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)

pH regulatory mechanisms in primary cultures of astrocytes from the cerebral cortex of neonatal audiogenic-seizure-susceptible DBA/2J (DBA) and genetically controlled C57BL/6J (C57) mice were studied with [14C]dimethyloxazolidine-2-4-dione (DMO) and [3H]-methyl-D-glucose (MDG). Effects of changing the concentration of Na+, K+, HCO3- or Cl- in medium, and/or of different transport blockers and metabolite inhibitor on intracellular pH (pHi) of cultured astrocytes were also studied. In nominal HCO3(-)-free HEPES-buffered Hanks' balanced salt solution (HEPES HBSS), when the pH of medium (pHo) was maintained at 7.4, the steady-state pHi of cultured astrocytes from DBA mice was 6.98 +/- 0.03, and that from C57 mice was 7.01 +/- 0.03. When the cells were incubated in HBSS containing 25 mM HCO3- and equilibrated with 5% CO2 (HCO3- HBSS, pHo = 7.4), pHi of both DBA and C57 astrocytes was approximately 0.1-0.15 pH units higher than that in HEPES HBSS. Reducing the pH or the Na+ concentration in media (pHo, [Na+]o) of either HEPES HBSS or HCO3- HBSS, pHi of both DBA and C57 astrocytes decreased markedly (0.25-0.45 pH units lower than the controls). The decrease in pHi was greater in HEPES HBSS than in HCO3- HBSS. Reducing the Cl- concentration ([Cl-]o) in either HEPES or HCO3- HBSS, pHi of astrocytes increased by 0.05-0.1 pH units. Increasing the K+ concentration ([K+]o) of or adding Ba2+ to the media increased the pHi of both DBA and C57 astrocytes accordingly. SITS, an anion transport inhibitor, decreased the pHi of both DBA and C57 astrocytes in HCO3- HBSS but not in HEPES HBSS. It enhanced the response of pHi to reduction in pHo. Amiloride, a Na(+)-H+ exchange inhibitor, decreased the pHi of both DBA and C57 astrocytes more in HEPES HBSS than in HCO3- HBSS. It enhanced the response of pHi to reduction in pHo and [Na+]o. Ouabain, an Na+,K(+)-ATPase inhibitor, decreased the pHi of cultured astrocytes in HEPES HBSS, but not in HCO3- HBSS. It also enhanced the response of pHi to changing pHo and [Na+]o in HEPES HBSS. Acetazolamide, a carbonic anhydrase inhibitor, decreased the pHi of astrocytes in both HEPES and HCO3- HBSS. Both bumetanide, an Na+,K+/Cl- cotransport blocker, and KCN, a metabolic inhibitor, produced no significant effect on the steady-state pHi or the response of pHi to changing ionic concentration in media in both DBA and C57 astrocytes.
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PMID:Studies on pH regulatory mechanisms in cultured astrocytes of DBA and C57 mice. 139 16

The activity of carbonic anhydrase (CA), a glial enzyme, was measured in the epileptic cortex of audiogenic DBA/2 mice and of cats with a freeze lesion. In mice, the activity increased with age from birth to 24 days, but were always higher in audiogenic mice than in normal C57/BL mice, reflecting species differences. The difference between the two strains increased sharply from 25 to 40 days of age, after the period of maximal audiogenic susceptibility. Acetazolamide, a CA-specific inhibitor, greatly decreased the seizure severity score of DBA/2 mice after a single intraperitoneal (i.p.) administration (150 mg/kg). After 24 days of age, when CA activities were high, the effect of acetazolamide was less important, suggesting that the increased cortical CA activity might reflect a protective mechanism. In cats with a freeze lesion, no significant changes in CA activities were observed in the actively discharging primary and secondary foci as compared with the nonepileptogenic perifocal cortex and the control cortex of sham-operated animals. The results indicate that the cortex of genetically susceptible audiogenic mice has an increased CA activity. The hypothesis of an adaptive glial mechanism, relating to the age-dependent decrease of seizure susceptibility in DBA/2 mice, is postulated.
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PMID:Glial contribution to seizure: carbonic anhydrase activity in epileptic mammalian brain. 189 18

Increases in regional cerebral blood flow have been described in a variety of cerebral pathologic states, including stroke and seizure disorders. The usefulness of technetium-99m-labeled cysteinate dimer as a marker in the measurement of regional cerebral blood flow was tested in five cynomolgus monkeys. To expand the range of blood flow to beyond the normal limits, 40 mg/kg i.v. of the carbonic anhydrase inhibitor acetazolamide was administered. Regional cerebral blood flow in all five monkeys was measured using radiolabeled microspheres (before and after acetazolamide) and the marker (after acetazolamide) in 60-70 samples from 12 brain regions. Acetazolamide significantly increased the mean +/- SEM regional cerebral blood flow measured using microspheres from 0.56 +/- 0.21 to 1.71 +/- 0.9 ml/min/g (p less than 0.01 for each region). A significant positive correlation was found between regional cerebral blood flow values calculated using microspheres and the marker after normalizing the values to those in the cerebellum (r = 0.773, p less than 0.0001). The mean +/- SEM regional cerebral blood flow determined using the marker in a single monkey (1.21 +/- 0.04 ml/min/g) did not differ significantly from that determined in the same monkey using microspheres (1.13 +/- 0.04 ml/min/g). These data support the potential use of this new brain perfusion imaging agent to assess regional cerebral blood flow over a clinically relevant range of blood flows.
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PMID:Regional cerebral blood flow and distribution of [99mTc]ethyl cysteinate dimer in nonhuman primates. 236 7

The generation of focal cortical epilepsy as observed in human partial complex seizures is presumably due to enhanced physiologic responses or paroxysmal depolarization shifts (PDSs). However, the molecular mechanism that underlies these phenomena remains unknown. It could be due to a genetically determined error in a structural or regulatory protein or to posttranslational events that modulate membrane excitability. Since neither neuronal PDSs or interictal EEG spikes are sufficient to produce clinical epilepsy, the clinical expression of epilepsy may need the breakdown of neuronal or glial mechanisms that limit the spread of seizures. Hence, biochemical membrane studies of neurons and glia are necessary to understand the expression of human and experimental epilepsy. This chapter will review the role of glia in controlling neuronal excitability and neuron-glia relationships in experimental and human epilepsy. Data exploring the hypothesis that glial control of extracellular K+ or (K+)o is deficient in focal epilepsy induced by cold lesions will be reviewed. The role of glial carbonic anhydrase (CA) and glial control of putative amino acid transmitters in audiogenic epilepsy will be discussed. In the cold lesion, (K+)o activation constants of synaptosomal (Na+,K+)-ATPase are significantly decreased in the actively firing chronic focus, suggesting that the apparent affinity of the synaptosomal enzyme for K+ was increased within epileptic tissue that was actively firing. Interestingly, while sustained focal paroxysms could raise synaptosomal (Na+,K+)-ATPase, glial (Na+,K+)-ATPase and its activation by (K+)o remained decreased during sustained paroxysms in both acute and chronic lesions. Moreover, while the decrease of the absolute level of glial enzyme activity was less evident 45 days after lesion production, the poor response of glial enzyme to (K+)o never reversed to "normal" values. Hence, these experiments provided new information that glial (Na+,K+)-ATPase responds to K+ in a different manner when compared to synaptic enzyme. Glial ATPase and its activation by (K+)o remain decreased in either actively discharging acute lesions or in the indolent chronic foci. This could mean a reduction in the ability of glial membranes to maintain (K+)o homeostasis. As already suggested by Dichter, the impairment in glial control of elevated (K+)o could be mainly responsible for the transition of interictal discharges to ictal episodes, within the primary and the secondary foci.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neuron-glia relationships in human and experimental epilepsy: a biochemical point of view. 287 19

The clinical utility of the carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ) is limited because of rapid development of tolerance to its effects. Tolerance is thought to develop as a result of glial cell proliferation and/or increased CA synthesis. DBA mice, susceptible to audiogenic seizures (AGSs) in an age-dependent manner, have increased CA activity as compared with C57 (non-audiogenic seizure susceptible) mice at 21 and 110 days of age. The present work utilized ACTZ to help determine the relationship between increased CA activity in brain and AGSs in DBA mice. Also, minimal electroshock seizure threshold (EST) was measured at various ages in DBA and C57 mice to determine age-related changes in CNS excitability. EST was significantly lower in DBA as compared with C57 mice at 18 days and between 40 and 115 days of age, suggesting that DBA mice remain hyperexcitable to electrical stimulation after they develop resistance to AGSs. ACTZ ED50s against maximal electroshock seizures (MES) were significantly higher in DBA as compared with C57 mice at 26,36, and 115 days of age. This finding correlates with higher CA activity in this strain at 110 days of age, noted previously. However, at 21 days of age, when CA activity is also higher in DBA versus C57 mice, there were no significant differences in ACTZ ED50s against MES between the strains. ACTZ ED50s against AGSs in DBA mice were considerably lower than ACTZ ED50s against MES in either strain, suggesting that a particular fraction of CA is intimately involved in the production of AGSs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute and chronic acetazolamide administration in DBA and C57 mice: effects of age. 308 35

The mechanism by which animals develop tolerance to the antiepileptic effects of the carbonic anhydrase (CA) inhibitor, acetazolamide, was explored using a quantitative immunocytochemical method. Cerebral cortex sections of DBA/2J mice susceptible to audiogenic seizures and of C57BL/6J nonsusceptible mice were stained with antibody to mouse CA II in controls and following treatment with acetazolamide (40 and 200 mg/kg) for 1, 3, and 5 days. The percentage increases in CA II fluorescent intensity of cells from C57 mice treated with 40 and 200 mg/kg acetazolamide over those of untreated mice were 22 and 36%, respectively, after 1 day, 32 and 40%, respectively, after 3 days, and 17 and 40%, respectively, after 5 days of treatment. The corresponding percentage increases in fluorescent intensity of cells from DBA mice over controls were 13 and 32%, respectively, after 1 day, 17 and 41%, respectively, after 3 days, and 26 and 58%, respectively, after 5 days of treatment. The fluorescent intensity of cells from untreated DBA mice was 35% greater than those of untreated C57 mice. In C57 mice the maximum amount of CA II per cell at each dose occurred 24 h after acetazolamide treatment, whereas the amount in DBA mice continued to increase with time and dose up to 5 days. The differences between the two strains can be explained by changes in distribution of CA II to subcellular locations or by defects in phosphorylation of the molecule.
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PMID:Induction of new carbonic anhydrase II following treatment with acetazolamide in DBA and C57 mice. 309 10

The relationships between inhibition of carbonic anhydrase (CA) activity in cytoplasmic, microsomal, and myelin subcellular fractions obtained from cerebral cortex, subcortex, and cerebellum and electroshock seizure threshold (EST) and modification of the extension/flexion (E/F) ratio following maximal electroshock seizures (MES) were ascertained in Swiss-Webster mice given 40 and 200 mg/kg acetazolamide. The parameters were determined at 1, 4, and 24 h after administration of acetazolamide. The results showed that changes in the E/F ratio induced by acetazolamide correlated linearly (r = 0.90) with changes in CA activity in the cytoplasm of the subcortex. However, there was an inverse power function correlation (r = 0.92) between EST and CA activity in the myelin fraction of the cerebral cortex. The time course of acetazolamide inhibition of CA activity in these two fractions also paralleled the time course of its effects on EST and E/F ratio. Thus, acetazolamide decreases susceptibility to seizures (raises EST) by inhibiting myelin CA and prevents spread of seizure activity by inhibiting CA in the cytoplasm of glial cells. The CO2 that accumulates as a result of CA inhibition in these two fractions causes profound changes in brain function.
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PMID:Correlation between effects of acute acetazolamide administration to mice on electroshock seizure threshold and maximal electroshock seizure pattern, and on carbonic anhydrase activity in subcellular fractions of brain. 309 9

The effect of long-term treatment with valproic acid (VPA) on zinc (Zn) metabolism was studied in 15 children with absence seizures. During treatment with VPA the erythrocyte Zn content was significantly lower than that found in controls matched for sex and age. Plasma and urine values of Zn and of copper were within normal limits. It is suggested that the anticonvulsive action of VPA may be mediated through its effect on the metabolism of Zn in the brain and the concomitant changes in the activity of the enzymes glutamic acid decarboxylase and carbonic anhydrase.
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PMID:Effect of valproic acid therapy on zinc metabolism in children with primary epilepsy. 310 54

The use of ion-sensitive microelectrodes enabled us to follow the dynamic changes in extracellular pH (pHe) together with those in the extracellular concentration of some biologically important ions, particularly K+ and Ca2+. Activity-related changes in pHe were studied in isolated spinal cords of frogs and in spinal cords of rats in vivo. Repetitive electrical stimulation of an afferent input led either to triphasic alkaline-acid-acid changes (90% of frogs) or to triphasic alkaline-acid-alkaline changes (10% of frogs and rats) with the greatest changes in the lower dorsal horns. The transient acid shift by as much as 0.15-0.25 pH units is dominant and builds up during the stimulation. The changes in pHe were also found in response to various adequate stimuli applied to the skin on the hind limb. Using specific inhibitors of Na+/H+ exchange, K+-Cl- co-transport, Cl-/HCO3- exchange, the Na+/K+ pump and carbonic anhydrase, we found pHe homeostasis to be impaired and stimulation-induced changes in pHe decreased. We conclude that the pHe changes evoked by electrical or adequate stimulation of an afferent input are not determined by changes in extracellular strong ion concentration differences due to accumulation of lactate, since we found no effect of NaF, a metabolic blocker of lactate production. However, lactate accumulation has been demonstrated during seizures, spreading depression and anoxia. Recently, it has been recognized that the observed pHe changes can affect permeability of membrane ionic channels, neuronal excitability and glial cell function.
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PMID:Extracellular pH and stimulated neurons. 320 66

Novel sugar sulfamate 1 (McN-4853, topiramate) has been found to exhibit potent anticonvulsant activity analogous to that of phenytoin. In the maximal electroshock seizure test, orally at 2 h in mice, 1 had an ED50 of 39 mg/kg. Orally, 1 had a duration of action in excess of 8 h. Other aspects of the pharmacology of 1, as well as neurochemistry and carbonic anhydrase inhibition, are discussed. The conformational behavior of 1 in solution and in the solid state is discussed. A series of analogues of 1 were synthesized and examined for anticonvulsant properties.
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PMID:Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate and related compounds. 357 76


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