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)

Homocystinuria with elevated plasma homocysteine and methionine levels is the result of deficient activity of cystathionine synthetase, the enzyme catalyzing conversion of homocysteine to cystathionine. It is inherited as an autosomal recessive trait with a worldwide distribution. The major clinical manifestations result from the elevated plasma homocysteine level. The excitotoxic effect of homocysteic acid accounts for mental retardation and seizures. Interference with collagen cross-linking by sulfhydryl groups of homocysteine causes ectopia lentis and skeletal deformities. Sulfation factor-like effects contribute to disruption of vascular endothelium, which is followed by platelet thrombosis and widespread arterial and venous occlusions. Low methionine homocystinuria, with deficient remethylation of homocysteine, results from deranged vitamin B(12) metabolism and from deficient 5,10-methylene-tetrahydrofolate reductase. Administration of azaribine produces homocystinuria by mechanism not yet elucidated.
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PMID:Homocystinuria: pathogenetic mechanisms. 32 77

A 24-year-old male had a deficiency of the complex I (NADH coenzyme-Q-reductase) of the mitochondrial respiratory chain, which clinically presented as a mitochondrial encephalomyopathy, with lactic acidosis and stroke-like episodes (MELAS syndrome). The encephalopathic episodes were preceded by migraine and were characterized by focal deficit signs, motor partial seizures and hypodense areas in the CT scan. An echocardiographic diagnosis of hypertrophic cardiomyopathy without intracavitary thrombi was made. It is suggested that hypertrophic cardiomyopathy is caused by the mitochondrial abnormalities that have been reported in the myocardium, and that migraine and cerebral infarctions are associated with abnormalities in the mitochondria from the endothelium and smooth muscle fibres of the cerebral small arteries and arterioles.
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PMID:[Complex I (NADH coenzyme-Q-reductase) deficiency, MELAS syndrome and hypertrophic cardiomyopathy]. 190 55

The toxicities of antimalarial drugs vary because of the differences in the chemical structures of these compounds. Quinine, the oldest antimalarial, has been used for 300 years. Of the 200 to 300 compounds synthesised since the first synthetic antimalarial, primaquine in 1926, 15 to 20 are currently used for malaria treatment, most of which are quinoline derivatives. Quinoline derivatives, particularly quinine and chloroquine, are highly toxic in overdose. The toxic effects are related to their quinidine-like actions on the heart and include circulatory arrest, cardiogenic shock, conduction disturbances and ventricular arrhythmias. Additional clinical features are obnubilation, coma, convulsions, respiratory depression. Blindness is a frequent complication in quinine overdose. Hypokalaemia is consistently present, although apparently self-correcting, in severe chloroquine poisoning and is a good index of severity. Recent toxicokinetic studies of quinine and chloroquine showed good correlations between dose ingested, serum concentrations and clinical features, and confirmed the inefficacy of haemodialysis, haemoperfusion and peritoneal dialysis for enhancing drug removal. The other quinoline derivatives appear to be less toxic. Amodiaquine may induce side effects such as gastrointestinal symptoms, agranulocytosis and hepatitis. The main feature of primaquine overdose is methaemoglobinaemia. No cases of mefloquine and piperaquine overdose have been reported. Overdose with quinacrine, an acridine derivative, may result in nausea, vomiting, confusion, convulsion and acute psychosis. The dehydrofolate reductase inhibitors used in malaria treatment are sulfadoxine, dapsone, proguanil (chloroguanide), trimethoprim and pyrimethamine. Most of these drugs are given in combination. Proguanil is one of the safest antimalarials. Convulsion, coma and blindness have been reported in pyrimethamine overdose. Sulfadoxine can induce Lyell and Stevens-Johnson syndromes. The main feature of dapsone poisoning is severe methaemoglobinaemia which is related to dapsone and to its metabolites. Recent toxicokinetic studies confirmed the efficacy of oral activated charcoal, haemodialysis and haemoperfusion in enhancing removal of dapsone and its metabolites. No overdose has been reported with artemesinine, a new antimalarial tested in the People's Republic of China. The general management of antimalarial overdose include gastric lavage and symptomatic treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clinical features and management of poisoning due to antimalarial drugs. 330 66

Seizures were induced in female Wistar rats by electroconvulsive shock (ECS) or administration of pentetrazole (PTZ). Brain content of various prostanoids measured by radioimmunoassay showed time-dependent changes after the induction of convulsions; highest levels were found for PGD2 followed by PGF2 alpha, PGE2, TXB2 and 6-keto-PGF1 alpha. Analysis of the various arachidonic acid metabolites in seven parts of the rat brain dissected according to the method of Glowinski and Iversen revealed the largest increases in hippocampus and cerebral cortex and smaller ones also in hypothalamus and corpus striatum both after ECS and PTZ. The ratios of the different cyclo-oxygenase products remained virtually the same in whole brain as well as in those regions where the formation of prostaglandins was markedly elevated. 15-keto-13,14-dihydro-PGF2 alpha also increased simultaneously in parallel to its parent compound, PGF2 alpha and was detected in significant amounts only in hippocampus and cerebral cortex. However, concentrations of 15-keto-13,14-dihydro-PGF2 alpha in these brain regions as well as in whole brain represented only 3-10% of the amounts found for PGF2 alpha. Thus, the metabolizing enzymes 15-hydroxy-PG-dehydrogenase and delta 13-PG-reductase seem to be of minor importance for the inactivation of prostanoids in brain tissue.
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PMID:Regional distribution of arachidonic acid metabolites in rat brain following convulsive stimuli. 679

These studies investigate whether the neurosteroid and 5 alpha-reduced metabolite of testosterone (T), 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-Diol), has anti-seizure effects similar to its parent compound. In experiment 1, ovariectomized (ovx) Long-Evans rats (n = 20) were subcutaneously (s.c.) administered 32 mg/kg kainic acid or saline vehicle 10 min following 0.0, 3.0, or 7.5 mg/kg 3 alpha-Diol in 10% ethanol, propylene glycol vehicle (veh). During 2 h of observation of ictal activity, 3 alpha-Diol (3.0 and 7.5 mg/kg) prior to kainic acid significantly decreased the number and duration of partial and full seizures compared to the 0.0 3 alpha-Diol conditions and produced ictal activity that was comparable to 0.0 mg/kg 3 alpha-Diol no kainic acid controls (procedure controls). Animals that received 7.5 mg/kg 3 alpha-Diol prior to kainic acid had shorter latencies and distances to the hidden platform in a Morris Water Maze task than those that received 0.0 3 alpha-Diol, 1 week following ictal activity. Administration of 3 alpha-Diol (3.0 or 7.5 mg/kg) prior to kainic acid stimulation resulted in a greater number of identifiable neurons in the hilar region of the hippocampus, compared to 0.0 3 alpha-Diol condition. Experiment 2 was conducted to ascertain whether 3 alpha-Diol's anti-seizure effects were comparable to T and possibly a result of metabolism from T. Ovx rats (n = 36) were stereotaxically implanted with bipolar electrodes into the perforant pathway. One hour prior to perforant pathway stimulation, six rats were s.c. injected with either T (7.5 mg/kg), 3 alpha-Diol (7.5 mg/kg), 7.5 mg/kg T + 4MA (a 5 alpha-reductase inhibitor, 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza,5 alpha-androstan-3-one), 4MA alone, 10% propylene glycol vehicle (veh) with perforant pathway stimulation, or veh without perforant pathway stimulation. 3 alpha-Diol and T produced similar seizure activity, water maze performance, and neuronal integrity in the hilar region of the hippocampus that were comparable to unstimulated controls. Because the T and 3 alpha-Diol groups were not different from T + 4MA but tended to be different from 4MA alone on these measures, this suggests that 3 alpha-Diol and T can have similar anti-seizure effects which may be due to actions of neurosteroids.
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PMID:Androgenic neurosteroids: anti-seizure effects in an animal model of epilepsy. 969 38

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) is the enzyme responsible for the interconversion of corticosterone (CORT) to 11-dehydrocorticosterone (11-DHC). CORT is an adrenal hormone secreted during the stress response and it has widespread effects in many different target tissues. In addition, CORT can exacerbate damage caused by neurological insults, such as kainic acid-induced seizures. In addition to its protective role in the kidney, 11beta-HSD is also thought to play a role in steroid regulation in the brain. However, it is not known whether the enzyme is acting in vivo as a reductase or a dehydrogenase. If the enzyme is working as a reductase, converting 11-DHC to CORT, it has the potential to exacerbate neurotoxicity due to other agents. On the other hand, 11beta-HSD could be neuroprotective if the enzyme is acting as a dehydrogenase, deactivating CORT by converting it into 11-DHC. To characterize the enzyme in vivo, we have utilized glucocorticoid neuroendangerment in the hippocampus as an indirect assay of 11beta-HSD function. We have shown that 11-DHC can exacerbate kainic acid toxicity in adrenalectomized (ADX) rats and this exacerbation is blocked by the 11beta-HSD antagonist, carbenoxolone; these findings suggest that 11beta-HSD is working as a reductase in ADX rats. The presumptive reductase activity found in ADX rats was derived from both hippocampal and peripheral forms of the enzyme. In the presence of physiological levels of glucocorticoids, reductase activity was decreased and no dehydrogenase activity was detected. The present study demonstrates that 11beta-HSD reductase activity, both in vivo and in vitro, occurs only in the presence of low levels of circulating glucocorticoids.
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PMID:In vivo characterization of 11beta-hydroxysteroid dehydrogenase in rat hippocampus using glucocorticoid neuroendangerment as an endpoint. 998 27

A subgroup of children with arterial ischemic stroke in the pre- or perinatal period present with delayed diagnosis. We identified 22 children who met the following criteria: (1) normal neonatal neurological history, (2) hemiparesis and/or seizures first recognized after two months of age, and (3) computed tomography or magnetic resonance imaging showing remote cerebral infarct. Laboratory evaluations included protein C, protein S, antithrombin, activated protein C resistance screen (APCR), Factor V Leiden (FVL), prothrombin gene defect, methylene tetrahydrofolate reductase variant (MTHFR), anticardiolipin antibody (ACLA), and lupus anticoagulant. Not all children received all tests. Age at last visit ranged from 8 months to 16.5 years (median 4 years). Twelve were boys. Fourteen had left hemisphere infarcts. Median age at presentation was 6 months. Eighteen had gestational complications. Fourteen children had at least transient coagulation abnormalities (ACLA = 11, ACLA + APCR = 1, APCR = 2 with FVL + MTHFR = 1); six of these children had family histories suggestive of thrombosis. Cardiac echocardiogram was unremarkable in the 15 tested. Outcomes included persistent hemiparesis in 22; speech, behavior, or learning problems in 12; and persistent seizures in five, with no evidence of further stroke in any patient. The persistence and importance of coagulation abnormalities in this group need further study.
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PMID:Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. 1150 98

In the present study, the distribution of succinic semialdehyde dehydrogenase (SSADH) and succinic semialdehyde reductase (SSAR) in the hippocampus of the Mongolian gerbil and its association with various sequelae of spontaneous seizure were investigated in order to identify the roles of GABA shunt in the epileptogenesis and the recovery mechanisms in these animals. Both SSADH and SSAR immunoreactivities in the GABAergic neurons were significantly higher in the pre-seizure groups of seizure sensitive (SS) gerbil as compared to those seen in the seizure resistant (SR) gerbils. The distributions of both SSADH and SSAR immunoreactivities in the hippocampus showed significant differences after the on-set of seizure. At 3 h postictal, when compared to the pre-seizure group of SS gerbils, a decline in the immunoreactivities in the perikarya was observed. At 12 h after seizure on-set, the densities of both SSADH and SSAR immunoreactivities were begun to recover to the pre-seizure level of SS gerbils. These results suggest that the GABAergic neurons in the hippocampal complex of the SS gerbil may be highly activated. In addition, the imbalance of GABA shunt expressions in the GABAergic neurons may imply a malfunction of the metabolism of GABAergic neurons in the SS gerbils, and this defect may trigger seizure on-set. Therefore, the initiation of seizure, at least in gerbils, may be the result of a malfunction in GABA shunt in the GABAergic neurons.
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PMID:The altered expression of GABA shunt enzymes in the gerbil hippocampus before and after seizure generation. 1242 78

Gastrodin is one of the natural compound isolated from Gastrodia elata and has known anticonvulsant effects, although the exact pharmacological principles of this natural compound and its effects on other aspects of gamma-aminobutyric acid (GABA) metabolism in vivo have not been explored. Therefore, in the present study, the effects of gastrodin on GABA metabolism in the gerbil hippocampus were examined, in an effort to identify the antiepileptic characteristics of this substance. Gastrodin reduced the seizure score in the treated group, although the immunoreactivities of GABA synthetic enzymes and GABA transporters were unaltered in gastrodin-treated animals. Interestingly, in the gastrodin-treated group, GABA transaminase (GABA-T) immunoreactivity in the hippocampus, particularly in neurons, was significantly decreased. In the gastrodin-treated group, both succinic semialdehyde dehydrogenase (SSADH) and succinic semialdehyde reductase (SSAR) immunoreactivities in the hippocampus was also decreased significantly, which stood in contrast to the nontreated group, in which strong SSADH and SSAR immunoreactivities were detected. From the neuroanatomical viewpoint, these findings suggest that gastrodin may cause the elevation of GABA concentration by inhibiting the GABA shunt.
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PMID:Gastrodin decreases immunoreactivities of gamma-aminobutyric acid shunt enzymes in the hippocampus of seizure-sensitive gerbils. 1254 9

The reduced progesterone metabolite tetrahydroprogesterone is a potent positive modulator of GABA(A) chloride conductance that exerts powerful neuroinhibitiory and anti-seizure effects in animal models. Cyclic natural progesterone use may lessen seizure frequency in women with catamenial seizure exacerbation. We report a case in which efficacy was eliminated during concomitant treatment with a reductase inhibitor. The observation suggests that a reduced metabolite, rather than progesterone itself, was responsible for improved seizure control.
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PMID:Seizure exacerbation associated with inhibition of progesterone metabolism. 1260 96


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