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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper comprises a series of experiments in rodent models of partial and generalized epilepsy which were designed to describe the anti-convulsant profile of the functionalized amino acid lacosamide. Lacosamide was effective against sound-induced seizures in the genetically susceptible Frings mouse, against maximal electroshock test (MES)-induced seizures in rats and mice, in the rat hippocampal kindling model of partial seizures, and in the 6Hz model of psychomotor seizures in mice. The activity in the MES test in both mice (4.5mg/kg i.p.) and rats (3.9 mg/kg p.o.) fell within the ranges previously reported for most clinically available anti-epileptic drugs. At both the median effective dose for MES protection, as well as the median toxic dose for rotorod impairment, lacosamide elevated the seizure threshold in the i.v. pentylenetetrazol seizure test, suggesting that it is unlikely to be pro-convulsant at high doses. Lacosamide was inactive against clonic seizures induced by subcutaneous administration of the chemoconvulsants pentylenetetrazol, bicuculline, and picrotoxin, but it did inhibit NMDA-induced seizures in mice and showed full efficacy in the homocysteine model of epilepsy. In summary, the overall anti-convulsant profile of lacosamide appeared to be unique, and the drug displayed a good margin of safety in those tests in which it was effective. These results suggest that lacosamide may have the potential to be clinically useful for at least the treatment of generalized tonic-clonic and partial-onset epilepsies, and support ongoing clinical trials in these indications.
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PMID:Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy. 1743 24

CBS is a vitamin B6-dependent transsulfuration enzyme needed to synthesize cysteine from methionine, catalyzing the condensation of serine with homocysteine to form cystathionine. A deficiency of CBS causes homocystinuria (MIM 236200), one of the most prevalent inborn errors, characterized by mental retardation, seizures, psychiatric disturbances, skeletal abnormalities and vascular disorders. Patients with CBS deficiency exhibit a major biochemical abnormality, hyperhomocysteinemia (HHcy), a condition associated with highly elevated plasma homocysteine levels. HHcy is recognized as a risk factor for several neurological diseases, such as cognitive impairment, dementia and Alzheimer's disease. Although the link between CBS deficiency and homocystinuria was first described over 40 years ago and mental retardation was the first clinical feature of the disease to be classified, very little is known about the role of CBS in the CNS. Here we show the regional and cellular distribution of CBS in the adult and developing mouse brain. In the adult mouse brain, CBS was expressed ubiquitously, but most intensely in the cerebellar molecular layer and hippocampal dentate gyrus. Immunohistochemical analysis revealed that CBS is preferentially expressed in cerebellar Bergmann glia and in astrocytes throughout the brain. At early developmental stages, CBS was expressed in neuroepithelial cells in the ventricular zone, but its expression changed to radial glial cells and then to astrocytes during the late embryonic and neonatal periods. Moreover, CBS was significantly accumulated in reactive astrocytes in the hippocampus after kainic acid-induced seizures, and cerebellar morphological abnormalities were observed in CBS-deficient mice. These results support the role of CBS in the development and maintenance of the CNS, and suggest that radial glia/astrocyte dysfunction might be involved in the complex neuropathological features associated with abnormal homocysteine metabolism.
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PMID:[Disruption of amino acid metabolism in astrocyte and neurological disorders--possible implication of abnormal glia-neuron network in homocystineuria]. 1766 44

D,L-homocysteine thiolactone (H), a reactive homocysteine metabolite, contributes to total homocysteine pool. The aim of the present study was to determine the effects of H after acute application in increasing doses to rats. Adult Wistar rat were intraperitoneally administered saline or H in increasing doses (5.5, 8.0, or 11.0 mmol/kg). For electroencephalographic (EEG) recordings, three gold-plated screws were implanted into the skull and animals were supervised. We observed H-induced two types of seizures, the coexistence of convulsive and nonconvulsive epilepsy. Dose-related increase in the number and severity (0-4) of displaying convulsions was recorded. In H(5.5) group, the majority of seizure episodes were grade 1 (62.5 and 0% lethality), in H(8) 40% grade 2, and in H(11) grade 4 in 42.11% (100% lethal outcome). EEGs recordings in convulsive animals showed a high-voltage spike-wave and polyspikes complexes. The second, absence-like, nonconvulsive seizures were accompanied by the EEGs mostly with 6-8 Hz spikes-and-wave discharges (SWD). Latency time to the generalized clonic-tonic seizures overlapped with the time of the maximal median number and median duration of the SWD per 15 min during 90-min observing period. The results show that acute H administration significantly changes neurons, EEG tracings, and behavioral responses and suggests a possible model for studying petit mal epilepsy.
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PMID:Two types of seizures in homocysteine thiolactone-treated adult rats, behavioral and electroencephalographic study. 1897 5

Hyperhomocysteinemia is associated with various pathologies including cardiovascular disease, stroke, and cognitive dysfunctions. Systemic administration of homocysteine can trigger seizures in animals, and patients with homocystinuria suffer from epileptic seizures. Available data suggest that homocysteine can be harmful to human cells because of its metabolic conversion to homocysteine thiolactone, a reactive thioester. A number of reports have demonstrated a reduction of Na+/K+-ATPase activity in cerebral ischemia, epilepsy and neurodegeneration possibly associated with excitotoxic mechanisms. The aim of this study was to examine the in vivo effects of D,L-homocysteine and D,L-homocysteine thiolactone on Na+/K+- and Mg2+-ATPase activities in erythrocyte (RBC), brain cortex, hippocampus, and brain stem of adult male rats. Our results demonstrate a moderate inhibition of rat hippocampal Na+/K+-ATPase activity by D,L-homocysteine, which however expressed no effect on the activity of this enzyme in the cortex and brain stem. In contrast, D,L-homocysteine thiolactone strongly inhibited Na+/K+-ATPase activity in cortex, hippocampus and brain stem of rats. RBC Na+/K+-ATPase and Mg2+-ATPase activities were not affected by D,L-homocysteine, while D,L-homocysteine thiolactone inhibited only Na+/K+-ATPase activity. This study results show that homocysteine thiolactone significantly inhibits Na+/K+-ATPase activity in the cortex, hippocampus, and brain stem, which may contribute at least in part to the understanding of excitotoxic and convulsive properties of this substance.
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PMID:The activity of erythrocyte and brain Na+/K+ and Mg2+-ATPases in rats subjected to acute homocysteine and homocysteine thiolactone administration. 1922 40

The topic of alcohol withdrawal syndrome (AWS), including delirium tremens and especially seizures, is reviewed. From mice and rat studies, it is known that both N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors are involved in AWS. During alcohol intoxication chronic adaptations of NMDA and GABA receptors occur, and during alcohol withdrawal a hyperexcitable state develops. In studies on humans, during intoxication the NMDA receptors are activated and mediate tonic inhibition. In withdrawal, a rebound activation of these receptors occurs. Both GABA-A and GABA-B receptors, especially the alpha2 subunit of GABA-A receptors, are also likely involved. Homocysteine increases with active drinking, and in withdrawal, excitotoxicity likely is induced by a further increase in homocysteine, viewed as a risk factor for AWS and also as a screening tool. The dopamine transporter gene is also associated with AWS. Characteristics involves changes in the ECG, especially an increase in QT interval, and EEG changes, including abnormal quantified EEG, at times periodic lateralized epileptiform discharges, and especially seizures, usually occurring 6-48h after the cessation of drinking. Therapy has emphasized benzodiazepines, mainly diazepam and lorazepam, but more standard antiepileptic drugs, like carbamazepine and topiramate, are also effective and safe.
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PMID:Alcohol withdrawal seizures. 1924 88

Chronic alcoholism is associated with hyperhomocysteinemia. Herp (homocysteine-induced endoplasmic reticulum [ER] protein) levels are elevated as a response to ER stress prior to mitochondrial dysfunction and cell death. The Lesch classification system has been applied in many studies and has been found useful. This study was undertaken to assess Herp mRNA expression in actively drinking patients with alcoholism who were classified according to Lesch's typology. Herp mRNA expression levels were measured by quantitative PCR in the blood of 76 male alcoholic patients. Patients were classified according to Lesch's typology (type I-IV). With respect to Lesch's typology, a significant difference in Herp mRNA expression regarding the four subtypes could be shown (F[3,72]=2.83, P=.044). In a logistic regression model (dependent variable Herp dichotomized by a median-split; adjusted for age and homocysteine levels) the subtype II differed statistically significant from the others (odds ratio, 5.75; 95% confidence interval, 2.07-15.98; P=.001). Type II alcoholic patients had a statistically significant higher expression of Herp mRNA due to upregulation of the expression of this neuroprotective cell non-chaperone by toxic effects of ethanol. These findings might explain why type II patients do not express severe withdrawal symptomatology (i.e., withdrawal seizures). These findings may be useful in the understanding and treatment considerations of different subtypes of alcohol dependence.
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PMID:Herp mRNA expression in patients classified according to Lesch's typology. 1925 Nov 10

The emerging research on biomarkers in alcohol dependence has lead to a deeper understanding of the neurobiological mechanisms in alcoholism. The molecular networks and the pathophysiological circuits are complex and not completely unrevealed up to now. One of the most interesting biomarkers described to play an important role in alcohol dependence is the amino-acid homocysteine, which has particularly been linked with brain atrophy and withdrawal seizures. However, the molecular networks of homocysteine are complex and include an important impact on epigenetic regulation via homocysteine's action as a methyl-group donator in human metabolism. So, alterations in human homocysteine levels can influence DNA-methylation of specific gene areas which may change expression and synthesis of proteins possibly important for the genesis and maintenance of alcohol dependence.
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PMID:Homocysteine, alcoholism and its molecular networks. 1943 47

Addiction research focusing on homocysteine metabolism and its association with aspects of alcohol dependence has revealed important findings. Recent literature on this topic has been taken into account for the review provided. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the homocysteine metabolism. Plasma homocysteine levels are influenced by the single-nucleotide polymorphism (SNP) MTHFR C677T. Besides genetic factors, environmental factors have an impact on homocysteine plasma levels too. Thus, chronic alcohol intake is associated with elevated homocysteine plasma concentrations. Elevation of plasma homocysteine concentration is considered as a predictor for the occurrence of alcohol withdrawal seizures and--as homocysteine is a cardiovascular risk factor--might contribute to the higher risk for myocardial infarction among alcohol dependent patients. Homocysteine acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has excitotoxic effects. Furthermore, it has been demonstrated that homocysteine has neurotoxic effects especially on dopaminergic neurons. As the rewarding effects of alcohol are mediated by the dopaminergic system, a homocysteine-dependent impairment of the reward system possibly leads to an altered drinking behaviour according to the deficit hypothesis of addiction. Homocysteine is involved in the metabolism of methyl groups and DNA-methylation plays a role in regulation of gene expression. Therefore it has been suggested that homocysteine is an important epigenetic factor. It remains to be determined whether alcohol dependent patients benefit from homocysteine lowering strategies, e.g., via supplementation of folate, vitamin B6 and B12. In this respect it is not clear yet, if a supplementation therapy can reduce the risk for the occurrence of alcohol withdrawal seizures.
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PMID:Alterations in homocysteine metabolism among alcohol dependent patients--clinical, pathobiochemical and genetic aspects. 1963 Jul 5

The role of NO in epileptogenesis has been studied in different experimental models, and the reported results have been highly contradictory. The current study aimed to determine the role of NO in mechanisms of D: ,L: -homocysteine-thiolactone (H) induced seizures by testing the action of L: -arginine (NO precursor) and L: -NAME (NOS inhibitor) on behavioral and electroencephalographic (EEG) manifestations of H-induced seizures. The same holds true with the brain Na(+)/K(+)- and Mg(2+)-ATPase activity in adult male Wistar rats. We showed that the pretreatment with L: -arginine (300, 600 and 800 mg/kg, i.p.) in a dose-dependent manner significantly decreased lethality, seizure incidence and a number of seizure episodes and prolonged latency time to the first seizure elicited by a convulsive dose of H (8 mmol/kg, i.p.). L: -Arginine (800 mg/kg) completely reversed the inhibitory effect of H on the Na(+)/K(+)-ATPase activity in the hippocampus, the cortex and the brain stem and decreased the H-induced spike-and- wave discharges (SWD) formation in EEG. On the other hand, pretreatment with L: -NAME (200, 500 and 700 mg/kg, i.p.) potentiated a subconvulsive dose of H (5.5 mmol/kg, i.p) by increasing incidence and severity determined by a descriptive-rating scale (0-4) and shortening the latency time to the first seizure. The L: -NAME reversed H-induced alterations in the Na(+)/K(+)-ATPase activity in the cortex and the brain stem but not in the hippocampus. At last, the potentiated SWD appearance in EEG and an increased number of lethal outcomes occurred. In the present work, the modulation of NO levels, with the NO precursor and NOS inhibitor, was shed more light on its mechanism of action and answered the question whether NO could be included in the list of anticonvulsant agents in the D: ,L: -homocysteine thiolactone experimental model of seizures in adult rats.
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PMID:The role of nitric oxide in homocysteine thiolactone-induced seizures in adult rats. 1971 60

Sulfite oxidase is a mitochondrial enzyme encoded by the SUOX gene and essential for the detoxification of sulfite which results mainly from the catabolism of sulfur-containing amino acids. Decreased activity of this enzyme can either be due to mutations in the SUOX gene or secondary to defects in the synthesis of its cofactor, the molybdenum cofactor. Defects in the synthesis of the molybdenum cofactor are caused by mutations in one of the genes MOCS1, MOCS2, MOCS3 and GEPH and result in combined deficiencies of the enzymes sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. Although present in many ethnic groups, isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are rare inborn errors of metabolism, which makes awareness of key clinical and laboratory features of affected individuals crucial for early diagnosis. We report clinical, radiologic, biochemical and genetic data on a Brazilian and on a Turkish child with sulfite oxidase deficiency due to the isolated defect and impaired synthesis of the molybdenum cofactor, respectively. Both patients presented with early onset seizures and neurological deterioration. They showed no sulfite oxidase activity in fibroblasts and were homozygous for the mutations c.1136A>G in the SUOX gene and c.667insCGA in the MOCS1 gene, respectively. Widely available routine laboratory tests such as assessment of total homocysteine and uric acid are indicated in children with a clinical presentation resembling that of hypoxic ischemic encephalopathy and may help in obtaining a tentative diagnosis locally, which requires confirmation by specialized laboratories.
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PMID:Functional deficiencies of sulfite oxidase: Differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia. 1979 32


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