Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9NRP7 (fused)
 58,367 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several mouse mutations cause unstable locomotion, tremor, seizures, and a reduced lifespan because of deficient myelin formation in the central nervous system. Mutant alleles at the shiverer (shi) locus are the only ones in this series with a selective molecular defect, namely, in myelin basic proteins (MBPs), which are virtually absent in shi homozygotes and 50% reduced in heterozygotes. In the present study, backcross and intercross matings indicate recombination of 21.2 +/- 3.3% between myelin deficient, shimld, and fused phalanges, syfp, a marker near the middle of chromosome 18. Recombination of shimld with twirler (Tw), a marker near the centromere, is 45.7 +/- 4.9%. Thus, the shi locus maps near the distal end of mouse chromosome 18 and is the first available marker for this region. Given the evidence of other workers that an MBP locus maps to the same mouse chromosome, and that part of this chromosome may be syntenic with an MBP-PEPA region on human chromosome 18, it is likely that shi is in or near an MBP gene.
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PMID:Shiverer gene maps near the distal end of chromosome 18 in the house mouse. 241 73

Ultrastructural changes in hippocampal granule cells, mossy fibers and mossy fiber boutons were examined following the administration of picrotoxin in adult rats. Generalized seizures occurred within 5-10 min after the intraperitoneal injection of picrotoxin. The electron-microscopic examination of hippocampal tissues from rats that had been perfused with fixative during the seizure revealed that the large dense-core vesicles increased in number and accumulated on the presynaptic membranes of mossy fiber boutons; some of these vesicles appeared to be fused with the membranes, and omega-shaped exocytotic profiles were frequently seen. Furthermore, greatly increased numbers of coated vesicles (60-90 nm in diameter) were observed on the maturing faces of Golgi fields of granule cells. Thus, our study not only indicates an increased incidence of exocytosis of large dense-core vesicles during picrotoxin-induced seizures, but also suggests that these vesicles are replaced in excess from the perikaryon of the granule cell.
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PMID:Ultrastructural changes in granule cell somata and mossy fibers of the rat hippocampus during picrotoxin-induced convulsions. 253 36

Kainic acid (KA, 8-15 ng) was injected into the amygdala of conscious freely moving rats via chronically implanted fused silica cannulas. At 15-25 min after the injection, most rats suffered a limbic seizure attack of short duration, consisting of mastication, forelimb clonus, and raising on hind limbs, behaviorally indistinguishable from kindled seizures. Typically, the attack was followed by stereotypies, intense exploration, and by 1 or 2 more attacks. About 60 min after the injection, most rats appeared normal again and histopathological changes in their brains did not exceed those seen in vehicle-injected rats. In 3 cases, however, recurrent seizures culminated in behavioral status epilepticus 60-90 min after the injection. The status epilepticus was stopped by i.p. injection of diazepam (10 mg/kg) after a duration of 10 min (1 case) and 30 min (2 cases), respectively. After 10 min status epilepticus, we observed marginal neuronal damage with slight gliosis in both hippocampi (CA3 and CA1); after 30 min, hippocampal histopathology was more pronounced, with additional necrosis of the ipsilateral piriform cortex. After 0.8 microgram KA, a hundredfold higher dose, the incidence of limbic seizures during the first 40 min was not significantly higher (9/12) than after the lower KA doses (13/19). However, a significantly higher proportion of rats exhibited long-lasting seizure activity, associated with confluent destruction of CA3 pyramidal cells and additional seizure-related brain damage. Our results show that limbic motor seizures do not inevitably lead to histopathological changes in the brain, provided they do not culminate in a state of permanent seizure activity.
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PMID:Limbic seizures without brain damage after injection of low doses of kainic acid into the amygdala of freely moving rats. 274 56

The relationship between seizure propensity and the vascular anatomy of the anterior cerebral arteries, or stroke induced by unilateral ligation of the common carotid artery, was investigated utilizing well differentiated colonies of seizure-prone (SP) and non-seizure-prone (NSP) gerbils. Twenty SP and 20 NSP gerbils were perfused with a latex dye and the vascular patterns of the anterior cerebral arteries (ACA) were analyzed. In addition, 30 SP and 30 NSP gerbils were subjected to unilateral ligation of the common carotid artery and the number developing stroke (determined by clinical observation as well as by microscopic examination of the brain) was recorded. We found that in all animals the ACAs formed a fused-central vessel which vascularized the olfactory bulbs, as well as two lateral vessels (rostral arteries) that vascularized a previously undescribed nasal plexus. Neither the vascular pattern of the ACA, nor the frequency of occurrence of stroke following unilateral ligation was related to seizure propensity.
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PMID:Brain vasculature and induced ischemia in seizure-prone and non-seizure-prone gerbils. 705 30

An apparently balanced de novo translocation between chromosomes X and 20, 46,X,t(X;20)(Xp20q;Xq20p), was identified in a severely retarded 13-year-old female with macrocephaly, bilateral overfolded pinnae, elbow contractures, clinodactyly, and seizures. BudR-pulse studies show the normal X chromosome to be late replicating in both lymphocytes (50 cells) and skin fibroblasts (25 cells). An HPRT deficient Chinese hamster line was fused with lymphocytes from the patient, and hybrid lines were derived in HAT medium. Cytogenetic and biochemical analyses of these hybrid lines show that the locus for adenosine deaminase is in the cen leads to qter region and that the locus for inosine triphosphatase is in the pter leads to cen region of human chromosome 20.
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PMID:Regional mapping of ADA and ITP on human chromosome 20: cytogenetic and somatic cell studies in an X/20 translocation. 737 31

The structure of rat brain-derived neurotrophic factor (BDNF) gene is complex; four 5' exons are linked to separate promoters and one 3' exon is encoding the BDNF protein. To analyze the relative importance of the regulatory regions in vivo, we have generated transgenic mice with six different promoter constructs of the BDNF gene fused to the chloramphenicol acetyl transferase reporter gene. High level and neuronal expression of the reporter gene, that in many respects recapitulated BDNF gene expression, was achieved by using 9 kb of genomic sequences covering the promoter regions that lie adjacent to each other in the genome (promoters I and II and promoters III and IV, respectively) and by including sequences of BDNF intron-exon splice junctions and 3' untranslated region in the constructs. The genomic regions responsible for the in vivo upregulation of BDNF expression in the axotomized sciatic nerve and in the brain after kainic acid-induced seizures and KCl-induced spreading depression were mapped. These data show that regulation of the different aspects of BDNF expression is controlled by different regions in vivo, and they suggest that these promoter constructs may be useful for targeted expression of heterologous genes to specific regions of the central and peripheral nervous systems in an inducible manner.
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PMID:Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced expression in transgenic mice. 782 14

We examined 2 siblings with schizencephaly. A 23-year-old female (Case-1) had a mild left hemiparesis, and her 25-year-old brother (Case-2) presented a quadriplegia. Both cases achieved a borderline intellectual level and both had seizure disorders. The magnetic resonance imaging (MRI) of Case-1 revealed thickened gray matter around the fused schizencephalic clefts in the bilateral frontal lobes, mild ventricular enlargement and absence of the septum pellucidum. And, the MRI result of Case-2 disclosed similar but more severe abnormalities. The positron emission tomography (PET) using 18F-Fluoro-2-deoxy-D-glucose of Case-1 demonstrated focal hypermetabolic activity in the ectopic gray matter with the absence of epileptic discharges on the electroencephalogram on the day of PET study. And the single photon emission computed tomography (SPECT) using 123I-N-isopropyl-p-iodoamphetamine of Case-1 delineated focal hyperperfusion in the same lesions. The PET and SPECT findings are unique, since previous reports have indicated focal hypoperfusion and hypometabolism in abnormal gray matter. Familial schizencephaly is a very rare malformation, and this is the first report of that in Japan. Further evaluation in similar cases is needed to determine the pathophysiology of this anomaly.
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PMID:[Two siblings with familial schizencephaly--report of a family and review in relation to clinical features and neuroradiological findings]. 893

We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that was discovered in our laboratories. Systematic structural modification of the parent compound was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacological importance of several molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4, 5-fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the hydrindane carbocyclic analogues 95, 96, 100, and 104 are presented. We also report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite 93a required the preparation and use of the novel sulfur dichloride reagent, BocN=SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ-37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than 1 in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, 2 was not active in diverse in vitro receptor binding and uptake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e. g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examination of several analogues of 2 (83a-r, 85-87, 90a, 91a, 93a) indicated that potent anticonvulsant activity is associated with relatively small alkyl substituents on nitrogen (Me/H, 83a; Me/Me, 83m; Et/H, 83b; allyl/H, 83e; c-Pr/H, 83j; c-Bu/H, 83k) and with limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite 87a/b. The potent anticonvulsants 83a and 83j had greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity. The alpha-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation (ref 29), were nearly twice as potent as topiramate (1). The L-fructose enantiomers of 1 (106) and 2 (107), synthesized from L-sorbose, were found to have moderate anticonvulsant activity, with eudysmic ratios (MES ED50 in mice at 4 h, po) of 1:106 = 1.5 and 2:107 = 3.5. The log P values for 1 and 2 were determined experimentally to be 0.53 and 0.42, respectively, which are less than the optimal 2.0 for CNS active agents. However, analogues with more favorable calculated log P (clogP) values, in conjunction with just minor steric perturbation according to the developed SAR profile, such as 47 (clogP = 2.09), 83m (1.93), and 86 (1.50), did not display improved potency: 47 is less potent than 1, 83m is equipotent with 2, and 86 is less potent than 2. Although the measured log P value for diethyl analogue 31 is 1.52, this did not translate into enhanced potency relative to 1. (ABSTRACT TRUNCATED)
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PMID:Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. 954 21

Peri-ictal single-photon emission computed tomography (SPECT) of the brain is increasingly used in localizing the seizure focus in presurgical evaluation of patients with partial epilepsy. However, traditional side-by-side visual interpretation of ictal and interictal SPECT films is hampered by differences in slice location and tracer activity. Precise correlation of the seizure focus with a high-quality image of the underlying brain anatomy can improve the physician's understanding of seizure neurophysiology and assist in surgical planning. Computer-based methods have been developed for aligning, normalizing, and subtracting digital ictal and interictal SPECT images of the patient's brain to produce a map of the blood flow changes occurring between the seizure and resting states. These maps are then aligned with a high-resolution magnetic resonance image (MRI) of the patient's brain anatomy and fused to identify anatomical regions involved in the seizure. The purpose of this article is to review the technical components and clinical implementation of subtraction ictal SPECT, as well as to discuss recent technological advances that could extend and improve the diagnostic and localizing capacity of this method.
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PMID:Subtraction ictal SPECT coregistered to MRI for seizure focus localization in partial epilepsy. 1085 23

According to the cDNA sequence of anti-neuroexcitation peptide of scorpion Buthus martensii Karsch, the putative mature anti-neuroexcitation peptide (ANEP) encoding DNA fragment was obtained by a PCR method, then was cloned into expression plasmid pET28a, fused with His tag at its 3' end. When expressed in E. coli BL21 (DE3), the expression of recombinant ANEP was 15% of total cellular proteins, while most recombinant ANEP products existed in the form of insoluble inclusion bodies. Coexpression of molecular chaperones or protein disulfide isomerase could not improve its solubility. The recombinant ANEP in the cell lysate was purified to homogeneity by metal chelating affinity chromatography and Superdex 30 chromatography. In bioassay with convulsive mice model induced by thiosemicarbazide, recombinant ANEP could apparently delay the convulsion seizure of model animals by 18% and showed anti-neuroexcitatory activity.
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PMID:Expression of anti-neuroexcitation peptide (ANEP) of scorpion Buthus martensii Karsch in Escherichia coli. 1132 Nov 63


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