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)

Sudden cooling of the isolated spinal cord of frogs results in characteristic seizure-like activity in the hind legs. In the present investigation, these spinal seizures induced by sudden cooling (SSSC) were studied to determine whether excitatory amino acids (EAAs) are involved in the mediation of this activity. The nonspecific EAA antagonist, L-glutamic acid diethyl ester and cis-2,3-piperidine dicarboxylic acid inhibited the clonic and tonic phase of SSSC after intralymphatic or intrathecal administration. The antagonist gamma-D-glutamylaminomethylsulfonic acid and gamma-D-glutamyltaurine also suppressed both phases after intrathecal injections. The NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid, DL-2-amino-7-phosphonoheptanoic acid, and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid were effective inhibitors of the tonic phase and actually prolonged the duration of the clonic phase, an effect similar to that observed after low doses of gamma-D-glutamylglycine. SSSC were resistant to spinal perfusion to tetrodotoxin (1 microM). The concentrations of glutamate, aspartate, and glycine were increased in the Ringer's solution surrounding rapidly cooled spinal cord slices, but only in cords from species that elicited some magnitude of SSSC, not in cords from species resistant to induction of SSSC. Our data support the hypothesis that EAAs play a role in SSSC via activation of quisqualate receptors.
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PMID:Spinal seizures evoked by sudden cooling of amphibian isolated spinal cords: involvement of excitatory amino acids. 183 Aug 37

Selective antagonists of quinolinic acid (2,3-pyridine dicarboxylic acid, QUIN)--an endogenous convulsant tryptophan metabolite, administered intracerebroventricular to mice, were identified during comparison with the following intracerebroventricular convulsants: l-kynurenine, aspartic, glutamic, N-methyl-DL-aspartic and kainic acids. It is suggested that the antagonism arises due to a common fragment of the structure which consists of two carboxylic groups at two nearest carbon atoms of the ring and of one nitrogen atom in the alpha-position. The selective action of the compounds found against QUIN supports the suggestion that QUIN produces seizures via N-methyl-D-aspartate binding sites.
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PMID:[Selective anticonvulsive action of N-substituted imidazole-4,5-dicarboxylic acids against quinolinic acid]. 296 57

Beta-N-methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) are chemically related amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA; a form of primary lateral sclerosis). A single large dose of BOAA or BMAA causes seizures in newborn mice and postsynaptic neuronal edema and degeneration in CNS explants. We report that the acute neurotoxic actions of these amino acids are blocked selectively by specific glutamate-receptor antagonists (administered intracerebroventricularly) (i.c.v.) prior to the amino acid. Administration of BOAA i.c.v. to neonatal mice (ED100 = 50 micrograms) elicits a spectrum of time-dependent behavioral states including arm and leg rigidity, convulsions, and resting tremor. These are blocked in a dose-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring (A2) and kainate (KA)-preferring (A3) glutamate receptors (ED50s; 2.8 micrograms, rigidity; 1.4 micrograms, convulsions; 2.4 micrograms, resting tremor). BMAA induces a transitory hyperexcitable state followed by a long-lasting whole-body shake/wobble (ED100 = 1,000 micrograms, i.c.v.). These responses are antagonized selectively and dose-dependently by 2-amino-7-phosphonoheptanoic acid (AP7), an N-methyl-D-aspartate (NMDA) or A1 glutamate-receptor antagonist (ED50 = 0.45 microgram). Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate-receptor species. BMAA likely exerts most of its action indirectly via the A1 glutamate receptor, while BOAA acts principally at the A2 and/or A3 receptor.
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PMID:Specific antagonism of behavioral action of "uncommon" amino acids linked to motor-system diseases. 314 80

Several excitatory amino acid antagonists were tested for an ability to prevent spontaneous convulsions seen during the barbital abstinence syndrome in rats. Barbital-dependent animals were continuously infused intracerebroventricularly (i.c.v.) for the first 48 h following barbital withdrawal with either saline, 2-amino-7-phosphonoheptanoic acid (APH), magnesium sulfate, glutamyldiethyl ester (GDEE) or cis-2,3-piperidine dicarboxylic acid (PDA) using the highest dosages which did not affect normal behavior of the rats. All animals were observed continuously from 12 to 48 h postwithdrawal and the number of spontaneous convulsions observed in each animal was recorded. After this time, animals were killed by focused microwave irradiation and the cerebellas were collected for determination of cyclic guanosine monophosphate (cGMP) levels. While both APH and MgSO4 dramatically prevented convulsions, only APH prevented the withdrawal-induced elevation of cerebellar cGMP. PDA and GDEE had no statistically significant effect on either cerebellar cGMP levels or on convulsive activity. Although the effect of GDEE was not statistically significant, the number of convulsions was reduced to 1/3 those seen in control animals. These data implicate N-methyl-d-aspartate (NMDA) receptor-mediated pathways in seizure activity associated with the barbital abstinence syndrome and show that the withdrawal-induced elevation of cerebellar cGMP can occur without the induction of convulsions.
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PMID:Anticonvulsive activity of several excitatory amino acid antagonists against barbital withdrawal-induced spontaneous convulsions. 337 64

A second child with a more severe deficiency of malonyl CoA decarboxylase is described. He is mildly mentally retarded and presented with vomiting, a seizure, hypoglycaemia and mild metabolic acidosis during a urinary tract infection. The urine contained increased amounts of malonic, methylmalonic, succinic, adipic, glutaric and suberic acids. Mitochondrial malonyl CoA decarboxylase activity in cultured fibroblast extracts was 4% of the mean control value. A high fat, low carbohydrate diet led to symptomatic hypoglycaemia, a moderate metabolic acidosis and excretion in the urine of large amounts of the same organic acids and 3-hydroxybutyrate. Only relatively small quantities of malonic, methylmalonic and succinic acid were excreted in the urine when the boy was fed an isocaloric low fat, high carbohydrate diet. Acute fat and lysine loads led to increased excretion of malonic acid in the urine without affecting the excretion of the other organic acids. Experience with this patient suggests that malonyl CoA decarboxylase serves an important function in the mitochondrion by preventing accumulation of malonyl CoA. The importance of the enzyme is best seen when fat is the main metabolic fuel. The mechanisms by which malonyl CoA produces its complex metabolic effects remain to be elucidated.
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PMID:Malonyl coenzyme A decarboxylase deficiency. Clinical and biochemical findings in a second child with a more severe enzyme defect. 370 68

Two dicarboxylic piperazine derivatives, 1-(p-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (pCB-PzDA) and 1-(p-bromobenzoyl)-piperazine-2,3-dicarboxylic acid (pBB-PzDA), that block excitation at glutamate receptors have been evaluated as anticonvulsants in rodent models of epilepsy by i.c.v. or i.p. injection. In DBA/2 mice, pBB-PzDA (0.01 mumol i.c.v.) or pCB-PzDA (0.03 mumol i.c.v.) protects against the clonic and tonic seizures induced by loud sound. Protection is also seen following i.p. injection of pBB-PzDA (0.33-1.0 mmol/kg) or pCB-PzDA (0.66-1.0 mmol/kg). In Swiss S mice suppression of seizure activity induced by i.c.v. injection of excitatory amino acid agonists shows that both compounds are preferentially active against alpha-kainate, with the following rank orders (for pBB-PzDA); alpha-kainate greater than quisqualate greater than N-methyl-D-aspartate greater than quinolinate greater than L-glutamate; and (for pCB-PzDA): alpha-kainate greater than quinolinate greater than N-methyl-D-aspartate greater than quisqualate greater than L-glutamate. These compounds are the most potent preferential alpha-kainate antagonists so far tested. The relationship between antagonism at the various receptor subtypes and anticonvulsant action is not adequately defined.
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PMID:Anticonvulsant activity of two novel piperazine derivatives with potent kainate antagonist activity. 389 72

Spiro[4.5]decane-2-carboxylic acid (12a), spiro[4.5]decane-2,2-dicarboxylic acid (11a), spiro[4.6]undecane-2-carboxylic acid (12b), spiro[4.6]undecane- 2,2-dicarboxylic acid (11b), and spiro[4.6]undecane-2-acetic acid (13) were synthesized by an improved method and evaluated for anticonvulsant activity. These analogues were synthesized to evaluate the role of the carboxylic acid group as an essential substituent in valproic acid (di-n-propylacetic acid, 1). Carbocyclic spiranes are known to resist metabolic alteration so that any activity elicited by these compounds would be due to the carboxylic acid function and not to any metabolic change. Spiro[4.6]undecane-2-carboxylic acid (12b) was the most active analogue tested and the pentylenetetrazol and picrotoxin evaluations of 12b compared favorably to 1. However, 12b failed to provide adequate protection against maximal electroshock seizures, bicuculline, or strychnine in mice. Possible reasons for these results are discussed.
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PMID:Spiro[4.5] and spiro[4.6] carboxylic acids: cyclic analogues of valproic acid. Synthesis and anticonvulsant evaluation. 392 Mar 94

A 7-year-old boy developed a severe unilateral grand mal seizure at the age of 5 years (phenobarbitone therapy); 1.5 years later valproate (2-propylpentanoic acid, VPA) was added to the therapy. After a seizure-free period of 3 months the patient died from hepatic failure resembling Reye syndrome. Several plasma and urine samples from the final stage before and during peritoneal dialysis were analyzed by GC/MS. The predominant feature was the abnormally increased formation of both 3 mono- and 4 double unsaturated metabolites of VPA amounting in plasma to 58%-71% of the sum of VPA plus all analyzed metabolites (controls maximal 15%) and in urine to 34%-61% (controls maximal 10%). The beta-oxidation pathway of VPA was shown to be suppressed (lack of 3-keto-VPA), whereas metabolites from the omega-oxidation pathway could still be measured (urinary 5-OH-VPA plus 2-propylglutaric acid ca. 1.6%, controls more than 10%). 4-en-VPA (2-propyl-4-pentenoic acid) (5%-21% in plasma) and 4,4'-dien-VPA (2(2-propenyl)-4-pentenoic acid) (4%-7%) have been found as abnormal unsaturated metabolites not detectable in controls. Additional typical findings were the high excretion of adipic acid, suberic acid, and 4-octen-1,8-dicarboxylic acid demonstrating the enhanced capacity of omega-oxidation in fatty acid oxidation.
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PMID:Abnormal metabolism of valproic acid in fatal hepatic failure. 641 45

Anticonvulsant and convulsant effects of various piperidine dicarboxylic acids have been evaluated following their intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection in DBA/2 mice, a strain of mice genetically susceptible to sound-induced seizures. Protection against sound-induced seizures occurred after intraventricular administration of (+/-)cis-2,3-piperidine dicarboxylic acid (0.017-0.045 mumol), (+/-)trans-2,3-piperidine dicarboxylic acid (0.018-0.33 mumol) and (+/-)cis-2,4-piperidine dicarboxylic acid (0.57-1.68 mumol). Protection against sound-induced seizures occurred after intraperitoneal injection of (+/-)cis-2,3-piperidine dicarboxylic acid (0.52-1.8 mmol/kg). Myoclonus or convulsions occurred at various times after the intraventricular injection of cis-2,3-piperidine dicarboxylic acid, trans-2,3-, cis-2,4-, cis-2,5- and cis-2,6-, piperidine dicarboxylic acids, and after the intraperitoneal injection of trans-2,3-piperidine dicarboxylic acid. The latter effect was blocked by pretreatment with 2-amino-7-phosphonoheptanoic acid (0.33 mmol/kg, i.p.) a potent and specific antagonist of excitation induced by N-methyl-D-aspartate. The anticonvulsant action of cis-2,3-piperidine dicarboxylic acid and the convulsant action of trans-2,3-piperidine dicarboxylic acid were associated with predominant antagonist and agonist actions respectively, at receptors preferring N-methyl-D-aspartate.
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PMID:Anticonvulsant and proconvulsant properties of a series of structural isomers of piperidine dicarboxylic acid. 672 32

Metabotropic glutamate receptor (mGluR)-induced neuronal injury in the brain was further investigated in the rat. The highly selective mGluR agonist 1S,3R-1-aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD) was infused stereotaxically into the left dorsal hippocampus of adult rats. Control (2 microliters saline injected) rats had minimal tissue injury that was confined to the area around the injection site. In contrast, a dose of 250 nmol/2 microliters 1S,3R-ACPD produced a moderate number of swollen and injured cells in polymorphic, pyramidal and molecular layers of the injected hippocampus which was observed at 4 and 8 h post-injection. However, at 24 h few injured or necrotic cells were found. A dose of 1000 nmol/2 microliters 1S,3R-ACPD produced severe cellular injury in polymorphic, pyramidal and molecular layers of the hippocampus at 4, 8, or 24 h. At 24 h after this higher dose of 1S,3R-ACPD, a number of necrotic cells (i.e. pyramidal neurons of area CA1) were found. Both doses of 1S,3R-ACPD produced seizures in animals that were characterized by multiple episodes of wet dog shakes, staring, immobility, facial automatisms, rearing, bilateral forelimb clonus, and loss of postural control. These data support a possible role for excessive mGluR activation in pathological states of convulsions and neurodegeneration.
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PMID:Reversible and irreversible neuronal injury induced by intrahippocampal infusion of the mGluR agonist 1S,3R-ACPD in the rat. 760 Jan 86


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