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)

A rational, chemical, synthetic effort to identify promising low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists for use as antiepileptic drugs led to the discovery of AR-R 15035AR, or [RS]-alpha-phenyl-2-pyridine-ethanamine.2HCl. Chiral separation followed by intensive in vivo screening resulted in the selection of the [S] enantiomer, AR-R 15896AR, as the best compound for further preclinical development. AR-R 15896AR prevented tonic seizures in rodents for up to 6 to 8 h in response to maximal electroshock (MES), 4-aminopyridine, bicuculline, or strychnine, as well as characteristic seizures following injections of N-methyl-DL-aspartic or kainic acids. AR-R 15896AR was ineffective in two kindling models of epilepsy, did not produce tolerance to MES, and was devoid of proconvulsant and phencyclidine-like properties in mice and rats, respectively. Therapeutic indices for AR-R 15896AR were comparable to or exceeded those for standard anticonvulsants. Orally administered AR-R 15896AR rapidly entered the rat brain and was eliminated in parallel from the plasma and plasma-free compartment. A dose-response relationship between plasma and brain levels after p.o. or i.v. administration of AR-R 15896AR and protection against MES was highly correlative. The time course for loss of protection against MES mirrored the elimination of the compound from brain and plasma. The total brain concentration (25 microM) of drug at the ED50 value (approximately 3 mg/kg) for protection against MES seizures was consistent with the reported affinity of AR-R 15896AR at the N-methyl-D- aspartic acid binding site (IC50 value = 1.3 microM). The present findings demonstrated the attractiveness of AR-R 15896AR as a candidate for further development to treat epilepsy.
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PMID:[S]-AR-R 15896AR-A novel anticonvulsant: acute safety, pharmacokinetic and pharmacodynamic properties. 986 62

The effects of drugs affecting GABA and glutamic acid receptors on theophylline-induced seizures were investigated in mice. Theophylline elicited tonic seizures in mice in a dose dependent manner. Muscimol, DABA and AOAA significantly prolonged the onset and significantly decreased the incidence of theophylline-induced seizures. Baclofen significantly delayed the onset of the tonic seizures induced by theophylline. Bicuculline and picrotoxin significantly shortened the onset and significantly increased the incidence of seizures induced by a low dose of theophylline and also significantly antagonized muscimol-attenuating effect against theophylline seizures. N-methyl-DL-aspartic acid significantly shortened the onset and significantly increased the incidence of seizures elicited by a low dose of theophylline. D-(-)-2-amino-phosphonopentanoic acid effectively delayed the onset and significantly decreased the incidence of seizures elicited by theophylline and also significantly antagonized the potentiating effect of N-methyl-DL-aspartic acid on seizures induced by a low dose of theophylline. Dextromethorphan and ketamine profoundly shortened the onset of theophylline-induced seizures. Clonidine effectively prolonged the onset and significantly decreased the incidence of theophylline-induced seizures. These data indicate that GABA(A) and N-methyl-D-aspartic acid receptors may mediate theophylline-elicited tonic seizures in mice.
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PMID:Gamma-aminobutyric acid and glutamic acid receptors may mediate theophylline-induced seizures in mice. 1021 93

Catecholamine-induced polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress. Two modes of inheritance have been described: autosomal dominant and autosomal recessive. Mutations in the ryanodine receptor 2 gene (RYR2), which encodes a cardiac sarcoplasmic reticulum (SR) Ca(2+)-release channel, were recently shown to cause the autosomal dominant form of the disease. In the present report, we describe a missense mutation in a highly conserved region of the calsequestrin 2 gene (CASQ2) as the potential cause of the autosomal recessive form. The CASQ2 protein serves as the major Ca(2+) reservoir within the SR of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor. The mutation, which is in full segregation in seven Bedouin families affected by the disorder, converts a negatively charged aspartic acid into a positively charged histidine, in a highly negatively charged domain, and is likely to exert its deleterious effect by disrupting Ca(2+) binding.
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PMID:A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. 1170 30

Water extract of Leonotis leonurus was tested for anticonvulsant activity against seizures produced in mice by pentylenetetrazole, picrotoxin, bicuculline and N-methyl-DL-aspartic acid (intraperitoneal injections). L. leonurus extract in the doses of 200 and 400 mg/kg respectively protected 37.5% and 50% of animals used and significantly (p < 0.05; Student's t-test) delayed pentylenetetrazole (90 mg/kg)-induced tonic seizures. Similarly, the same doses of L. leonurus extract significantly (p < 0.05; Student's t-test) delayed the onset of tonic seizures produced by picrotoxin (8 mg/kg) and N-methyl-DL-aspartic acid (400 mg/kg). However, all the doses of aqueous extract of L leonurus used did not alter the seizures induced by bicuculline (20 mg/kg) to any significant extent. The data suggest that the extract of L. leonurus has anticonvulsant activity and may probably be acting through non-specific mechanisms, since it affects both gabaergic and glutaminergic systems. High performance liquid chromatography (HPLC) and phytochemical tests carried out respectively show a spectrum profile, characteristic of L. leonurus and the presence of alkaloids, saponins and tannins in the extract.
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PMID:Anticonvulsant activity of aqueous extract of Leonotis leonurus. 1204 62

Hughlings Jackson at the turn of the century defined epilepsy as a disorder originating in a "morbid nutrition" of the neuron. With the advances in modern neurochemistry, it is becoming increasingly clear that a chronic seizure predisposition or a lowering of the brain's discharge threshold can be demarcated by a number of biochemical markers. They include a tendency for an increased release of glutamate with or without GABAergic impairment, (intra)neural tissue alterations in water redistribution/osmolarity or other distortions of the cytoarchitecture, and an elevation of ionic calcium inside the cell. These changes are dominantly shared parameters of the seizure prone brain. Magnetic resonance spectroscopy (MRS) shows that cerebral levels of glutamate + glutamine (Glx) are increased interictally in epileptogenic regions in human partial epilepsy; other findings using this technique suggest damage to (cellular/mitochondrial) membranes, denoted by N-acetyl-aspartic acid (NAA) changes and a decreased energy capability. The merging of previous in vitro and ex vivo findings in neurophysiology and neurochemistry with magnetic resonance spectroscopy technology provides a powerful new methodology to interpret and to obtain clinical insight into the metabolic alterations that underlie an epileptogenic process. In this review some of these basic neurochemical and electrophysiological mechanisms are discussed. In addition, certain adjuncts to established antiepileptic drug therapy are suggested in the hope that over the long term they may help in correcting the primary metabolic deficits.
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PMID:Metabolic parameters of epilepsy: adjuncts to established antiepileptic drug therapy. 1260 9

In previous studies for the development of new anticonvulsants, we found that N-Cbz-alpha-amino-N-alkylsuccinimides exhibited significant anticonvulsant activities in the Maximal electroshock seizure (MES) and Pentylenetetrazole induced seizure (PTZ) tests, and also their anticonvulsant activities were dependent on the N-alkyl substituents existent in their structures. Based on these estimations, N-Cbz-alpha-amino-N-hydroxysuccinimide and various N-Cbz-alpha-amino-N-alkoxysuccinimides were prepared in order to develop more active anticonvulsants and to examine the effects of N-hydoxy or N-alkoxy groups on their anticonvulsant activities. The (R)- or (S)-N-Cbz-alpha-amino-N-hydroxysuccinimide and N-Cbz-alpha-amino-N-alkoxysuccinimides were prepared from the corresponding (R)- or (S)-N-Cbz-aspartic acid through the known synthetic procedures. Their anticonvulsant activities in the MES and PTZ test were evaluated. All of these compounds except 3a showed significant anticonvulsant activities against the PTZ test, but these compounds were not active in the MES test. The most active compound in the PTZ test was (R)-N-Cbz-alpha-amino-N-benzyloxysuccinimide (ED50=62.5 mg/kg). In addition, the anticonvulsant activities of these compounds were dependent on their N-substited groups. The order of anticonvulsant activity against the PTZ test, as judged from the ED50 values for (R) series was N-benzyloxy > N-hydroxy > N-isopropoxy > N-methoxy > N-ethoxy; for the (S) series N-ethoxy > N-benzyloxy > N-methoxy > N-isopropoxy.
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PMID:Synthesis and anticonvulsant evaluation of N-Cbz-alpha-amino-N-alkoxysuccinimides. 1508 29

Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is characterized by episodes of syncope, seizures or sudden death, in response to physical activity or emotional stress, and affects mainly young children with morphologically normal hearts. We have recently described an autosomal recessive form of the disorder in seven families from a Bedouin tribe in the north of Israel, and mapped the disease-causing gene to chromosome 1p13-1p21. Direct sequencing of the calsequestrin 2 (CASQ2), a candidate gene from within the linkage interval, revealed a negatively charged aspartic acid change to a positively charged histidine at position 307 of the protein. CASQ2 serves as the major calcium reservoir within cardiac myocytes. This mutation occurs in a highly conserved residue of the protein. The implication of the calcium release cascade in this disease, may lead to a better understanding of the pathophysiologic events underlying ventricular tachycardia, and to the use of drugs directly involved in intracellular calcium control for the treatment of the CPVT patients.
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PMID:A missense mutation in CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. 1517 29

Activity-dependent brain-derived neurotrophic factor (BDNF) expression is Ca2+-dependent, yet little is known about the Ca2+ channel contributions that might direct selective expression of the multiple BDNF transcripts. Here, effects of pilocarpine-induced seizure activity on total BDNF expression and on the individual sensitivity of BDNF transcripts to glutamate receptor and Ca2+ channel blockers were evaluated using hippocampal slice cultures and in situ hybridization of transcript-specific cRNA probes directed against mRNAs for the four 5' exons (I-IV) of the BDNF gene. mRNAs for nerve growth factor (NGF) and tyrosine kinase B (trkB) also were studied. Pilocarpine (5 mM) induced a dose- and time-dependent increase in total BDNF (exon V) mRNA expression in the dentate granule cells and CA3-CA1 pyramidal cells with maximal effects at 6 and 24 h, respectively. Increases were blocked by co-treatment with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX: 25 microM) and the N-methyl-d-aspartic acid receptor antagonist 2-amino-5-phosphonovaleric acid (APV; 25 microM), whereas the L-type voltage sensitive Ca2+ channel blocker nifedipine (20 microM) was without detectable effect. Maximal NGF and trkB mRNA expression was induced by pilocarpine at 4 and 12 h, respectively. For the individual BDNF transcripts, APV blocked pilocarpine-induced increases in transcript II, whereas nifedipine blocked increases in transcripts I and III. Transcript IV levels were not altered by treatment. These results indicate that transcript II makes the greatest contribution to pilocarpine effects on total BDNF mRNA content in this model and provides evidence for regional and Ca2+ channel-specific differences in activity-dependent regulation of the different BDNF transcripts in hippocampus.
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PMID:Differential expression of brain-derived neurotrophic factor transcripts after pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry. 1518 16

The goal of this study was to elucidate the anti-convulsion mechanisms of ear-point stimulation in rat with experimental seizure. We prepared the epilepsy rats by intrahippocampal injection of penicillin. One hour later the lower 1/2 auricular lobules of seizure rats, containing ear-points Pizhixia and Shenmen etc., was electrically stimulated, which was imitated as ear-point electrical acupuncture in humans. Radioimmunoassay and biochemical techniques were used to determine the contents of somatostatin and amino acid neurotransmitters in hippocampus of rats. The outcomes revealed epileptiform behaviors of rat were appeared after penicillin-injected. The contents of somatostatin, aspartic acid, glutamine and GABA were increased. When these rats were subsequently given the ear-point electrical stimulation, the convulsion behaviors were definitely improved. At the same time the contents of the somatostatin, aspartic acid and glutamine in hippocampus of seizure rat were significantly decreased correspondingly. The contents of glycine, taurine and GABA had increased. Based on the results above, it was suggestive that ear-point electrical stimulation had anti-epilepsy effects, which might be involved in the decreases of the contents of the somatostatin, aspartic acid and glutamine, and increases of the contents of glycine, taurine and GABA in hippocampus of seizure rat.
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PMID:The effects of ear-point stimulation on the contents of somatostatin and Amino acid neurotransmitters in brain of rat with experimental seizure. 1538 88

Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic syndrome with a marked clinical and genetic heterogeneity. Here we report the molecular characterization of a large pedigree with a severe clinical form of GEFS+. Genetic linkage analysis implied the involvement of the FEB3 in the disease phenotype of this family (parametric two-point lod-score of 2.2). Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit. The amino-acid replacement lies in the pore-forming region of domain IV of SCN1A. Our observations are consistent with the genotype-phenotype correlation studies suggesting that mutations in the pore-forming loop of SCN1A can lead to a clinically more severe epileptic syndrome.
Seizure 2005 Mar
PMID:A novel SCN1A mutation associated with severe GEFS+ in a large South American pedigree. 1569 66


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