Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

To distinguish the role of Mn superoxide dismutase (MnSOD) from that of cytoplasmic CuZn superoxide dismutase (CuZnSOD), the mouse MnSOD gene (Sod2) was inactivated by homologous recombination. Sod2 -/- mice on a CD1 (outbred) genetic background die within the first 10 days of life (mean, 5.4 days) with a complex phenotype that includes dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, metabolic acidosis and ketosis, and a severe reduction in succinate dehydrogenase (complex II) and aconitase (a TCA cycle enzyme) activities in the heart and, to a lesser extent, in other organs. These findings indicate that MnSOD is required to maintain the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide. On the other hand, Lebovitz et al. reported an independently derived MnSod null mouse (Sod2tmlLeb) on a mixed C57BL/6 and 129Sv background with a different phenotype. Because a difference in genetic background is the most likely explanation for the phenotypic differences, the two mutant lines were crossed into different genetic backgrounds for further analyses. To study the phenotype of Sod2tmlLeb mice CD1 background, the Sod2tmlLeb mice were crossed to CD1 for two generations before the -/+ mice were intercrossed to generate -/- mice. The life span distribution of CD1 < Sod2-/- > Leb was shifted to the left, indicating a shortened life span on the CD1 background. Furthermore, the CD1 < Sod2-/- > Leb mice develop metabolic acidosis at an early stage as was observed with CD1 < Sod2-/- > Cje. When Sod2tmlCje was placed on C57BL/6J (B6) background, the -/- mice were found to die either during midgestation or within the first 4 days after birth. However, when the B6 < Sod2 -/+ > Cje were crossed with DBA/2J (D2) for the generation of B6D2F2 < Sod2-/- > Cje mice, an entirely different phenotype, similar to that described by Lebovitz et al., was observed. The F2 Sod -/- mice were able to survive up to 18 days, and the animals that lived for more than 15 days displayed neurological abnormalities including ataxia and seizures. Their hearts were not as severely affected as were those of the CD1 mice, and neurological degeneration rather than heart defect appears to be the cause of death.
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PMID:The use of transgenic and mutant mice to study oxygen free radical metabolism. 1067 32

The objective of this study was to determine the role of mitochondrial superoxide radical-mediated oxidative damage in seizure-induced neuronal death. Using aconitase inactivation as an index of superoxide production, we found that systemic administration of kainate in rats increased mitochondrial superoxide production in the hippocampus at times preceding neuronal death. 8-Hydroxy-2-deoxyguanosine, an oxidative lesion of DNA, was also increased in the rat hippocampus following kainate administration. Manganese(III) tetrakis(4-benzoic acid)porphyrin, a catalytic antioxidant, inhibited kainate-induced mitochondrial superoxide production, 8-hydroxy-2-deoxyguanosine formation and neuronal loss in the rat hippocampus. Kainate-induced increases of mitochondrial superoxide production and hippocampal neuronal loss were attenuated in transgenic mice overexpressing mitochondrial superoxide dismutase-2. We propose that these results demonstrate a role for mitochondrial superoxide production in hippocampal pathology produced by kainate seizures.
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PMID:Mitochondrial superoxide production in kainate-induced hippocampal damage. 1111 5

Status epilepticus (SE) in humans and animal models results in significant cerebral damage and an increased risk of subsequent seizures, associated with a characteristic pattern of neuronal loss particularly affecting the hippocampus. Seizure related cell death is considered to be excitotoxic, but studies have been limited, concentrating on terminal events rather than initial mechanisms. We have studied the biochemical events in the first few days following SE. Self-sustaining limbic SE was induced in adult rats using perforant path stimulation, and animals were allowed to recover. Biochemical studies were performed at 16, 44 h and 8 days following SE, using spectrophotometric enzyme assays and HPLC on regional brain homogenates compared with those from sham-operated controls. Haematoxylin and eosin histology was also undertaken at each time point. Brain aconitase and alpha-ketoglutarate dehydrogenase (alphaKDH) activity were both significantly (P<0.05) reduced by approximately 20% in the first 16-44 h following status, but had returned to normal by 8 days. These enzymes are part of the tri-carboxylic acid (Krebbs) cycle in the mitochondrial matrix, and are known to be sensitive to free radical, especially peroxynitrite damage. There was a similar decrease in reduced glutathione levels. Histological studies confirmed evidence of acute neuronal damage up to 44 h, and neuronal loss by 8 days. This is the first in vivo demonstration of this pattern of mitochondrial dysfunction and loss of brain glutathione following SE. The pattern of abnormalities is consistent with reversible mechanisms being involved in excitotoxic cell damage. This, together with the timing of changes, suggests new avenues for therapeutic intervention.
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PMID:Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat. 1190 34

The mechanisms underlying the decreased vulnerability of the immature brain to seizure-induced neuronal death remain unknown. We asked whether oxidative stress plays a role in the resistance of immature animals to seizure-induced brain damage. Mitochondrial aconitase inactivation and 8-hydroxy-2-deoxyguanosine (8-OHdG) were used as indices of steady-state mitochondrial superoxide (O(2)(-)) production and oxidative DNA damage, respectively. Kainate-induced seizures resulted in increased mitochondrial aconitase inactivation and 8-OHdG formation in adult (postnatal day 30 or more), but not in immature rats (postnatal days 12 and 21). Kainate administration did not induce manganese superoxide dismutase (MnSOD) or CuZnSOD in immature or adult rats. This developmental increase in mitochondrial O(2)(-) production and oxidative DNA damage following kainate seizures suggests that mitochondrial oxidative stress may be a key factor that renders the developing brain resistant to seizure-induced brain damage.
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PMID:Age dependence of seizure-induced oxidative stress. 1269 79

A role for astroglia in epileptogenesis has been hypothesised but is not established. Low doses of fluorocitrate specifically and reversibly disrupt astroglial metabolism by blocking aconitase, an enzyme integral to the tricarboxylic acid cycle. We used cerebral cortex injections of fluorocitrate, at a dose that we demonstrated to inhibit astroglial metabolism selectively, to determine whether astroglial disturbances lead to seizures. Rats were halothane-anesthetized, and 0.8 nmol of sodium fluorocitrate was injected into the cerebral cortex. Extradural electroencephalogram (EEG) electrodes were implanted, after which the anesthesia was ceased and the animals were observed. In all experiments, 14 of 15 fluorocitrate-treated animals exhibited epileptiform EEG discharges, with some animals exhibiting convulsive seizures. Discharges commenced as early as 30 min postfluorocitrate injection. Intraperitoneal octanol, but not halothane by inhalation, given to test the possible participation of gap junctions in EEG discharge generation, blocked or delayed the occurrence of discharges after fluorocitrate. These results indicate that focal cerebrocortical astroglial dysfunction leads to focal epileptiform discharges and sometimes to convulsive seizures and that the process possibly depends on effects mediated by gap junctions.
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PMID:Fluorocitrate-mediated astroglial dysfunction causes seizures. 1313 May 18

Epileptic seizures can occur as a result of mitochondrial dysfunction. Mitochondria have vital functions such as energy generation, control of cell death, neurotransmitter synthesis, and free radical production. Which of these critical mitochondrial functions contributes to epileptic seizures is unknown. We demonstrate here that a subset of mice with partial deficiency of the mitochondrial superoxide dismutase (Sod2(-/+)) show increased incidence of spontaneous and handling-induced seizures that correlates with chronic mitochondrial oxidative stress (increased aconitase inactivation and 8-hydroxy-2'-deoxyguanosine formation in mitochondria) and diminished mitochondrial oxygen utilization. Before the age at which spontaneous seizures appear in a subset of the mice, Sod2(-/+) mice demonstrated increased susceptibility to behavioral seizures, mitochondrial aconitase inactivation, and neurodegeneration induced by the administration of kainate. These data suggest that chronic mitochondrial oxidative stress initiated by superoxide (O(2)(.-)) radicals is sufficient to increase seizure susceptibility due to aging, environmental stimulation, or excitotoxin administration. Sod2(-/+) mice showed an age-related decrease in the expression of glial glutamate transporters (GLT-1 and GLAST), suggesting that oxidant-induced inhibition of glutamate transport may play a mechanistic role in rendering some Sod2(-/+) mice susceptible to seizures. In summary, mitochondrial oxidative stress and resultant dysfunction may be an important mechanism underlying certain seizure disorders.
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PMID:Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(-/+) mice. 1498 Jun 99

Although there is evidence that astrocytes support neuronal function, the contribution of astrocytes to seizure onset and termination is not known. To determine whether there are changes in seizure susceptibility or neuronal damage when the ability of astrocytes to generate ATP is reduced, 0.5 nmol of fluorocitrate (FC) was injected into the right ventricle. Injection of FC alone did not produce electrographic or behavioral seizures and did not stress or injure neurons or astrocytes, as measured with silver stain and immunohistochemistry for HSP32 or HSP72. However, in animals pretreated with FC, administration of kainic acid, at a dose that does not initiate seizures in control animals (7 mg/kg), caused wet dog shakes and neuronal damage in the hilus. Wet dog shakes did not cause any neuronal damage in control animals. If the dose of FC was increased to 0.75 nmol, then subsequent administration of the same dose of kainic acid (7 mg/kg) caused stage 3-5 seizures. Injection of FC also reduced the dose of pilocarpine needed to produce seizures. Given simultaneously with FC, isocitrate, which bypasses the biochemical inhibition of aconitase, blocked the effects of FC in both kainic acid and pilocarpine treated animals. The data demonstrate that inhibition of aconitase in astrocytes lowers the doses of both kainic acid and pilocarpine that will cause behavioral seizures and may increase neuronal vulnerability to seizures.
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PMID:Inhibition of aconitase in astrocytes increases the sensitivity to chemical convulsants. 1527 69

Mitochondrial dysfunction has been implicated as a contributing factor in diverse acute and chronic neurological disorders. However, its role in the epilepsies has only recently emerged. Animal studies show that epileptic seizures result in free radical production and oxidative damage to cellular proteins, lipids, and DNA. Mitochondria contribute to the majority of seizure-induced free radical production. Seizure-induced mitochondrial superoxide production, consequent inactivation of susceptible iron-sulfur enzymes, e.g., aconitase, and resultant iron-mediated toxicity may mediate seizure-induced neuronal death. Epileptic seizures are a common feature of mitochondrial dysfunction associated with mitochondrial encephalopathies. Recent work suggests that chronic mitochondrial oxidative stress and resultant dysfunction can render the brain more susceptible to epileptic seizures. This review focuses on the emerging role of oxidative stress and mitochondrial dysfunction both as a consequence and as a cause of epileptic seizures.
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PMID:Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. 1554 15

The time course and critical determinants of mitochondrial dysfunction and oxidative stress following limbic status epilepticus (SE) were investigated in hippocampal sub-regions of an electrical stimulation model in rats, at time points 4-44h after status. Mitochondrial and cytosolic enzyme activities were measured spectrophotometrically, and reduced glutathione (GSH) concentrations by HPLC, and compared to results from sham controls. The earliest change in any sub-region was a fall in GSH, appearing as early as 4h in CA3 (-13%, p<0.05), and persisting at all time points. This was followed by a transient fall in complex I activity (CA3, 16h, -13%, p<0.05), and later changes in aconitase (CA1,-18% and CA3, -22% at 44h, p<0.05). The activity of the cytosolic enzyme glyceraldehyde-3-phosphate-dehydrogenase was unaffected at all time points. It is known that GSH levels are dependent both on redox status, and on the availability of the precursor cysteine, in turn dependent on the cysteine/glutamate antiporter, for which extracellular glutamate concentrations are rate limiting. Both mechanisms are likely to contribute indirectly to GSH depletion following seizures. That a relative deficiency in GSH precedes later changes in the activities of complex I and aconitase in vulnerable hippocampal sub-regions, occurring within a clinically relevant therapeutic time window, suggests that strategies to boost GSH levels and/or otherwise reduce oxidative stress following seizures, deserve further study, both in terms of preventing the biochemical consequences of SE and the neuronal dysfunction and clinical consequences.
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PMID:Depletion of reduced glutathione precedes inactivation of mitochondrial enzymes following limbic status epilepticus in the rat hippocampus. 1629 Mar 21


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