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)

In this review, recent studies on the electrophysiological effects of de novo synthesized ("endogenous") kynurenic acid (KYNA) are discussed. Endogenous KYNA is normally formed as a byproduct of tryptophan metabolism. Evidence for a physiological role in neuronal excitability has not been strong, in part because brain levels are much lower than the KD of KYNA at the glycine site of the NMDA receptor, where KYNA is thought to exert its most potent effect. The results suggest that, unexpectedly, even low concentrations of endogenous KYNA have physiological consequences. These levels of KYNA reduced the number of hippocampal slices with spontaneous epileptiform discharges after exposure to buffer lacking magnesium. However, effects on evoked responses to single afferent stimuli were not detected. Taken together, the data argue for a potentially important role of endogenous KYNA in suppression of seizure-like activity, and suggest a novel approach to anticonvulsant drug development that could have few side effects.
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PMID:Electrophysiological effects of exogenous and endogenous kynurenic acid in the rat brain: studies in vivo and in vitro. 1102

Metabolism of tryptophan (TRP) through the kynurenine (KYN) pathway in brain, liver, and kidney produces intermediates including the neuroactive agonist quinolinic acid (QA) and the antagonists kynurenic acid (KA) and anthranilic acid (AA) for N-methyl D-aspartate (NMDA) receptors in the central nervous system. We hypothesized that elevated concentrations of QA, KA, or AA can moderate the convulsions that are observed during exposure of rats to hyperbaric oxygen (HBO). We found that i.p. administration of TRP or KYN (both of which cross the blood-brain barrier) had no effect on HBO-induced seizures. However, AA (administered i.p.) or gavage administration of the KYN pathway blocking drug Ro 61-8048, both of which enter the brain from the circulatory system, affect the time to first convulsion and/or coma during HBO in a manner consistent with a modulatory role for seizure activity.
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PMID:Evidence that kynurenine pathway metabolites mediate hyperbaric oxygen-induced convulsions. 1103 31

The discovery of focal or multifocal cortical lesions using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning in the majority of infants with West syndrome has led to a surgical approach in the treatment of some patients with intractable infantile spasms. The locations of these lesions should be concordant with localization of focal ictal and/or interictal electroencephalographic (EEG) abnormalities prior to proceeding with cortical resection. When a single lesion is present on the MRI or PET, and there is good correlation with EEG localization, surgical treatment is generally quite favorable in terms of both seizure control and cognitive development. Interictal glucose metabolism PET scans in children with intractable cryptogenic infantile spasms show unifocal cortical hypometabolism in about 20% of cases. In the majority, however, multifocal asymmetric hypometabolism is suggestive of multifocal underlying lesions, possibly multifocal cortical dysplasia. When the pattern of glucose hypometabolism is symmetric, a lesional etiology is less likely, thus neurometabolic or neurogenetic disorders should be considered. Therefore, the pattern of glucose hypometabolism on PET in infants with intractable cryptogenic spasms is a useful guide to decide whether a medical or surgical approach should be undertaken. In order to achieve the best cognitive outcome with surgery, it is important to resect the entire 'nociferous' area rather than just the seizure focus. Our research with new PET imaging probes has attempted to provide a comprehensive evaluation of the epileptogenic zone including the 'nociferous' cortex. We have used [(11)C]flumazenil (FMZ), which labels gamma aminobutyric acid(A) (GABA(A)) receptors, and have found this to be particularly useful in showing: (i) decreased receptor binding with medial temporal involvement thus indicating resection of medial temporal structures, (ii) the peri-lesional epileptogenic zone surrounding MRI lesions, (iii) the seizure onset zone in MRI-negative cases, and (iv) potential secondary epileptic foci. Another recently developed PET probe, alpha[(11)C]methyl-L-tryptophan (AMT) which is a precursor for the serotonin and the kynurenine metabolism pathways, is capable of differentiating between epileptogenic and non-epileptogenic tubers in patients with tuberous sclerosis complex and intractable epilepsy (including infantile spasms). Subsequently, we have applied AMT PET in patients with multifocal cortical dysplasia to determine the predominant seizure focus, and the results have been promising with regard to seizure control but not cognitive development. Thus, the introduction of newer more specific PET probes for epilepsy has led to improved and more accurate localization of seizure foci that should ultimately improve outcome of epilepsy surgery in West syndrome.
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PMID:Surgical treatment of West syndrome. 1170 Dec 75

Generalized epilepsy with febrile seizures plus type 1 is an inherited human epileptic syndrome, associated with a cysteine-to-tryptophan (C121W) mutation in the extracellular immunoglobin domain of the auxiliary beta1 subunit of the voltage-gated sodium channel. The mutation disrupts beta1 function, but how this leads to epilepsy is not understood. In this study, we make several observations that may be relevant for understanding why this beta1 mutation results in seizures. First, using electrophysiological recordings from mammalian cell lines, coexpressing sodium channel alpha subunits and either wild-type beta1 or C121Wbeta1, we show that loss of beta1 functional modulation, caused by the C121W mutation, leads to increased sodium channel availability at hyperpolarized membrane potentials and reduced sodium channel rundown during high-frequency channel activity, compared with channels coexpressed with wild-type beta1. In contrast, neither wild-type beta1 nor C121Wbeta1 significantly affected sodium current time course or the voltage dependence of channel activation. We also show, using a Drosophila S2 cell adhesion assay, that the C121W mutation disrupts beta1-beta1 homophilic cell adhesion, suggesting that the mutation may alter the ability of beta1 to mediate protein-protein interactions critical for sodium channel localization. Finally, we demonstrate that neither functional modulation nor cell adhesion mediated by wild-type beta1 is occluded by coexpression of C121Wbeta1, arguing against the idea that the mutant beta1 acts as a dominant-negative subunit. Together, these data suggest that C121Wbeta1 causes subtle effects on channel function and subcellular distribution that bias neurons toward hyperexcitabity and epileptogenesis.
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PMID:Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1. 1248 63

Epilepsy surgery has been successfully performed in patients with tuberous sclerosis complex (TSC) and seizures arising from a restricted epileptogenic area. The outcome of cortical excision depends on accurate pre-surgical identification of the epileptogenic tuber. [11C] alpha-methyl-L-tryptophan (alpha-MTrp) was originally developed to measure serotonin synthesis in vivo with positron emission tomography (PET). However in pathologic conditions its uptake may also depend on the synthesis of quinolinic or kynurenic acid via the kynurenine pathway. Increased levels of serotonin and quinolinic acid have been observed in epileptogenic lesions, raising the possibility that alpha-MTrp PET may localize the epileptogenic area. The aim of this study was to correlate alpha-MTrp PET uptake with the localization of the epileptogenic area and with interictal spike frequency in patients with TSC. alpha-MTrp uptake was measured in 8 patients (2 males, mean age 29.6+/-14.9 years, range 3-50 years) with intractable partial epilepsy due to TSC. All patients underwent scalp EEG monitoring during the PET scan. In four (50%), increased uptake of alpha-MTrp occurred in the epileptogenic area alone. Two (25%) patients showed multifocal abnormalities and the remaining two (25%) did not show focal changes. PET localization was mostly seen in patients with frequent interictal abnormalities on the EEG. Furthermore, there was a significant correlation between alpha-MTrp uptake and the frequency of interictal spikes (r=0.6; P<0.05). alpha-MTrp PET is a promising diagnostic tool in the localization of the epileptogenic area in patients with TSC.
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PMID:alpha-[11C]-Methyl-L-tryptophan PET identifies the epileptogenic tuber and correlates with interictal spike frequency. 1253 53

A quantal perceptive model of brain function has been postulated by several groups. Reiki-like healing practices in seizure disorder (ILAE classification-II E-generalized seizures-tonic clonic), involving transfer of life force or low level of electromagnetic force (EMF) from the healer to the recipient patient, may act via quantal perceptive mechanisms. Increased synthesis of an endogenous membrane Na+-K+ ATPase inhibitor digoxin and a related tyrosine / tryptophan transport defect has been demonstrated in refractory seizure disorder (ILAE classification-II E-generalized seizures-tonic clonic). Reiki-like healing practices in refractory epilepsy results in a reduction in seizure frequency. Reiki-like healing practices produce membrane stabilization and stimulation of membrane Na+-K+ ATPase activity by quantal perception of low levels of EMF. The consequent intracellular hypermagnesemia inhibits HMG CoA reductase activity and digoxin synthesis resulting in the alteration of the neutral amino acid transport (tryptophan / tyrosine) defect. A hypothalamic digoxin-mediated quantal perception model of brain function is proposed. The phenomena of biological transmutation and consequent hypermagnesemia occurring in the resultant neuronal quantal state is also discussed.
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PMID:Changes in the isoprenoid pathway with transcendental meditation and Reiki healing practices in seizure disorder. 1457 Oct 6

Non-Asian individuals with Down syndrome are much more likely to develop epileptic seizure disorders than individuals without Down syndrome. Examination of nutrient and metabolite levels in patients with these two seemingly disparate disorders reveals numerous similarities. Compared to individuals without these disorders, individuals with Down syndrome and individuals with seizures may have lower levels of vitamin A, vitamin B1, folate, vitamin B12, vitamin C, magnesium, manganese, selenium, zinc, carnitine, carnosine, choline, and possibly serine. Excesses of copper, cysteine, phenylalanine, and superoxide dismutase are also sometimes encountered in both disorders. In addition to common nutritional lower levels and excesses, disorders of metabolism involving vitamin B6, vitamin D, calcium, and tryptophan may play a common role. This paper hypothesizes that nutritional factors may account for the high joint occurrence of these conditions. Further examination of these data may provide insights into nutritional, metabolic and pharmacological treatments for both conditions.
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PMID:Down syndrome and epilepsy: a nutritional connection? 1472 2

The following NEKY have been studied: 1-kynurenine (KYN), 3-hydroxyKYN (3HKYN), kynurenic (KYNA), anthranilic (ANT), 3-hydroxyANT (3HANT), quinolinic (QUIN), picolinic (PICA), xanthurenic (XAN), nicotinic (NIC) acids, 3-indole-pyruvate (IPA), nicotinamide (NAM). NEKY antagonize the central effects of precursors of serotonin (tryptophan and 5-HTP), and tryptamine as well. Seizures induced by central administration of KYN and QUIN are prevented by centrally injected dopamine and diminished by noradrenaline and adrenaline. KYN, 3HANT, PIC and NIC potentiate oxotremorine hypothermia mediated by acetylcholine. Central administration of GABA, glycine or taurine, as well as proline and melatonin, prevented seizures induced by QUIN and KYN. Behavioral inhibitory effects of these amino acids are diminished by pretreament with KYN, 3HKYN and QUIN. Elevation of concentrations of corticosteroids is resulted in rise of level of NEKY due to hormonal induction of liver tryptophan pyrrolase and brain 2,3 dioxigenase. NEKY, in their turn, activate both enzymes. Thus, a "vicious circle" is formed and it supports an elevated level of NEKY for a long time, hours and days. Long-lasting increased concentrations of NEKY in tissues can lead to significant after-effects and numerous pathogenic consequences. One can not exclude that a rise of the level of some NEKY, e.g. KYNA, IPA, PIC and XAN, may play an "adaptogenic" role in stress antagonizing some pathologic effects of KYN and QUIN, e.g. anxiogenic, neurotoxic and proconvulsive. It has been demonstrated that the excitatory NEKY, KYN, 3HKYN, QUIN, possess an anxiogenic activity in the standard animal models of anxiety. NEKY with opposite neuroactivities, namely KYNA, IPA, PICA and XAN, have a pharmacological profile of anxiolytics and antagonize both anxiogenic NEKY and standard anxiogens, like caffeine, pentylenetetrazole and yohimbine. Major emphasis is made on KYN as a putative endogenous anxiogen. Studies on the interaction of NEKY with other endogenous metabolites involved in anxiety (beta-phenylethylamine, cholecystokynine, melatonin) are in progress.
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PMID:Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. 1520 24

The kynurenine pathway converts tryptophan into various compounds, including l-kynurenine, which in turn can be converted to the excitatory amino acid receptor antagonist kynurenic acid, which may therefore serve as a protective agent in such neurological disorders as epileptic seizures. Kynurenic acid, however, has a very limited ability to cross the blood-brain barrier, whereas kynurenine passes the barrier easily. In this study, we tested the hypothesis that kynurenine administered systemically together with probenecid, which inhibits kynurenic acid excretion from the cerebrospinal fluid, results in an increased level of kynurenic acid in the brain that is sufficiently high to provide protection against the development of pentylentetrazol-induced epileptic seizures. CA3 stimulation-evoked population spike activity was recorded from the pyramidal layer of area CA1 of the rat hippocampus, and in another series of behavioural experiments, water maze and open-field studies were carried out to test the presumed protective effect of kynurenine + probenecid pre-treatment against pentylenetetrazol-induced seizures. This study has furnished the first electrophysiological proof that systemic kynurenine (300 mg/kg, i.p.) and probenecid (200 mg/kg, i.p.) administration protects against pentylenetetrazol-induced (60 mg/kg, i.p.) epileptic seizures.
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PMID:Kynurenine administered together with probenecid markedly inhibits pentylenetetrazol-induced seizures. An electrophysiological and behavioural study. 1552 25

Music constitutes an ideal means to create a sense of suspense in films. However, there has been minimal investigation into the underlying cerebral organization for perceiving danger created by music. In comparison, the amygdala's role in recognition of fear in non-musical contexts has been well established. The present study sought to fill this gap in exploring how patients with amygdala resection recognize emotional expression in music. To this aim, we tested 16 patients with left (LTR; n = 8) or right (RTR; n = 8) medial temporal resection (including amygdala) for the relief of medically intractable seizures and 16 matched controls in an emotion recognition task involving instrumental music. The musical selections were purposely created to induce fear, peacefulness, happiness and sadness. Participants were asked to rate to what extent each musical passage expressed these four emotions on 10-point scales. In order to check for the presence of a perceptual problem, the same musical selections were presented to the participants in an error detection task. None of the patients was found to perform below controls in the perceptual task. In contrast, both LTR and RTR patients were found to be impaired in the recognition of scary music. Recognition of happy and sad music was normal. These findings suggest that the anteromedial temporal lobe (including the amygdala) plays a role in the recognition of danger in a musical context.
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PMID:Impaired recognition of scary music following unilateral temporal lobe excision. 1569 60


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