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)

Epilepsy is caused by an electrical hyperexcitability in the CNS. Because K+ channels are critical for establishing and stabilizing the resting potential of neurons, a loss of K+ channels could support neuronal hyperexcitability. Indeed, benign familial neonatal convulsions, an autosomal dominant epilepsy of infancy, is caused by mutations in KCNQ2 or KCNQ3 K+ channel genes. Because these channels contribute to the native muscarinic-sensitive K+ current (M current) that regulates excitability of numerous types of neurons, KCNQ (Kv7) channel activators would be effective in epilepsy treatment. A compound exhibiting anticonvulsant activity in animal seizure models is retigabine. It specifically acts on the neuronally expressed KCNQ2-KCNQ5 (Kv7.2-Kv7.5) channels, whereas KCNQ1 (Kv7.1) is not affected. Using the differential sensitivity of KCNQ3 and KCNQ1 to retigabine, we constructed chimeras to identify minimal segments required for sensitivity to the drug. We identified a single tryptophan residue within the S5 segment of KCNQ3 and also KCNQ2, KCNQ4, and KCNQ5 as crucial for the effect of retigabine. Furthermore, heteromeric KCNQ channels comprising KCNQ2 and KCNQ1 transmembrane domains (attributable to transfer of assembly properties from KCNQ3 to KCNQ1) are retigabine insensitive. Transfer of the tryptophan into the KCNQ1 scaffold resulted in retigabine-sensitive heteromers, suggesting that the tryptophan is necessary in all KCNQ subunits forming a functional tetramer to confer drug sensitivity.
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PMID:Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. 1590 87

Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of alpha-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones (P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery.
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PMID:Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). 1596 22

In high concentrations or after prolonged exposure, the N-methyl-D-aspartate receptor agonist quinolinic acid (QUIN) induces lipid peroxidation, oxidative stress, and cell death in the adult brain, and after i.c.v. injection induces seizures and increases blood-brain barrier permeability. As QUIN is substantially increased in plasma and brain of fetal sheep after endotoxin treatment or maternal tryptophan loading, we examined the effects of increasing plasma QUIN concentrations on the brain of late gestation fetal sheep. Continuous fetal infusion of QUIN (0.1 mmol/h i.v.; n=4) for 12 h increased plasma QUIN concentrations from 22.3+/-6.0-210.8+/-31.4 microM; the infusion of vehicle [normal saline] had no effect on QUIN concentrations (n=4). At 24 h after QUIN infusion glial fibrillary acidic protein immunoreactivity was significantly increased in cerebral gray matter and the granule cell layer of cerebellum, and the lipid peroxide product 4-hydroxynonenal-immunoreactivity and albumin-immunoreactivity were present throughout the cytoplasm of cerebellar Purkinje cells. Extravasation of albumin into the brain was not observed, indicating the cerebral microvasculature with respect to permeability to plasma proteins was normal at the time of analysis. We suggest that increased glial fibrillary acidic protein and 4-hydroxynonenal result from oxidative stress induced by QUIN, and that the increased intracellular albumin in cerebellar Purkinje cells may be an adaptive response.
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PMID:Quinolinic acid promotes albumin deposition in Purkinje cell, astrocytic activation and lipid peroxidation in fetal brain. 1602 35

In 2000, amino acid residue G75 of the facilitative glucose transporter GLUT1 was identified by mutagenesis as being essential for transport function [Olsowski, A., et al. (2000) Biochemistry 39, 2469-74]. In 2002, we identified a heterozygous missense mutation substituting glycine at residue 75 for tryptophan in a 10-year-old girl with intractable seizures and low glucose concentrations in the cerebrospinal fluid indicative of GLUT1 deficiency. Glucose uptake into erythrocytes of the patient was 36% of controls, and GLUT1-specific immunoreactivity was normal, indicating a functional GLUT1 defect. In silico three-dimensional modeling of the G75W mutant provided a smaller gyration radius for transmembrane segment 2 as the potential pathogenic mechanism in this patient. This case illustrates a GLUT1 mutation characterized in vitro and later confirmed by disease itself and highlights the potential of basic science and clinical medicine to collaborate for the benefit of patients.
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PMID:Bench meets bedside: a 10-year-old girl and amino acid residue glycine 75 of the facilitative glucose transporter GLUT1. 1617 77

In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.
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PMID:A diet-induced mouse model for glutaric aciduria type I. 1687 Aug 80

The effects of per orally administered tryptophan on serotonin and GABA levels in different brain areas were found to depend on initial levels of seizure susceptibility. Elimination of difference in the content of investigated mediator between animals with high and low seizure susceptibility was observed. Serotonin level was approximated to the initial one in rats with high seizure susceptibility but GABA level was approximated to the initial one in rats with low seizure susceptibility. Possible mechanismes of realization of tryptophan therapeutic effects are discussed.
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PMID:[Effect of tryptophan on mediator content in the brain tissue of rats with different levels of seizure susceptibility]. 1656 39

The brain serotoninergic (5HTergic) system of epileptic subjects can influence their vulnerability to stress. We studied the putative dependency of 5HT neurotransmission parameters on emotional stress, and the presence, types and severity of seizures using rats with genetic generalized (absence and/or audiogenic) epilepsy, of WAG/Rij and Wistar strains. The animals were stressed by exposure to a short aversive noise or left without sound stimulation. Tissue concentrations of 5HT, tryptophan (TRT) and 5-hydroxyindolacetic acid (5HIAA) were assessed by HPLC. The stressor activated the 5HTergic system within thalamus (5HIAA elevated), frontal cortex (5HT, TRT elevated), hypothalamus (increased TRT) in all rats. However, the normal (non-epileptic) rats displayed the highest response in the frontal cortex and the lowest one in the thalamus, as compared to the epileptic rats. Absence-epileptic rats exhibited higher thalamic 5HIAA increase than their controls. Significant correlations existed between propensity of absence epilepsy and 5HTergic parameters measured in the cortex and hypothalamus of absence-epileptic rats. No major difference was found between groups with and without audiogenic epilepsy. The results imply that the stress response depends on the presence of epileptic pathology and the seizure type and severity. The brain 5HT may be involved in the control of the paroxysms and behaviour in absence-epileptic subjects.
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PMID:The brain 5HTergic response to an acute sound stress in rats with generalized (absence and audiogenic) epilepsy. 1671 30

The widely used antidepressants Specific Serotonin Reuptake Inhibitors (SSRI) have been tried with success as anticonvulsants in cases of nonsymptomatic epilepsy. This attempt was performed on the basis of experimental data suggesting the involvement of impairments of the serotonin system in the genesis of epilepsy. This overview summarizes the clinical data and presents biochemical and neurochemical evidences suggesting the mechanism of the therapeutic effects of SSRI in nonsymptomatic epilepsy. In particular, studies on blood-borne neutral amino acids and platelet serotonin transporter (SERT) in epileptics suggest: (a) That a decreased brain availability of tryptophan may be related to some types of epilepsy. (b) That reduction of the density of SERT may be a homeostatic reaction in the brain following epileptic seizures.
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PMID:Successful treatment of epilepsy with serotonin reuptake inhibitors: proposed mechanism. 1675 59

The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.
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PMID:Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-D-aspartate neurotoxicity. 1762 27

In spite of the large number of antiepileptic drugs (AEDs) actually available, the problem of drug-resistant epilepsy has not been solved. No AEDs are efficacious in patients with pharmacoresitant epilepsy, so new hypothesises about the mechanisms of pharmacoresistance are needed. In the last years the ideas on the role of brain serotonin in epilepsy have been turned upside down: increasing the available brain serotonin is thought now to have an antiepileptic effect. Antidepressant drugs like selective serotonin re-uptake inhibitors, i.e., fluoxetine, have proved to be useful in seizure control. Tryptophan (Trp), an essential amino acid, is the only brain precursor of serotonin, it competes with the other large neutral amino acids (LNAAs) for the carrier of blood-brain barrier (BBB). Our own data has shown a lowering of plasmatic LNAA levels in epileptic patients, on the basis of these results we could estimate a decrease of a 1/3 in the Trp brain intake rate in epileptics in respect to controls. Increasing plasmatic Trp levels increases brain serotonin synthesis. Trp and 5-hydroxytryptophan (5-HTP) were tested as an add on in epilepsy, but the clinical outcome was controversial. Free amino acids are not fully adsorbed by the gastro-intestinal system, furthermore LNAAs, and also 5-HTP is a LNAA, compete to cross the intestinal membrane for the same carrier, like for the BBB. The best way to increase the plasmatic Trp level is a protein rich in Trp and poor in the other LNAAs. Unfortunately Trp is a limited amino acid in proteins. We report the clinical results obtained by adding a whey protein to the antiepileptic therapy of drug-resistant epileptic patients: alpha-lactoalbumin, rich in Trp and poor in the other LNAAs.
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PMID:Potentiation of brain serotonin activity may inhibit seizures, especially in drug-resistant epilepsy. 1782 1


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