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 newly synthesized affinity ligand, (R,S)-5-isothiocyanonicotine (ISCN-N) was found to inhibit irreversibly the binding of [3H]methylcarbamylcholine (a specific nicotinic receptor ligand) to brain membranes. Plots of percent inhibition versus ligand concentration yielded an IC50 of 7 x 10(-8) M for SCN-N and Ki values of 6 x 10(-9) and 2 x 10(-9) M for (R,S)-5-aminonicotine and (S)-nicotine, respectively. The IC50 value for irreversible inhibition of [3H]methylcarbamylcholine by SCN-N was 2 x 10(-7) M. The affinity ligand irreversibly inhibited brain nicotinic receptors in vivo in a dose-dependent manner, the inhibition being 49% at a dose of 20 mumol/kg. Behavioral studies in mice revealed that SCN-N had less than one-fifth the potency of nicotine in producing muscle weakness and seizures, whereas 5-aminonicotine was without significant behavioral effects at doses up to 20 mumol/kg.
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PMID:5-Isothiocyanonicotine: a high-affinity irreversible ligand for brain nicotinic receptors. 801 Sep 81

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are key mediators of seizure spread in the nervous system and represent promising targets for antiepileptic drugs. There is emerging evidence that AMPA receptors may play a role in epileptogenesis and in seizure-induced brain damage. This evidence suggests that AMPA receptor antagonists could have broad utility in epilepsy therapy. Regional, developmental, and disease-associated variations in AMPA receptors produced by differential expression of AMPA receptor subunits and variations in posttranscriptional processing, including alternative splicing and pre-mRNA editing, provide a diversity of functionally distinct AMPA receptor isoforms that allow opportunities for selective drug targeting. Four types of AMPA receptor antagonist are discussed in this chapter: (a) competitive AMPA recognition site antagonists, including those of the quinoxalinedione and newer nonquinoxalinedione classes, (b) 2,3-benzodiazepine noncompetitive (allosteric) antagonists, (c) desensitization enhancing antagonists, exemplified by SCN-, and (d) antagonists of Ca(2+)-permeable AMPA receptors, including polyamine amide arthropod toxins and their synthetic analogues. Competitive and noncompetitive AMPA receptor antagonists are broad-spectrum anticonvulsants in animal seizure models. Their effectiveness and safety for humans remain to be determined. There is evidence that these antagonists can potentiate the antiseizure activity of N-methyl-D-aspartate (NMDA) receptor antagonists and conventional antiepileptic drugs. This evidence suggests that the preferred use of AMPA receptor antagonists may be in combination therapies. Agents that enhance desensitization may have advantages in comparison with other AMPA receptor antagonists to the extent that they preferentially block high-frequency synaptic signaling and avoid depressing AMPA receptors on interneurons, which would lead to disinhibition and enhanced excitability. Evidence has accumulated that Ca(2+)-permeable AMPA receptors (those lacking the edited GluR2 subunit) may play a role in epileptogenesis and the brain damage occurring with prolonged seizures. Because Ca(2+)-permeable AMPA receptors are predominately expressed in gamma-aminobutyric acid (GABA)ergic interneurons, it is hypothesized that some forms of epilepsy might be caused by reduced GABA inhibition resulting from Ca(2+)-permeable AMPA receptor-mediated excitotoxic death of interneurons. It is further proposed that drugs that selectively target Ca(2+)-permeable AMPA receptors might have antiepileptogenic and neuroprotective properties. Certain polyamine toxins and their analogues are channel-blocking AMPA receptor antagonists that selectively inhibit Ca(2+)-permeable AMPA receptors. These substances might give clues to the development of such antagonists.
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PMID:AMPA receptors in epilepsy and as targets for antiepileptic drugs. 1051 78

Mutations in the voltage-gated sodium channels SCN 1 A and SCN 2 A are responsible for several types of human epilepsy. Variable expressivity among family members is a common feature of these inherited epilepsies, suggesting that genetic modifiers may influence the clinical manifestation of epilepsy. The transgenic mouse model Scn 2 a(Q 54) has an epilepsy phenotype as a result of a mutation in Scn 2 a that slows channel inactivation. The mice display progressive epilepsy that begins with short-duration partial seizures that appear to originate in the hippocampus. The partial seizures become more frequent and of longer duration with age and often induce secondary generalized seizures. Clinical severity of the Scn 2 a(Q 54) phenotype is influenced by genetic background. Congenic C57BL/6J.Q 54 mice exhibit decreased incidence of spontaneous seizures, delayed seizure onset, and longer survival in comparison with [C57BL/6J x SJL/J]F(1).Q 54 mice. This observation indicates that strain SJL/J carries dominant modifier alleles at one or more loci that determine the severity of the epilepsy phenotype. Genome-wide interval mapping in an N(2) backcross revealed two modifier loci on Chromosomes 11 and 19 that influence the clinical severity of of this sodium channel-induced epilepsy. Modifier genes affecting clinical severity in the Scn 2 a(Q 54) mouse model may contribute to the variable expressivity seen in epilepsy patients with sodium channel mutations.
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PMID:Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a. 1624 25

Mutations in the SCN 1 A gene, encoding the neuronal voltage-gated sodium channel alpha1 subunit, cause SMEI, GEFS+, and related epileptic syndromes. We herein report the R1575C-SCN 1 A mutation identified in a patient with Rasmussen encephalitis. R1575C were constructed in a recombinant human SCN 1 A and then heterologously expressed in HEK293 cells along with the human beta1 and beta2 sodium channel accessory subunits. Whole-cell patch-clamp recording was used to define biophysical properties. The R1575C channels exhibited increased channel availability and an increased persistent sodium current in comparison to the wild-type. These defects of electrophysiological properties can result in neuronal hyperexitability. The seizure susceptibility allele may influence the pathogenesis of Rasmussen encephalitis in this case.
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PMID:Rasmussen encephalitis associated with SCN 1 A mutation. 1803 52

Approximately 50% of all carriers of 2q21-q31 deletions present epileptic seizures. The band 2q24 constitutes the smallest commonly deleted segment in these patients, and contains the voltage-gated sodium channel genes SCN1A and SCN2A, associated with Dravet syndrome and benign familial neonatal-infantile seizures, respectively. A further putative locus involving epilepsy in the region was previously identified through disruption of the SLC4A10 gene by translocation. In the course of performing high-resolution DNA copy number analyses on syndromic mentally impaired individuals, we encountered three patients with overlapping deletions in chromosome region 2q24. Two of these patients exhibited epileptic seizures in addition to mental deficiency. The deletion in one of the epileptic patients did not include the SCN cluster, demonstrating that a less severe form of epilepsy maps to an adjacent genomic region. This second region comprises about 3 Mb and contains the candidate gene SLC4A10, providing further support for the potential role of this gene in epilepsy.
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PMID:Two distinct regions in 2q24.2-q24.3 associated with idiopathic epilepsy. 2120 6

The circadian pattern of seizures in people with epilepsy (PWE) was first described two millennia ago. However, these phenomena have not received enough scientific attention, possibly due to the lack of promising hypotheses to address the interaction between seizure generation and a physiological clock. To propose testable hypotheses at the molecular level, interactions between circadian rhythm, especially transcription factors governing clock genes expression, and the mTOR (mammalian target of rapamycin) signaling pathway, the major signaling pathway in epilepsy, will be reviewed. Then, two closely related hypotheses will be proposed: (1) Rhythmic activity of hyperactivated mTOR signaling molecules results in rhythmic increases in neuronal excitability. These rhythmic increases in excitability periodically exceed the seizure threshold, displaying the behavioral seizures. (2) Oscillation of neuronal excitability in SCN modulates the rhythmic excitability in the hippocampus through subiculum via long-range projections. Findings from published results, their implications, and proposals for new experiments will be discussed. These attempts may ignite further discussion on what we still need to learn about the rhythmicity of spontaneous seizures.
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PMID:Molecular mechanism of circadian rhythmicity of seizures in temporal lobe epilepsy. 2318 39

Seizure patterns observed in patients with epilepsy suggest that circadian rhythms and sleep/wake mechanisms play some role in the disease. This review addresses key topics in the relationship between circadian rhythms and seizures in epilepsy. We present basic information on circadian biology, but focus on research studying the influence of both the time of day and the sleep/wake cycle as independent but related factors on the expression of seizures in epilepsy. We review studies investigating how seizures and epilepsy disrupt expression of core clock genes, and how disruption of clock mechanisms impacts seizures and the development of epilepsy. We focus on the overlap between mechanisms of circadian-associated changes in SCN neuronal excitability and mechanisms of epileptogenesis as a means of identifying key pathways and molecules that could represent new targets or strategies for epilepsy therapy. Finally, we review the concept of chronotherapy and provide a perspective regarding its application to patients with epilepsy based on their individual characteristics (i.e., being a "morning person" or a "night owl"). We conclude that better understanding of the relationship between circadian rhythms, neuronal excitability, and seizures will allow both the identification of new therapeutic targets for treating epilepsy as well as more effective treatment regimens using currently available pharmacological and non-pharmacological strategies.
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PMID:The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy. 3271 61