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  • Blackwell Science Ltd  (10)
  • 1990-1994  (10)
  • 1925-1929
  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: A 3.7-kb cDNA fragment, designated rat-XT1, was isolated from a rat whole-brain cDNA library. The nucleotide sequence of XT1 codes for a 727 amino acid protein with a calculated molecular mass of 81,139 Da and 12 putative transmembrane domains. This protein shares significant homology (28–32%) with the monoamine- (dopamine, norepinephrine, serotonin), amino acid- (taurine, proline, GABA, glycine), choline-, and betaine-, Na+/Cl−-dependent transporters. The homology is especially high within the first, second, sixth, and eighth transmembrane domains (45–75%). Thus, XT1 clearly belongs to the Na+/Cl−-dependent neurotransmitter transporter superfamily. However, XT1 may define a new subfamily of transporter because it differs structurally from other members of this family in that the extracellular loop linking transmembrane domains 7 and 8 and the C-terminal tail are significantly larger in size. Transient or stable expression of rat-XT1 failed to confer to the transfected cells the ability to transport actively any of the 〉60 established or putative neurotransmitter substances assessed. Northern blot analyses of peripheral and neural tissues demonstrated that expression of the 8-kb XT1 mRNA is essentially restricted to the nervous system. In situ hybridization demonstrated a broad but discrete localization of XT1 message in the CNS, particularly in the cerebellum (Purkinje and granular cell layers), the hippocampus (pyramidal and granular cell layers), and the thalamus and throughout the cerebral cortex. This distribution parallels that of the neurotransmitters glutamate and aspartate; however, neither of these excitatory amino acids is a substrate for transport. One noticeable exception to the codistribution of the mRNA for rat-XT1 and these excitatory neurotransmitters is the cerebellar Purkinje cell layer, in which GABAergic neurons are localized. The gene encoding for XT1 is localized to the mouse chromosome 3 in the vicinity of the locus for the mouse neurological disorder spastic (spa).
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The time course of changes in extracellular glutamic acid levels and their Ca2+ dependency were studied in the rat striatum during focal cerebral ischaemia, using microdialysis. Ischaemia-induced changes were compared with those produced by high K+-evoked local depolarization. To optimize time resolution, glutamate was analysed continuously as the dialysate emerged from the microdialysis probe by either enzyme fluorimetry or biosensor. The Ca2+ dependency of glutamate changes was examined by perfusing the probe with Ca2+-free medium. With normal artificial CSF, ischaemia produced a biphasic increase in extracellular glutamate, which started from the onset of ischaemia. During the first phase lasting ∼10 min, dialysate glutamate level increased from 5.8 ± 0.9 µM· min−1 to 35.8 ± 6.2 µM where it stabilized for ∼3 min. During the second phase dialysate glutamate increased progressively to its maximum (82 ± 8 µM), reached after 55 min of ischaemia, where it remained for as long as it was recorded (3 h). The overall changes in extracellular glutamate were similar when Ca2+ was omitted from the perfusion medium, except that the first phase was no longer detectable and, early in ischaemia, extracellular glutamate increased at a significantly slower rate than in the control group (2.2 ± 1 µM· min−1; p 〈 0.05). On the basis of these data, we propose that most of the glutamate released in the extracellular space in severe ischaemia is of metabolic origin, probably originating from both neurons and glia, and caused by altered glutamate uptake mechanisms. Comparison with high K+-induced glutamate release did not suggest that glutamate “exocytosis,” early after middle cerebral artery occlusion, was markedly limited by deficient ATP levels.
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  • 3
    ISSN: 1468-2982
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In November 1990 a nationwide survey of migraine was conducted in France on a representative sample of residents aged 15 years and older. The diagnosis of migraine was based on the International Headache Society (IHS) classification. In a previous study, we validated a diagnostic algorithm which classifies headache sufferers as IHS migraine, “borderline” migraine, possible migraine and non-migrainous headache. The overall prevalence of migraine patients with the IHS criteria in the present study was 8.1%; another 4% were classified as “borderline” migraine, which we in fact considered as definite migraine. Age, gender and occupation were found to be risk factors for migraine. Neither frequency and duration of attacks nor length of time of disease differed with gender. Expressed intensity of attacks, however, was greater in females.
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  • 4
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Spermine and other polyamines both stimulate and inhibit N-methyl-d-aspartate receptor function, probably by interacting with two separate sites. To characterize these two actions, the effect of spermine on the binding kinetics of the channel blocker [3H]dizocilpine was studied in the presence of glutamate and glycine. Low concentrations (10 µM) of spermine increased the association and dissociation rates without modifying equilibrium binding, indicating that spermine increases the accessibility of [3H]dizocilpine to the channel by interacting with a high-affinity, stimulatory site. At higher concentrations (1 mM), spermine markedly decreased equilibrium [3H]-dizocilpine binding by decreasing both affinity and Bmax, indicating that spermine allosterically inhibits binding by interacting with a second, low-affinity site. The presumed polyamine antagonists arcaine, diethylenetriamine, and 1,10-diaminodecane completely inhibited equilibrium [3H]dizocilpine binding, probably by interacting with the inhibitory polyamine site or other sites, but not with the stimulatory polyamine site. Low concentrations (10 µM) of ifenprodil completely reversed the increase in association rate produced by spermine, whereas higher concentrations (IC50 = 123 µM) inhibited equilibrium binding, indicating that ifenprodil is both a potent antagonist of the stimulatory site and a low-affinity ligand of the inhibitory site. The polyamine agonists spermine, spermidine, and neomycin interacted with the inhibitory site, but produced only partial inhibition of equilibrium [3H]dizocilpine binding.
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  • 5
    ISSN: 1468-2982
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand 123I-3-iodo-6-methoxybenzamide (123I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of 123I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities.
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  • 6
    ISSN: 1468-2982
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The results of the very first large-scale placebo-controlled dose-response trial with the novel selective 5-hydroxytryptamine1-like (5HT1-like) receptor agonist sumatriptan are presented. We studied the efficacy and tolerability of subcutaneous injections of 1 mg, 2 mg and 3 mg of sumatriptan in alleviating migraine attacks in a double-blind, placebo-controlled, parallel-group, multicentre clinical trial. Six-hundred and ninety patients were randomized and 685 received study medication. At 30 min, reduction of headache severity to mild or none (primary efficacy endpoint) was achieved in 22.% (95% CI: 15–28%) of placebo-treated patients and in 39% (CI: 31–46%) of patients treated with 1 mg sumatriptan, 44% (CI: 36–51%) treated with 2 mg sumatriptan and 55% (CI: 48–63%) treated with 3 mg sumatriptan. Differences from placebo were 17% (CI: 8–27%) for 1 mg sumatriptan, 22% (CI: 13–32%) for 2 mg sumatriptan and 34% (CI: 24–44%) for 3 mg sumatriptan (p 〈 0.001 for all three comparisons). Other migraine symptoms were also more effectively treated by sumatriptan than by placebo. Subsequently, an open-label 3 mg dose subcutaneous sumatriptan was given to partial or non-responders. Thirty minutes after this open dose the response rate to sumatriptan had improved to between 70 and 80%. Adverse events after sumatriptan were minor and short-lived. We conclude that subcutaneous sumatriptan is well tolerated in doses up to 3 + 3 mg and may rapidly abort migraine attacks.
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  • 7
    Electronic Resource
    Electronic Resource
    USA/Oxford, UK : Blackwell Science Ltd
    Cephalalgia 12 (1992), S. 0 
    ISSN: 1468-2982
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
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  • 8
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Paralytic tremor (pt) is a sex-linked mutation in rabbit that affects myelination of the CNS. Myelin in the pt brains represents ∼30% of the normal levels. Previously we showed that the pt mutation affects primarily proteolipid protein (Plp) gene expression. In the present study we investigated the relative effect of the pt mutation on two distinctive Plp gene products, PLP- and DM-20-specific messenger RNAs. Our results showed that both PLP and DM-20 are affected and that the ratio DM-20/PLP was higher in pt rabbits than in age-matched controls. We sequenced normal rabbit PLP cDNA and characterized pt mutation at the DNA level. Rabbit PLP sequence, deduced from cDNA, differs from the human protein only at Thr198. Sequence analysis of the mutant cDNA revealed a transversion T → A in exon 2 of the Plp gene. This point mutation, which is placed at the end of the first potential transmembrane domain, results in a substitution of His36 by a glutamine. This transversion abolishes a restriction site that enabled us to screen a large number of animals and observe a perfect correlation between the pt allele and the abnormal phenotype.
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  • 9
    Electronic Resource
    Electronic Resource
    USA/Oxford, UK : Blackwell Science Ltd
    Cephalalgia 13 (1993), S. 0 
    ISSN: 1468-2982
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Migraine patients have chronically low systemic 5-HT, predisposing them to develop migrainous headache once an attack has been initiated. Changes in platelet 5-HT content are not causally related, but reflect similar changes at a neuronal level. Stimulation of vascular 5-HT1 receptors, probably located in the vessel wall within the dural vascular bed, may alleviate the headache and associated symptoms, but does not interact with earlier mechanisms within the pathophysiological cascade. These receptors are of an as yet unidentified 5-HT1 subtype, closely resembling, but not identical to 5-HT1D receptors. Activation of these receptors results in vasoconstriction, inhibiting depolarization of sensory perivascular afferents within the trigemino-vascular system and thus stopping the headache. Additional inhibition of the release of vasoactive neuropeptides may be involved, but seems to be of only secondary clinical importance.
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  • 10
    Electronic Resource
    Electronic Resource
    USA/Oxford, UK : Blackwell Science Ltd
    Cephalalgia 12 (1992), S. 0 
    ISSN: 1468-2982
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: After the synthetic serotonin 5-hydroxytryptamine (5-HT) became available in the early 1950s, attempts were soon under way to study the nature of 5-HT receptors. Using the guinea-pig isolated ileum, Gaddum and Picarelli (1957) suggested that 5-HT-induced contractions were mediated by a morphine-sensitive “M” receptor located on the parasympathetic ganglion and a dibenzyline-sensitive “D” receptor located on the smooth muscle. Though this classification was used during the next three decades, it was realized that some effects of serotonin, for example vasoconstriction within the carotid vascular bed, were not mediated by either “M” or “D” receptors. When radioligand binding studies led to the identification of 5-HT1 and 5-HT2“receptors” in the rat brain membranes, it became increasingly apparent that the two receptor classifications were not identical. Thus, a new framework for serotonin receptor nomenclature and classification was proposed: 5-HT1-like (5-HT1), 5-HT2 (formerly “D”) and 5-HT3 (formerly “M”) receptors. At the present time, several subtypes of 5-HT1receptors as well as a 5-HT4 receptor are also recognized. As the serotonin receptor classification was emerging to indicate that carotid vasoconstriction by serotonin is mediated by a subtype of 5-HT1 receptors, on the migraine front it was being suggested that the disease is associated with vasodilatation within the cranial extracerebral circulation and deranged serotonin metabolism and that certain antimigraine drugs caused a selective carotid vasoconstriction, probably via serotonin receptors. Therefore, Humphrey and colleagues conceived that synthesis of serotonin derivatives may lead to a compound that would elicit highly selective carotid vasoconstriction and abort migraine attacks. Indeed, via the synthesis of 5-carboxamidotryptamine and AH25086, sumatriptan was designed. The drug acts as an agonist at the vasoconstrictor 5-HT1receptor subtype and has proved highly effective in the therapy of migraine attacks.
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