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)

Seizures are one of the most frequently occurring neurologic phenomena in childhood; an inborn error of metabolism should always be considered in the diagnostic workup of patients with seizures after more common causes have been excluded. Many of the known inborn metabolic errors associated with seizures can be detected by metabolite measurement in urine or blood. It is now recognized, however, that there are several conditions in which peripheral metabolite profiles remain normal. Abnormal metabolism is indicated only by the accumulation or absence of specific metabolites within the central nervous system. Some of these disorders can be detected by in vivo magnetic resonance spectroscopy. More often, an etiology can be ascertained only by analysis of specific metabolites in cerebrospinal fluid. This review describes the utility of cerebrospinal fluid metabolite analysis in the differential diagnosis of inborn errors of metabolism that lead to infantile epilepsy. These include disorders of central nervous system energy metabolism, creatine synthesis and transport, serine biosynthesis, and glucose transport, together with defects affecting the gamma-aminobutyric acid (GABA), catecholamine, and serotonin neurotransmitter systems. In addition, information is provided regarding detection of an early-onset seizure disorder that responds to folinic acid.
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PMID:Value of lumbar puncture in the diagnosis of infantile epilepsy and folinic acid-responsive seizures. 1259 55

We studied a strain of exon replacement mice ("L9'S knock-in") whose alpha4 nicotinic receptor subunits have a leucine to serine mutation in the M2 region, 9' position (Labarca et al., 2001); this mutation renders alpha4-containing receptors hypersensitive to agonists. Nicotine induced seizures at concentrations (1 mg/kg) approximately eight times lower in L9'S than in wild-type (WT) littermates. At these concentrations, L9'S but not WT showed increases in EEG amplitude and theta rhythm. L9'S mice also showed higher seizure sensitivity to the nicotinic agonist epibatidine, but not to the GABA(A) receptor blocker and proconvulsant bicuculline. Dorsiflexion of the tail (Straub tail) was the most sensitive nicotine effect found in L9'S mice (0.1 mg/kg). The L9'S mice were hypersensitive to galanthamine- and tacrine-induced seizures and Straub tails. There were no apparent neuroanatomical differences between L9'S and WT mice in several brain regions. [(125)I]Epibatidine binding to brain membranes showed that the mutant allele was expressed at approximately 25% of WT levels, presumably because of the presence of a neomycin selection cassette in a nearby intron. (86)Rb efflux experiments on brain synaptosomes showed an increased fraction of function at low agonist concentrations in L9'S mice. These data support the possible involvement of gain-of-function alpha4 receptors in autosomal dominant nocturnal frontal-lobe epilepsy.
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PMID:Increased sensitivity to agonist-induced seizures, straub tail, and hippocampal theta rhythm in knock-in mice carrying hypersensitive alpha 4 nicotinic receptors. 1268 43

We examined the effect of melatonin on brain levels of amino acids and nitric oxide (NO) after pentylenetetrazole (PTZ)-induced seizures in rats. Animals were treated with melatonin (10-160 mg/kg, i.p.) 30 min before PTZ administration (100 mg/kg, s.c.), and were killed 3 hr later. At the dose of 80 mg/kg, melatonin significantly increased the latency (5.7-12.7 min) and decreased the duration (31.2-18.4 s) of the first seizure, reducing PTZ induced mortality from 87.5 to 25%. After kill, brains were removed and neurotransmitters and nitrite levels measured in prefrontal cortex (PF), parieto-temporal cortex (PF), striatum (ST), hippocampus (HP) and brain stem (BS) by high performance liquid chromatography. PTZ treatment increased glutamine levels in all brain areas studied, without changes in glutamate, gamma-amino butyric acid (GABA) and glycine. Aspartate and taurine increased in PF and PT and in HS and PT, respectively. Melatonin administration displayed a dose-dependent effect. At doses of 10-40 mg/kg, melatonin counteracted the PTZ-induced glutamine increase and reduced both glutamate and aspartate levels in the studied areas, with minor changes in GABA and glycine content. At doses of 80 and 160 mg/kg, the levels of glutamine, and glutamate, and to a lesser extent aspartate increased, whereas serine levels did not change. These two doses of melatonin also increased taurine, GABA and glycine in most brain areas studied. Treatment with melatonin (40-160 mg/kg) significantly decreased nitrite content in PT cortex, ST and BS areas of epileptic rats, without changes in the other brain regions. The results suggest that the anticonvulsant property of melatonin involves a modulation of both brain amino acids and NO production.
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PMID:Changes in brain amino acids and nitric oxide after melatonin administration in rats with pentylenetetrazole-induced seizures. 1282 14

Strychnine-sensitive glycine receptors (GlyRs) inhibit neurotransmission in the spinal cord and brainstem. To better define the function of this receptor in vivo, we constructed a point mutation that impairs receptor function in the alpha1-subunit and compared these knock-in mice to oscillator (spdot) mice lacking functional GlyR alpha1-subunits. Mutation of the serine residue at amino acid 267 to glutamine (alpha1S267Q) results in a GlyR with normal glycine potency but decreased maximal currents, as shown by electrophysiological recordings using Xenopus oocytes. In addition, single-channel recordings using human embryonic kidney 293 cells indicated profoundly altered properties of the mutated GlyR. We produced knock-in mice bearing the GlyR alpha1 S267Q mutation to assess the in vivo consequences of selectively decreasing GlyR efficacy. Chloride uptake into brain synaptoneurosomes from knock-in mice revealed decreased responses to maximally effective glycine concentrations, although wild-type levels of GlyR expression were observed using 3H-strychnine binding and immunoblotting. A profound increase in the acoustic startle response was observed in knock-in mice as well as a "limb clenching" phenotype. In contrast, no changes in coordination or pain perception were observed using the rotarod or hot-plate tests, and there was no change in GABA(A)-receptor-mediated chloride uptake. Homozygous S267Q knock-in mice, like homozygous spdot mice, exhibited seizures and died within 3 weeks of birth. In heterozygous spdot mice, both decreased 3H-strychnine binding and chloride flux were observed; however, neither enhanced acoustic startle responses nor limb clenching were seen. These data demonstrate that a dominant-negative point mutation in GlyR disrupting normal function can produce a more dramatic phenotype than the corresponding recessive null mutation, and provides a new animal model to evaluate GlyR function in vivo.
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PMID:Glycine receptor knock-in mice and hyperekplexia-like phenotypes: comparisons with the null mutant. 1295 67

Metabotropic glutamate (mGlu) receptors have multiple actions on neuronal excitability through G-protein-linked modifications of enzymes and ion channels. They act presynaptically to modify glutamatergic and gamma-aminobutyric acid (GABA)-ergic transmission and can contribute to long-term changes in synaptic function. The recent identification of subtype-selective agonists and antagonists has permitted evaluation of mGlu receptors as potential targets in the treatment of epilepsy. Agonists acting on group I mGlu receptors (mGlu1 and mGlu5) are convulsant. Antagonists acting on mGlu1 or mGlu5 receptors are anticonvulsant against 3,5-dihydroxyphenylglycine (DHPG)-induced seizures and in mouse models of generalized motor seizures and absence seizures. The competitive, phenylglycine mGlu1/5 receptor antagonists generally require intracerebroventricular administration for potent anticonvulsant efficacy but noncompetitive antagonists, e.g., (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydrocyclopenta[c]furan-1-on (BAY36-7620), 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) block generalized seizures with systemic administration. Agonists acting on group II mGlu receptors (mGlu2, mGlu3) to reduce glutamate release are anticonvulsant, e.g., 2R,4R-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC], (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268). The classical agonists acting on group III mGlu receptors such as L-(+)-2-amino-4-phosphonobutyric acid, and L-serine-O-phosphate are acutely proconvulsant with some anticonvulsant activity. The more recently identified agonists (R,S)-4-phosphonophenylglycine [(R,S)-PPG] and (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] and (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid [ACPT-1] are all anticonvulsant without proconvulsant effects. Studies in animal models of kindling reveal some efficacy of mGlu receptor ligands against fully kindled limbic seizures. In genetic mouse models, mGlu1/5 antagonists and mGlu2/3 agonists are effective against absence seizures. Thus, antagonists at group I mGlu receptors and agonists at groups II and III mGlu receptors are potential antiepileptic agents, but their clinical usefulness will depend on their acute and chronic side effects. Potential also exists for combining mGlu receptor ligands with other glutamatergic and non-glutamatergic agents to produce an enhanced anticonvulsant effect. This review also discusses what is known about mGlu receptor expression and function in rodent epilepsy models and human epileptic conditions.
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PMID:Glutamate metabotropic receptors as targets for drug therapy in epilepsy. 1296 43

We have previously shown that the intrahippocampal microinjection of okadaic acid (OKA), a potent inhibitor of serine/threonine protein phosphatases, induces epileptic seizures, neuronal death, and the hyperphosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. We administered OKA by reverse microdialysis in the hippocampus of awake and halothane-anesthetized rats, with simultaneous collection of microdialysis fractions and recording of the EEG activity, and subsequent histological analysis. OKA produced intense behavioral and persistent EEG seizure activity in the awake rats but not in the anesthetized animals, and did not significantly alter the extracellular concentration of glutamate and aspartate detected in the microdialysis fractions. One day after the experiment a remarkable neurodegeneration of CA1 hippocampal region was observed in both the awake and the anesthetized rats. We conclude that the OKA-induced epilepsy cannot be ascribed to increased extracellular glutamate, but to an increased sensitivity of NMDA receptor. We propose that halothane protected against the epilepsy because it blocks NMDA receptor overactivation, and that the neurodegeneration of CA1 region is independent of this overactivation and due probably to alterations of cytoskeletal proteins consequent to the OKA-induced hyperphosphorylation.
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PMID:Epilepsy, neurodegeneration, and extracellular glutamate in the hippocampus of awake and anesthetized rats treated with okadaic acid. 1457 Mar 96

Malnutrition and/or seizure in the developing brain cause hippocampal damages. However, underlying mechanisms remain unclear. The malnutrition group (MN) subjected with malnutrition alone was culled to 20-22 rats per dam on postnatal day 1 (P1). The rats subjected to lithium-pilocarpine (Li/PC)-induced status epilepticus at P21 were grouped as the SE group. The rats subjected to malnutrition and subsequent status epilepticus were grouped as the MS group. Visual-spatial memory test using the Morris water maze task was performed at P80. Following behavioral tests, the hippocampus was evaluated for histological lesions and phosphorylated cAMP-responsive, element-binding protein at serine-133 (pCREB(Ser-133)), an important transcription factor underlying learning and memory in the mammalian brain. Here, the MN group exhibited decreased body weight at P21. There was no significant difference in the seizure duration and mortality between the SE and MS groups. In adulthood (P80), both the SE and MS groups showed the spatial learning deficit, hippocampal cell loss and decreased pCREB(Ser133) level within hippocampal CA1 region. Although the MN group demonstrated a decreased level of pCREB(Ser133), no distinguishable changes in the cognitive deficit and hippocampal neuronal loss were detected. Collectively, the present results suggest that early-life malnutrition led to a reduced phosphorylation of CREB(Ser133) in hippocampal CA1 in the absence of the long-term spatial learning deficit. This decreased phosphorylation of CREB(Ser133) could suggest that cascades of signal transduction responsible for the phosphorylation of CREB(Ser133) might be disturbed by early-life malnutrition. In addition, malnutrition caused no discernible synergistic effects on Li/PC-induced status epilepticus.
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PMID:Long-term effects of early-life malnutrition and status epilepticus: assessment by spatial navigation and CREB(Serine-133) phosphorylation. 1460 61

Scorpion human envenoming is a public health hazard in the southwest of Venezuela. Tityus zulianus is one of the scorpion species whose venom causes lung edema and cardiac failure in children. These occasionally deadly manifestations have been attributed to a massive sympathetic discharge. The intraperitoneal administration of T. zulianus venom (20 micrograms/g mouse) to anesthetized mice during subcutaneous microdialysis caused increased secretions, dyspnea, seizures and death between 30 min to 2 h. Seven amino acids were analyzed by capillary electrophoresis with laser induced fluorescence detection (CE-LIFD) in the collected samples before and after the venom administration. We found an increase of arginine (39%), phenylalanine (40%) and glutamate (94%), with no changes in valine, serine and aspartate, changes were significant when the injection of venom and vehicle were compared and before vs after venom injection. Further investigation is needed to know if the observed changes could be related to the molecular mechanisms of the venom or some of its components and therefore with the envenoming symptoms. To our knowledge, this is the first report with subcutaneous microdialysis and CE-LIFD coupling in scorpion envenomation studies in vivo, in mice.
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PMID:[Amino acid changes following intraperitoneal administration of Tityus zulianus scorpion venom in mice. Study with subcutaneous microdialysis and capillary electrophoresis]. 1472 83

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

We have previously proven that some synthetic kynurenines behave as antagonists of the N-methyl-d-aspartate receptor inhibiting neuronal subtype of nitric oxide synthase activity. We now investigate the anticonvulsant activity of four of these kynurenines in pentylenetetrazole (PTZ)-treated rats. The rats were treated with each kynurenine (10-160 mg/kg, s.c.) 30 min before PTZ administration (100 mg/kg, s.c.). Then, latency, duration and intensity of the first seizure and the percent animal survival were noted. PTZ-induced death was counteracted by high doses of kynurenines. Latency of the first seizure was significantly increased and its intensity reduced at the same doses, whereas the duration of the first seizure significantly decreased with doses of 20 mg/kg in most of the kynurenines tested. Three hours after PTZ administration, the surviving animals were sacrificed and the levels of brain amino acids and nitrite were measured. PTZ administration increased glutamate, glutamine, serine and taurine levels in different brain areas. High doses of kynurenines generally counteracted the effects of PTZ on excitatory amino acids, but they also reduced inhibitory aminoacids. However, the most consistent effect of kynurenines was the dose-dependent reduction of brain nitrite levels induced by PTZ. These results reveal a new family of anticonvulsant drugs that affect mainly to nitric oxide production in the brain.
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PMID:Effects of some synthetic kynurenines on brain amino acids and nitric oxide after pentylenetetrazole administration to rats. 1506 52


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