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)

Poisoning with potassium cyanide is usually fatal because of the inhibition of cytochrome oxidase. The parameters of oxygen metabolism in a patient with cyanide poisoning who was admitted in a coma with seizures was monitored. The administration of amyl nitrite and sodium thiosulfate led to a rapid improvement: the parameters reflecting oxygen metabolism improved and the plasma level of cyanide decreased. The patient revived 1 1/2 hours after treatment. The arterial ketone body ratio (AKBR), which is the ratio of acetoacetate to beta-hydroxybutyrate in arterial blood and which reflects the redox state in liver mitochondria, improved dramatically following treatment. Because the AKBR changes in relation to electron transport in liver mitochondria, it seems to be a logical parameter for evaluating the effect of potassium cyanide poisoning on electron transport. The AKBR also reflects the efficacy of treatment for cyanide poisoning.
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PMID:Changes in the parameters of oxygen metabolism in a clinical course recovering from potassium cyanide. 848 60

The study investigated the hypothesis that delayed cerebral injury after transient cerebral ischemia is associated with vasoconstriction and decreased cerebral oxygenation. Eight chronically instrumented, late gestation fetal sheep were subjected to 30 min of cerebral ischemia in utero. Cortical impedance (CI) and electrocorticogram (ECoG) were recorded to determine the time course of cellular dysfunction. Histologic outcome was assessed 4 d postischemia. Changes in cerebral vascular tone and oxygenation were observed during and for 4 d after the insult using near infrared spectroscopy to measure changes in total cerebral Hb ([tHb]), oxyhemoglobin ([Hbo2]), and oxidized cytochrome aa3 ([Cyto2]). Results are expressed as mean +/- SEM. CI increased transiently during ischemia; then a delayed increase commenced 17.5 +/- 2.3 h postischemia and peaked at 42.3 +/- 2.4 h. ECoG was depressed during and after the insult. Seizures started 13.6 +/- 3.0 h postinsult and persisted for 25.4 +/- 3.2 h. Increases in [tHb] indicated two periods of cerebral vasodilation: immediately after early reperfusion, lasting 2.3 +/- 0.4 h and peaking to 20 +/- 2.0 mumol.L-1; and a later phase, commencing 12.8 +/- 2.0 h postischemia, peaking to 43 +/- 4.0 mumol.L-1 and lasting 43.1 +/- 5.2 h. [Hbo2] was relatively elevated (18 +/- 3.0 mumol.L-1) during d 4 postischemia, demonstrating a delayed increase in mean cerebral oxygen saturation. [Cyto2] fell during the insult (-0.7 +/- 0.2 mumol.L-1); and, commencing at 28-30 h postischemia, fell progressively to reach a minimum of -5.0 +/- 2.8 mumol.L-1 at 78-80 h postischemia. A greater fall in [Cyto2] was related to worse cerebral injury (p < 0.05). Delayed cerebral injury is accompanied by vasodilation and increased mean cerebral oxygen saturation, although a progressive fall in [Cyto2] might indicate a fall in mitochondrial oxygenation, cell loss, or changes in tissue optical characteristics.
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PMID:Delayed vasodilation and altered oxygenation after cerebral ischemia in fetal sheep. 882 85

Disruption of early or late fetal brain development resulting in structural abnormalities may be associated with inborn errors of mitochondrial metabolism. It is common in patients with deficiency of pyruvate dehydrogenase activity and it has sporadically been described in patients with dysfunction of the tricarboxylic acid cycle. Mitochondrial respiratory chain disorders are not commonly known to interfere with early brain development. We describe here a girl with an encephalomyopathy likely to be due to a novel type of deficiency of cytochrome c oxidase (complex IV) activity that presented with severe hypotonia, myoclonic seizures, optic atrophy and elevated lactate concentration in cerebrospinal fluid shortly after birth. Cranial magnetic resonance imaging revealed hypoplasia of the cerebellum with rudimentary cerebellar hemispheres and relative sparing of the vermis. This case suggests that deficiency of cytochrome c oxidase and possibly respiratory chain disorders in general have to be considered in the differential diagnosis of cerebellar hypoplasia.
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PMID:Cerebellar hypoplasia in respiratory chain dysfunction. 889 74

After transient cerebral ischemia in fetal sheep, delayed disruptions in cerebral energetics are represented by a delayed increase in cortical impedance, a progressive decrease in the concentration of oxidized cytochrome oxidase as measured by near-infrared spectroscopy, and cortical seizures. Because the production of nitric oxide (NO), a potent mediator of neuronal death, is increased during this phase, the present study investigated whether inhibition of NO synthesis could ameliorate the delayed disruption in cerebral energetics. Eleven late gestation fetal sheep were subjected to 30 min of transient cerebral ischemia in utero. Two hours later, the treatment group (n = 5) received a continuous infusion of N(G)-nitro-L-arginine, a competitive inhibitor of NO synthase, whereas the control group (n = 6) received PBS. Changes in concentration of oxidized cytochrome oxidase, cortical impedance, and electrocortical activity were observed for 3 d. A delayed increase in cortical impedance of similar magnitude and duration commenced at 14+/-4 h in the control and at 15+/-3 h in the treatment groups. The progressive decrease in oxidized cytochrome oxidase signal, by -2.2+/-0.2 micromol/L in the control and -2.0+/-0.4 micromol/L in the treatment group at 72 h postischemia, was similar in both groups. In both groups, delayed cortical seizures were indicated by intense low-frequency electrocortical activity. In the treatment group, duration of cortical seizures was increased and the intensity of the final electrocortical activity was more depressed (-19+/-1 dB versus -10+/-2 dB). The results indicate that after cerebral ischemia in fetal sheep, NO synthase inhibition does not ameliorate the delayed disruptions in cerebral energetics. However, the effect of NO synthase inhibition on delayed cortical seizures may improve our understanding of the role of NO during this phase.
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PMID:Nitric oxide synthase inhibition and delayed cerebral injury after severe cerebral ischemia in fetal sheep. 1040 Jan 27

In neonates, asphyxia is a common cause of neuronal injury and often results in seizures. The authors evaluated whether blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors during asphyxia and early recovery with 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-(F)-quinoxaline (NBQX) ameliorates neurologic deficit and histopathology in 1-week-old piglets. Anesthetized piglets were exposed to a sequence of 30 minutes of hypoxia, 5 minutes of room air ventilation, 7 minutes of airway occlusion, and cardiopulmonary resuscitation. Vehicle or NBQX was administered intravenously before asphyxia (30 mg/kg) and during the first 4 hours of recovery (15 mg/kg/h). Neuropathologic findings were evaluated at 96 hours of recovery by light microscopic and cytochrome oxidase histochemical study. Cardiac arrest occurred at 5 to 6 minutes of airway occlusion, and cardiopulmonary resuscitation restored spontaneous circulation independent of treatment modalities in about 2 to 3 minutes. Neurologic deficit over the 96-hour recovery period was not ameliorated by NBQX. Seizure activity began after 24 to 48 hours in 7 of 10 animals with vehicle and in 9 of 10 of animals with NBQX. In each group, four animals died in status epilepticus. Neuropathologic outcomes were not improved by NBQX. The density of remaining viable neurons was decreased in parietal cortex and putamen by NBQX treatment. Metabolic defects in cytochrome oxidase activity were worsened by NBQX treatment. Seizure activity during recovery was associated with reduced neuronal viability in neocortex and striatum in piglets from both groups that survived for 96 hours. This neonatal model of asphyxic cardiac arrest and resuscitation generates neurologic deficits, clinical seizure activity, and selective damage in regions of basal ganglia and sensorimotor cortex. In contrast to other studies in mature brain, AMPA receptor blockade with NBQX failed to protect against neurologic damage in the immature piglet and worsened postasphyxic histopathologic outcome in neocortex and putamen.
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PMID:Effects of the AMPA receptor antagonist NBQX on outcome of newborn pigs after asphyxic cardiac arrest. 1045

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a
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PMID:Toxic action/toxicity. 1074 Aug 94

The syndrome of exercise intolerance, cramps, and myoglobinuria is a common presentation of metabolic myopathies and has been associated with several specific inborn errors of glycogen or lipid metabolism. As disorders in fuel utilization presumably impair muscle energy production, it was more than a little surprising that exercise intolerance and myoglobinuria had not been associated with defects in the mitochondrial respiratory chain, the terminal energy-yielding pathway. Recently, however, specific defects in complex I, complex III, and complex IV have been identified in patients with severe exercise intolerance with or without myoglobinuria. All patients were sporadic cases and all harbored mutations in protein-coding genes of muscle mtDNA, suggesting that these were somatic mutations not affecting the germ-line. Another respiratory chain defect, primary coenzyme Q10 (CoQ10) deficiency, also causes exercise intolerance and recurrent myoglobinuria, usually in conjunction with brain symptoms, such as seizures or cerebellar ataxia. Primary CoQ10 deficiency is probably due to mutations in nuclear gene(s) encoding enzymes involved in CoQ10 biosynthesis.
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PMID:Exercise intolerance and the mitochondrial respiratory chain. 1093 58

We report three children, each of whom seemed to have a primary mitochondrial disorder at presentation but was eventually diagnosed with an extramitochondrial inherited metabolic disease. The first patient presented at 6 months with developmental delay. Magnetic resonance imaging showed an abnormal signal in the white matter, and magnetic resonance spectroscopy showed elevated lactate peaks. A muscle biopsy showed complex IV deficiency, but leukocyte measurement of galactosylceramide beta-galactosidase activity was markedly diminished, consistent with Krabbe's disease. The second patient presented at birth with seizures and later had developmental delays. There was brain atrophy on neuroimaging. Serum and cerebrospinal fluid lactate levels were elevated. She had persistently elevated urine thiosulfate, which was diagnostic for molybdenum cofactor deficiency. The third child presented at 2 months with seizures and hypotonia. Magnetic resonance imaging showed an abnormal signal in the basal ganglia and surrounding white matter, whereas magnetic resonance spectroscopy showed elevated lactate peaks. A brain biopsy was diagnostic for Alexander's disease. These cases and others in the literature suggest that lactic acid elevation in the central nervous system can be found in a number of extramitochondrial neurologic diseases. Such diseases would constitute a third category of lactic acidosis.
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PMID:Lactic acid elevation in extramitochondrial childhood neurodegenerative diseases. 1157 6

We suggest that a dysregulation of energy metabolism in the brain of genetic absence epilepsy rats from Strasbourg (GAERS) could create a specific cerebral environment that would favor the expression of spike-and-wave discharges (SWD) in the thalamocortical loop, largely dependent on glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurotransmissions. We tested several aspects of metabolic activity in the brain of GAERS compared to a genetic strain of nonepileptic (NE) rats. Glucose metabolism was higher in all brain regions of GAERS compared to those of NE rats along the whole glycolytic and aerobic pathways, as assessed by regional histochemical measurement of lactate dehydrogenase and cytochrome oxidase activities. Branched-chain amino acids (BCAA) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine, when injected intraperitoneally, increased the number of SWD in GAERS but had only a slight effect on their duration. These data speak in favor of a BCAA- or alpha-KIC-induced change in neuronal excitability. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAA and alpha-KIC, by decreasing glutamatergic neurotransmission, could favor GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS. Finally, the transport of [1-(14)C]alpha-KIC in freshly isolated cortical neurons was lower in GAERS than in NE rats, and this difference was shown to be of metabolic origin. The addition of gabapentin, a specific inhibitor of BCAA transaminase (BCAT), reduced the transport of [1-(14)C]alpha-KIC in GAERS and NE rats to a level that became identical in both strains. This strain-dependent change was not related to a difference in the activity of BCAT, which was identical in GAERS and NE rats. The exact origin of this apparent metabolic dysregulation of energy metabolism in GAERS that could underlie the origin of seizures in that strain remains to be explored further.
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PMID:Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: study of the leucine-glutamate cycle. 1174 20

The present study is directed to study: (a) bax translocation and cytochrome c release as mediators of the mitochondrial pathway of apoptosis; (b) Fas-L (Fas-ligand) expression as an indicator of the possible involvement of the Fas/Fas-L signaling pathway; and (c) active caspase-3 expression as the main executioner of caspase-mediated apoptosis, in rats receiving an intraperitoneal injection of the glutamate analogue kainic acid (KA) at a dose of 9 mg/kg, which is sufficient to produce generalized seizures and excitotoxic cell death in the entorhinal cortex. Sub-fractionation studies of entorhinal cortex homogenates have shown cytochrome c and cytochrome oxidase IV localized in the mitochondrial fraction, and Bax localized in the cytosolic fraction. No modifications in the sub-cellular distribution of cytochrome c and Bax have been observed at 6 h and 24 h in KA-treated rats. Morphological studies have shown cytoplasmic shrinkage and nuclear condensation consistent with necrosis in the entorhinal cortex. Many neurons (about 30% of dying cells) are stained with the method of in situ end-labeling of nuclear DNA fragmentation. Yet only about 5% of dying cells have apoptotic morphology. A percentage of dying cells (5% at 6 h and 40% at 24 h) over-express Fas-L but only about 2% of dying cells at 24 h post-injection express cleaved caspase-3 (17 kD). The present data further support the concept that necrosis is the predominant form of cell death in the entorhinal cortex, although caspase-3-dependent apoptotic cell death may play a limited role, in the present paradigm of KA-induced excitotoxicity.
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PMID:Caspase-3-associated apoptotic cell death in excitotoxic necrosis of the entorhinal cortex following intraperitoneal injection of kainic acid in the rat. 1188 Feb 2


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