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)

We report the isolation, characterization, and total synthesis of a small peptide ligand for nicotinic acetylcholine receptors (nAChRs). It is highly active against the neuromuscular receptor in frog but not in mice. In contrast, it induces seizures when injected centrally in mice and rats, suggesting that it may target neuronal nAChRs in mammals. Although such receptors may be important in both normal cognition and the pathophysiology of several neuropsychiatric disorders, there are few ligands to discriminate between the multiple receptor subtypes. The new peptide is a highly divergent alpha-conotoxin from the snail Conus imperialis, which preys on polychaete worms. In this article, the purification, structural analysis, synthesis, and preliminary physiological characterization of alpha-conotoxin ImI (alpha-CTx-ImI) are reported. The sequence of the peptide is: Gly-Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg-Cys-NH2. The peptide shows striking sequence differences from all alpha-conotoxins of fish-hunting Conus, but its disulfide-bridging is similar: [2-8; 3-12]. We suggest that cone venoms may provide an array of ligands with selectivity for various neuronal nAChR subtypes.
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PMID:A nicotinic acetylcholine receptor ligand of unique specificity, alpha-conotoxin ImI. 820 95

We report a 38-year-old woman with a mild form of hyperglycinemia complicated with optic nerve atrophy and convulsion. She was normal at birth and showed normal mental and physical development. After the age of 13, her visual acuity rapidly decreased. At the age of 33, she had numerous episodes of tonic seizures lasting for 1-2 minutes. She had optic atrophy, but no intellectual impairment. Glycine levels of the plasma, urine and cerebrospinal fluid were markedly increased, but the CSF/serum glycine ratio was slightly higher than the normal range. Although there is one case of retinal impairment of hyperglycinemia in the literature, this is the first report of blindness with hyperglycinemia in a 38-year-old woman.
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PMID:Blindness due to non-ketotic hyperglycinemia: report of a 38-year-old, the oldest case to date. 831 63

A patient with neonatal glycine encephalopathy who had severe neurologic retardation, spasticity, and seizures died at 17 years of age. Glycine concentration was markedly elevated in brain tissue, especially in the cerebellum. Neuropathologic study revealed spongy myelinopathy throughout the central nervous system and calcium oxalate crystals in the cerebellum, which are probably derived from degradation of glycine. Myelinopathy appeared to be static compared to neonatal patients. The neurologic manifestations of neonatal glycine encephalopathy are probably due to neurotransmitter abnormalities, not to myelin damage.
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PMID:Neonatal glycine encephalopathy: biochemical and neuropathologic findings. 849 44

Glycine receptor antagonists have been proposed to have multiple therapeutic applications, including the treatment of stroke, epilepsy, and anxiety. The present study compared the biochemical and behavioral profiles of two strychnine-insensitive glycine receptor antagonists, MDL 100,458 (3-(benzoylmethylamino)-6-chloro-1H-indole-2- carboxylic acid) and MDL 102,288 (5,7-dichloro-1,4-dihydro-4-[[[4- [(methoxycarbonyl)amino]phenyl]sulfonyl]imino]-2-quinolinecarboxylic acid monohydrate). Both compounds potently inhibited [3H]glycine binding to rat cortical/hippocampal membranes (Ki = 136, 167 nM, respectively) without showing significant activity in 18 other receptor binding assays. In an in vitro functional assay, both compounds completely antagonized N-methyl-D-aspartate (NMDA)-stimulated cGMP accumulation in rat cerebellar slices. However, in contrast to their equipotency in the glycine receptor assay, MDL 100,458 was approximately 6-fold more potent than MDL 102,288 in the cGMP assay (IC50 values = 1.25, 7.8 microM, respectively). Behavioral tests demonstrated that MDL 102,288 and MDL 100,458 exhibited strikingly different in vivo profiles. MDL 100,458 antagonized audiogenic seizures in DBA/2J mice (ED50 = 20.8 mg/kg i.p.), whereas MDL 102,288 was without effect in the dose range tested (ED50 > 300 mg/kg i.p.). Central nervous system penetration did not appear to account for this difference. For example, MDL 102,288 was not active following direct intracerebroventricular administration (ED50 > 16 micrograms; vs. 0.78 microgram for MDL 100,458). In a test of anxiolytic activity, MDL 102,288 reduced separation-induced ultrasonic vocalizations in rat pups (ED50 = 6.3 mg/kg i.p.) whereas MDL 100,458 was only weakly active (ED50 = 80.8 mg/kg i.p.). Furthermore, the anxiolytic effect of MDL 102,288 was selective in that it occurred at doses that did not produce motoric disruption as measured by an inclined-plane test (ED50 > 160 mg/kg; therapeutic index > 25.4). In contrast, the anxiolytic activity of MDL 100,458 was non-selective in that it occurred at doses that also produced motoric disruption (ED50 = 57.7 mg/kg; therapeutic index = 0.7). Thus, two glycine receptor antagonists which have similar in vitro binding profiles as selective ligands for the strychnine-insensitive glycine receptor, demonstrate different in vitro and in vivo functional profiles. The reason for these differences is not clear, though one possibility could be that the compounds may act on different NMDA receptor subtypes. These data support the possibility that different glycine receptor antagonists may have different therapeutic targets.
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PMID:MDL 100,458 and MDL 102,288: two potent and selective glycine receptor antagonists with different functional profiles. 854 13

The effects of injections of naloxone, a universal opioid receptor antagonist, into the medial septal nucleus on hippocampal acetylcholine (ACh) release and behavior were investigated in freely moving rats by means of the microdialysis method. The injection of naloxone (2, 10 and 20 micrograms) produced a marked increase in hippocampal ACh release in a dose-dependent manner. These effects of naloxone were reversed by the post-injection of [D-Ala2, N-Me-Phe4, Gly-ol]-enkephalin (DAGO; 10 micrograms), an opioid mu receptor agonist. Furthermore, basal release of hippocampal ACh was significantly reduced by the injection of DAGO alone. It was also found that rats given an injection of naloxone showed an increase in motor activity and occasionally exhibited behavioral seizures. These effects of naloxone were also reversed by the post-injection of DAGO. The present results suggest that endogenous opioids ionically inhibit the activity of septo-hippocampal cholinergic neurons via mediation of mu opioid receptors in the medial septal nucleus. They also suggest that endogenous opioids modulate the incidence of seizures, at least in part, through opioid mu receptors in the medial septal nucleus.
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PMID:Medial septal injection of naloxone elevates acetylcholine release in the hippocampus and induces behavioral seizures in rats. 872 69

A reliable method was sought for the fast screening and simultaneous determination of amphetamine, morphine, heroin (acetomorphine), codeine (methylmorphine) and caffeine in biological fluids and drug seizures. Capillary zone electrophoresis (CZE) and micellar electrokinetic capillary chromatography (MEKC), with detection at 200 and 220 nm, were investigated for analytes in human serum and urine. When adequate separation was not achieved in preliminary studies with CZE, further development was focused on the MEKC method. Glycine buffer containing sodium lauryl sulfate (pH 10.5) was used for the MEKC separations. The analytes and carboxylic acids used as marker compounds could be screened by a short-capillary method in less than 2 min. In the simultaneous determination of the drugs in urine and serum a longer separation of 18 min was preferred so that all the compounds, the markers and the endogenous compounds absorbing at the detection wavelength could be adequately separated in a single run. The migration times of the compounds increased in the order caffeine, morphine, heroin, codeine and amphetamine. The repeatability of the separation was tested by using two carboxylic acids as marker compounds in the determination of the migration indices of the analytes. The relative standard deviations for the migration indices were less than 1%, which is accurate enough for the determination of the drugs in biological fluids.
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PMID:Determination of morphine analogues, caffeine and amphetamine in biological fluids by capillary electrophoresis with the marker technique. 876 52

The pilocarpine model of temporal lobe epilepsy was used to study the time-dependent changes in dentate gyrus circuitry after seizures. Seizures caused a decrease in mu- and delta-opioid receptor immunoreactive (MOR-IR and DOR-IR, respectively) neurons in the hilus and MOR-IR neurons in the granule cell layer. Additionally, diffuse DOR-IR, MOR-IR, and GABA immunoreactivities (GABA-IR) were increased in the inner molecular layer. Using the in vitro hippocampal slice preparation to study the physiological consequences of the anatomical changes, we found that the disinhibitory effects of the mu-opioid receptor agonist [D-Ala2, MePhe4,Gly-(ol)5]-enkephalin (DAMGO) and the GABAA receptor antagonist bicuculline were greatly depressed 5-13 d after pilocarpine injection but returned to control levels within 6 weeks. The amplitudes of monosynaptic evoked IPSCs and the effects of DAMGO on this parameter were also slightly decreased 5-13 d after pilocarpine injection but significantly increased at 6 weeks. DAMGO significantly decreased the mean amplitude of spontaneous IPSCs (sIPSCs) at 6 weeks after pilocarpine injection but not in controls. The delta-opioid receptor agonist [D-Pen2,5]-enkephalin (DPDPE) principally inhibited excitatory transmission in saline-treated animals without affecting either sIPSCs or evoked IPSCs. The DPDPE-induced inhibition of excitatory transmission became more pronounced at 6 weeks after pilocarpine injection. These results illustrate the anatomical reorganization and functional changes in dentate gyrus circuitry evident in an animal model of temporal lobe epilepsy and provide evidence of compensatory changes after trauma to the hippocampal formation.
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PMID:Changes in hippocampal circuitry after pilocarpine-induced seizures as revealed by opioid receptor distribution and activation. 898 72

The effects of valproate on CNS concentrations of gamma-aminobutyric acid (GABA), glulamate (GLU), glutamine (GLN); dopamine (DA), serotonin (5-HT), and metabolites were examined in tissue extracts of caudate nucleus of genetic substrains of Balb/c mice susceptible (EP) or resistant (ER) to audiogenic seizures. Generalized tonic-clonic seizures observed in EP mice were inhibited by valproate, administered 1 h prior to testing, in a dose-response fashion. Concentrations of GABA, GLU, and GLN, which were lower in EP mice than in ER mice, were significantly increased by valproate at doses of 180 and 360 mg/kg. Concentrations of homovanillic acid (HVA) and hydroxyindoleacetic acid (5-HIAA), metabolites of DA and 5-HT, were substantially increased by valproate at these doses. The in situ activity of tyrosine hydroxylase (TH) was not significantly influenced by valproate, whereas a valproate-induced increase in tryptophan hydroxylase (TPH) activity was observed in both striatum and in midbrain tegmentum. The data are consistent with the interpretation that anti-convulsive doses of valproate influences the intraneuronal metabolism of monoamines, GABA, and glutamate concurrently. Valproate's influence on the metabolism of both major inhibitory (GABA) and excitatory (GLY amino acids in striatum could contribute to its anti-convulsive effects in genetically seizure prone mice, as well as to the accumulation of DA and 5-HT metabolites.
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PMID:Effects of valproate on amino acid and monoamine concentrations in striatum of audiogenic seizure-prone Balb/c mice. 914 15

We report the development of a radioimmunoassay for prepro-TRH(160-169) (PS4), a thyrotropin-releasing hormone (TRH) enhancing peptide, and its use in characterizing the effect of electroconvulsive seizures on the levels of this peptide in various brain regions of male Wistar rats. We found that electroconvulsive seizures significantly elevated the PS4 levels in hippocampus, amygdala, pyriform (olfactory) cortex, and anterior cortex but not in striatum, motor cortex, locus ceruleus, or ventral lateral medulla. The levels of PS4 were highly correlated with the corresponding TRH (p-Glu-His-Pro-NH2) and TRH-Gly (p-Glu-His-Pro-Gly) levels in hippocampus, amygdala, and pyriform cortex, consistent with the prepro-TRH source of all of these peptides. The PS4 levels in hippocampus and amygdala were significantly correlated with the immobility time in the Porsolt forced swim test, an established animal model for antidepressant effects. The PS4 levels in peripheral blood, hypothalamus, anterior cortex, amygdala, and eyes increased severalfold at 20 min following intracisternal injection of 228 microg of this peptide, suggesting that it readily crosses the blood-brain barrier. The pituitary levels of PS4 and TRH-Gly, on the other hand, were decreased within 20 min by intracisternal PS4, suggesting PS4 stimulated the release of prepro-TRH peptides from the pituitary. Fresh rat and human serum rapidly degraded PS4, indicating that it may act primarily as a paracrine modulator of TRH effects in pituitary, brain, and reproductive system.
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PMID:Electroconvulsive seizures increase levels of PS4, the TRH-enhancing peptide [prepro-TRH(160-169)], in rat brain. 915 70

Glycine is a small neutral amino acid exhibiting weak anticonvulsant activities in vivo. Recently, studies have demonstrated that N-(benzyloxycarbonyl)glycine (1) antagonized seizures superior to glycine in addition to activity in the maximal electroshock (MES) test, a convulsive model where glycine is inactive. In the present study a series of ester and amide derivatives of 1 as well as esters of N-(3-phenylpropanoyl)glycine (5) have been prepared. The compounds were evaluated in the MES test as well as in several chemically induced seizure models. Among the derivatives investigated, N-(benzyloxycarbonyl)glycine benzylamide (16) was the most potent compound exhibiting an anticonvulsant activity in the MES test comparable to the drug phenytoin. Median effective doses (ED50) of 4.8 and 11.6 mg/kg were determined at 30 min and 3 h after i.p. administration, respectively. Compound 16 also effectively suppressed tonic seizures in different chemically induced models such as the strychnine, 3-mercaptopropionic acid, and pentylenetetrazole tests. Moreover, the compound studied here did not show acute neurotoxicity in the rotorod test up to a dose of 150 mg/kg. It is concluded that N-(benzyloxycarbonyl)glycine amides, especially 16, are potent anticonvulsant agents.
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PMID:N-(benzyloxycarbonyl)glycine esters and amides as new anticonvulsants. 943 18


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