparent Km and Vmax values for cerebellar microsomal docosahexaenoyl CoA synthesis. In conclusion, there were marked differences in the activation of polyenoic fatty acids in different parts of the brain and in subcellular fractions. Although bicuculline-induced convulsions accumulate free polyenoic fatty acids in the brain, no changes were detected when the fatty activation was assayed with exogenous cofactors, except in cerebellum.
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PMID:Synthesis of arachidonoyl coenzyme A and docosahexaenoyl coenzyme A in synaptic plasma membranes of cerebrum and microsomes of cerebrum, cerebellum, and brain stem of rat brain. 398 82

The aim of this study was to determine seizure-induced oxidative stress by measuring hippocampal glutathione (GSH) and glutathione disulfide (GSSG) levels in tissue and mitochondria. Kainate-induced status epilepticus (SE) in rats resulted in a time-dependent decrease of GSH/GSSG ratios in both hippocampal tissue and mitochondria. However, changes in GSH/GSSG ratios were more dramatic in the mitochondrial fractions compared to hippocampal tissue. This was accompanied by a mild increase in glutathione peroxidase activity and a decrease in glutathione reductase activity in hippocampal tissue and mitochondria, respectively. Since coenzyme A (CoASH) and its disulfide with GSH (CoASSG) are primarily compartmentalized within mitochondria, their measurement in tissue was undertaken to overcome problems associated with GSH/GSSG measurement following subcellular fractionation. Hippocampal tissue CoASH/CoASSG ratios were decreased following kainate-induced SE, the time course and magnitude of change paralleling mitochondrial GSH/GSSG levels. Cysteine, a rate-limiting precursor of glutathione was decreased following kainate administration in both hippocampal tissue and mitochondrial fractions. Together these changes in altered redox status provide further evidence for seizure-induced mitochondrial oxidative stress.
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PMID:Seizure-induced changes in mitochondrial redox status. 1641 13

We hypothesized that in epileptic brains citric acid cycle intermediate levels may be deficient leading to hyperexcitability. Anaplerosis is the metabolic refilling of deficient metabolites. Our goal was to determine the anticonvulsant effects of feeding triheptanoin, the triglyceride of anaplerotic heptanoate. CF1 mice were fed 0-35% calories from triheptanoin. Body weights and dietary intake were similar in mice fed triheptanoin vs. standard diet. Triheptanoin feeding increased blood propionyl-carnitine levels, signifying its metabolism. 35%, but not 20%, triheptanoin delayed development of corneal kindled seizures. After pilocarpine-induced status epilepticus (SE), triheptanoin feeding increased the pentylenetetrazole tonic seizure threshold during the chronically epileptic stage. Mice in the chronically epileptic stage showed various changes in brain metabolite levels, including a reduction in malate. Triheptanoin feeding largely restored a reduction in propionyl-CoA levels and increased methylmalonyl-CoA levels in SE mice. In summary, triheptanoin was anticonvulsant in two chronic mouse models and increased levels of anaplerotic precursor metabolites in epileptic mouse brains. The mechanisms of triheptanoin's effects and its efficacy in humans suffering from epilepsy remain to be determined.
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PMID:Anticonvulsant effects of a triheptanoin diet in two mouse chronic seizure models. 2069 Dec 64

Mitochondrial dysfunction and oxidative stress are known to occur following acute seizure activity but their contribution during epileptogenesis is largely unknown. The goal of this study was to determine the extent of mitochondrial oxidative stress, changes to redox status, and mitochondrial DNA (mtDNA) damage during epileptogenesis in the lithium-pilocarpine model of temporal lobe epilepsy. Mitochondrial oxidative stress, changes in tissue and mitochondrial redox status, and mtDNA damage were assessed in the hippocampus and neocortex of Sprague-Dawley rats at time points (24h to 3months) following lithium-pilocarpine administration. A time-dependent increase in mitochondrial hydrogen peroxide (H(2)O(2)) production coincident with increased mtDNA lesion frequency in the hippocampus was observed during epileptogenesis. Acute increases (24-48h) in H(2)O(2) production and mtDNA lesion frequency were dependent on the severity of convulsive seizure activity during initial status epilepticus. Tissue levels of GSH, GSH/GSSG, coenzyme A (CoASH), and CoASH/CoASSG were persistently impaired at all measured time points throughout epileptogenesis, that is, acutely (24-48h), during the 'latent period' (48h to 7days), and chronic epilepsy (21days to 3months). Together with our previous work, these results demonstrate the model independence of mitochondrial oxidative stress, genomic instability, and persistent impairment of mitochondrial specific redox status during epileptogenesis. Lasting impairment of mitochondrial and tissue redox status during the latent period, in addition to the acute and chronic phases of epileptogenesis, suggests that redox-dependent processes may contribute to the progression of epileptogenesis in experimental temporal lobe epilepsy.
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PMID:Persistent impairment of mitochondrial and tissue redox status during lithium-pilocarpine-induced epileptogenesis. 2121 30

Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re-filling the tricarboxylic acid (TCA) cycle with C4-intermediates (anaplerosis). Here, we injected mice with [1,2-(13) C]glucose 3.5-4 weeks after pilocarpine-induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of (13) C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two (13) C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control-fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin-fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin-fed SE mice showed few changes in most other metabolite levels and their (13) C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3-(13) C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C-4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl-CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.
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PMID:Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy. 2423 46

Epilepsy is a severe neurological disorder characterized by altered electrical activity in the brain. Important pathophysiological mechanisms include disturbed metabolism and homeostasis of major excitatory and inhibitory neurotransmitters, glutamate and GABA. Current drug treatments are largely aimed at decreasing neuronal excitability and thereby preventing the occurrence of seizures. However, many patients are refractory to treatment and side effects are frequent. Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults. In rodents, the pilocarpine-status epilepticus model reflects the pathology and chronic spontaneous seizures of TLE and the pentylenetetrazole kindling model exhibits chronic induced limbic seizures. Accumulating evidence from studies on TLE points to alterations in astrocytes and neurons as key metabolic changes. The present review describes interventions which alleviate these disturbances in astrocyte-neuronal interactions by supporting mitochondrial metabolism. The compounds discussed are the endogenous transport molecule acetyl-L-carnitine and the triglyceride of heptanoate, triheptanoin. Both provide acetyl moieties for oxidation in the tricarboxylic acid cycle whereas heptanoate is also provides propionyl-CoA, which after carboxylation can produce succinyl-CoA, resulting in anaplerosis-the refilling of the tricarboxylic acid cycle.
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PMID:Modification of Astrocyte Metabolism as an Approach to the Treatment of Epilepsy: Triheptanoin and Acetyl-L-Carnitine. 2643 81