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)

The alpha 2-antagonist, yohimbine has been shown to dose-dependently induce clonic seizures in mice. The convulsant effects of yohimbine are not due to alpha 2-antagonism, as other alpha 2-antagonists, such as rauwolscine and idazoxan, did not produce seizures at doses up to 100 mg/kg. Since GABAmimetic and excitatory amino acid antagonist agents attenuate yohimbine-induced seizures, the respective contribution of these systems to the production of yohimbine seizures was investigated. The CD50 dose of yohimbine (dose required to produce clonic seizures in 50% of the mice) was determined to be 25.5 mg/kg (s.c.). The CD15 dose of N-methyl-DL-aspartic acid (NMDLA), bicuculline and methyl-6,7-dimethoxy-4 ethyl-beta carboline-3-carboxylate (DMCM) significantly potentiated the convulsant effects of yohimbine, such that the CD50 dose was decreased from 25.5 mg/kg to 1.6, 10.9 and 9.9 mg/kg, respectively. Furthermore, the potentiation in the presence of NMDLA was significantly greater than either bicuculline or DMCM. These results suggest that yohimbine-induced seizures are not only mediated through the impairment of GABAergic transmission but moreover, by a possible endogenous enhancement of excitatory amino acid transmission. In addition, the effects of GABAmimetic agents, competitive and non-competitive NMDA receptor antagonists and strychnine-insensitive glycine receptor antagonists were compared in the yohimbine-, bicuculline- and NMDLA-induced seizure assays.
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PMID:Yohimbine-induced seizures involve NMDA and GABAergic transmission. 132 92

A significant increase in the plasma levels of glutamic acid and a significant decrease in aspartic acid and taurine in epileptic patients and their first degree relatives was reported more than a decade ago and an underlying genetic basis for these amino acid changes was suggested. The main objective of the present study was to determine the plasma levels of glutamic acid, aspartic acid and taurine in El mice which are an inbred epileptic mutant mouse strain. The results show a significant increase in plasma glutamic acid but no changes in aspartic acid or taurine in the epileptic mice as compared to controls. The data provide the first evidence of a significant increase in plasma glutamic acid in an animal model of hereditary epilepsy and substantiate the hypothesis that a genetic defect underlies the elevated plasma glutamic acid levels in association with epilepsy. The findings are also compatible with neurochemical and neurophysiological evidence implicating glutamic acid in the mechanism of seizures.
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PMID:Increased plasma glutamic acid in a genetic model of epilepsy. 135 88

The autosomal dominant trembler mutation (Tr), maps to mouse chromosome 11 (ref. 2) and manifests as a Schwann-cell defect characterized by severe hypomyelination and continuing Schwann-cell proliferation throughout life. Affected animals move clumsily and develop tremor and transient seizures at a young age. We have recently described a potentially growth-regulating myelin protein, peripheral myelin protein-22 (PMP-22; refs 7, 8), which is expressed by Schwann cells and found in peripheral myelin. We now report the assignment of the gene for PMP-22 to mouse chromosome 11. Cloning and sequencing of PMP-22 complementary DNAs from inbred Tr mice reveals a point mutation that substitutes an aspartic acid residue for a glycine in a putative membrane-associated domain of the PMP-22 protein. Our results identify the PMP-22 gene as a likely candidate for the mouse trembler locus and will encourage the search for mutations in the corresponding human gene in pedigrees with hypertrophic neuropathies such as Charcot-Marie-Tooth and Dejerine-Sottas diseases (hereditary motor and sensory neuropathies I and III).
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PMID:Trembler mouse carries a point mutation in a myelin gene. 155 43

Aspartame, the methyl ester of the dipeptide formed from combining phenylalanine and aspartic acid, was approved by the US Food and Drug Administration (FDA) in July 1981. FDA monitors complaints from consumers and health professionals through the Adverse Reaction Monitoring System, a passive surveillance program FDA has received 251 reports of seizures that have been linked to ingestion of aspartame by consumers. In most cases, information obtained from the complainants' medical records as well as data on consumption patterns, temporal relationships, and challenge tests did not support the claim that the occurrences of the seizures were linked to consumption of aspartame.
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PMID:An analysis of FDA passive surveillance reports of seizures associated with consumption of aspartame. 157 43

This study extends our previous work in which we described the presence of an interictal behavioral disturbance in a chronic animal model of temporal lobe epilepsy (TLE). In this study, we investigated the cerebrospinal fluid (CSF) neurotransmitter changes underlying the development of chronic recurrent seizures of temporal lobe origin and interictal behavioral disturbance in cats made epileptic after intrahippocampal injection of kainic acid (KA). Using high-performance liquid chromatography, we measured 22 putative neurotransmitter amino acids. After intrahippocampal KA injection, cats developed an initial acute period of intense seizure activity. Cisternal CSF amino acids, which were repeatedly sampled during the acute period through a permanent indwelling cannula, were unchanged apart from a mild elevation in CSF alanine. The high-level seizure activity gradually decreased, and cats entered a chronic epileptic period characterized by recurrent yet intermittent temporal lobe seizures. CSF GABA levels during the chronic epileptic period were significantly decreased. In contrast, CSF levels of other amino acids--alanine, tyrosine, taurine, aspartic acid, and glutamic acid--did not change significantly. Behavioral testing also showed a heightened interictal defensive reactivity during the chronic epileptic period. To the extent that CSF GABA concentration reflects brain GABA concentration, this study suggests that a decrease in brain GABA may contribute both to the epilepsy and interictal emotional lability of animals with a chronic seizure disorder of temporal lobe origin.
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PMID:Interictal behavioral alterations and cerebrospinal fluid amino acid changes in a chronic seizure model of temporal lobe epilepsy. 174 47

The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (+/-)-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [3H]glycine binding to rat cerebral cortex synaptic membranes with an IC50 of 12.5 microM, whereas (-)-HA-966 had an IC50 value of 339 microM. In electrophysiological experiments, (+)-HA-966 selectively antagonized NMDA receptor responses in rat cortical slices, whereas the (-)-enantiomer was much weaker. On cultured cortical neurones (+)-HA-966 inhibited glycine-potentiated NMDA responses with an IC50 = 13 microM compared with (-)-HA-966, which has an IC50 = 708 microM. In agreement with findings with racemic HA-966, even high concentrations of (+)-HA-966 did not completely inhibit NMDA responses, suggesting that (+)-HA-966 is a low-efficacy partial agonist. (+)-HA-966 produced parallel shifts to the right of the glycine concentration curve for potentiation of NMDA responses, resulting in an estimated pKb = 5.6. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures with ED50 values of 52.6 mg/kg of body weight (i.p.) and 900 mg/kg (i.v.), respectively. The coadministration of D-serine dose-dependently (10-100 micrograms into the cerebral ventricles per mouse) antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 (100 micrograms administered directly into the cerebral ventricles) against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to the (-)-enantiomer, which was greater than 25-fold more potent than the (+)-enantiomer. It is suggested that, as in the case of the sedative gamma-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action.
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PMID:Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative. 215 94

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. 255 Feb 53

Glutamic acid di-tert butyl ester (GTBE) was found to have a pronounced convulsant effect in mice and rats, producing recurrent clonic convulsions combined with postural and respiratory disturbances in a dosage of 0.5 mmol/kg (148 mg/kg). Tert-butyl ester derivatives of aspartic acid and alanine, and glutamic acid gamma-benzyl ester did not produce seizures. Various other glutamate esters, such as glutamic acid diethyl ester and glutamic acid dimethyl ester, have previously been found to have anticonvulsant effects, and also do not induce seizures. It is suggested that glutamic acid di-tert butyl ester may have specific pharmacological properties which differ from those of other known convulsant drugs.
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PMID:Convulsant properties of L-glutamic acid di-tert butyl ester. 286 66

Increased concentration of the excitatory neurotransmitter aspartic acid in actively spiking human epileptic cerebral cortex was recently described. In order to further characterise changes in the aspartergic system in epileptic brain, the behaviour of aspartic acid aminotransferase (AAT), a key enzyme involved in aspartic acid metabolism has now been examined. Electrocorticography performed during surgery was employed to identify cortical epileptic spike foci in 16 patients undergoing temporal lobectomy for intractable seizures. Patients with spontaneously spiking lateral temporal cortex (n = 8) were compared with a non-spiking control group (n = 8) of patients in whom the epileptic lesions were confined to the hippocampus sparing the temporal convexity. Mean activity of AAT in spiking cortex was significantly elevated by 16-18%, with aspartic acid concentration increased by 28%. Possible explanations for the enhanced AAT activity include increased proliferation of cortical AAT-containing astrocytes at the spiking focus and/or a generalised increase in neuronal or extraneuronal metabolism consequent to the ongoing epileptic discharge. It is suggested that the data provide additional support for a disturbance of central excitatory aspartic acid mechanisms in human epileptic brain.
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PMID:Aspartic acid aminotransferase activity is increased in actively spiking compared with non-spiking human epileptic cortex. 289 10

The effect of chronic administration of gamma-vinyl GABA (GVG; vigabatrin) on levels of neurotransmission-related amino compounds was studied in lumbar cerebrospinal fluid of 65 patients with complex partial epilepsy. The first sample of cerebrospinal fluid was taken before a 3-month period of treatment with 3 g gamma-vinyl GABA/day, and the second was taken afterwards. From patients who showed a greater than 50% reduction in seizures (responders) or marked improvement in global performance, a third sample was taken at the end of the next 3-month phase, during which 3 g or 1.5 g gamma-vinyl GABA had been administered daily. During treatment with 3 g gamma-vinyl GABA/day, 55% of the patients showed more than 50% reduction in complex partial seizures; and at the same time free GABA, total GABA, homocarnosine, and glycine concentrations in the cerebrospinal fluid increased by 104%, 151%, 194% and 16%, respectively. After reduction of the daily dose to 1.5 g, the levels of free GABA, total GABA and homocarnosine were still increased by 65%, 115% and 102%, respectively. gamma-Vinyl GABA correlated with the levels of free GABA (P less than 0.002) and glycine (P less than 0.001). Concentrations of homocarnosine at baseline and homocarnosine and total GABA during gamma-vinyl GABA treatment were lower (P less than 0.005) in the group of non-responders than in the responder group. Glutamic acid, glutamine, aspartic acid, asparagine, and taurine levels did not change during gamma-vinyl GABA treatment. In conclusion, administration of gamma-vinyl GABA reduces epileptic seizures and produces dosage-dependent increases in levels of free GABA, GABA-containing peptides and of glycine in cerebrospinal fluid, without concomitant change in levels of excitatory amino acids.
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PMID:Inhibitory and excitatory amino acids in CSF of patients suffering from complex partial seizures during chronic treatment with gamma-vinyl GABA (vigabatrin). 314 62


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