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)

Carbonic anhydrase (CA) activity plays an important role in controlling cerebrospinal fluid production and also influences neuroexcitation and susceptibility to seizures. Until recently, CA II was the only CA demonstrated in brain. Its distribution is limited to the epithelial cells of the choroid plexus and to the myelin-forming cells, the oligodendrocytes. In this report, we present immunoblots, using an antibody raised to CA IV from rat lung, that show that CA IV is also present in rat and mouse brain. Results of immunohistochemistry and immunoelectron microscopy on sections from rat and mouse brain are presented that show the distribution of CA IV to be quite distinct from that of CA II. CA IV is expressed on and is limited to the luminal surface of endothelial cells of cerebral capillaries. These results establish CA IV as a cytochemical marker associated with the blood-brain barrier and suggest an important role for CA IV in CO2 and HCO3- homeostasis in brain.
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PMID:Carbonic anhydrase IV on brain capillary endothelial cells: a marker associated with the blood-brain barrier. 149 71

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

Mutant Car2n/Car2n mice deficient in carbonic anhydrase II (CA II; a major brain CA isozyme) suffer from systemic acidosis and are more resistant to experimental seizures than their normal littermates (+/+ or +/Car2n). The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been shown to contribute to long-term potentiation (LTP) of synaptic transmission, hypoxic/ischemic neuronal injury and to be blocked by extracellular protons (acidosis). We compared the effects of hypoxia on synaptic transmission and LTP in field CA1 of hippocampal slices from CA II-deficient mice to their normal littermates. Slices were subjected to successive 5, 10 and 15 min-periods of hypoxia with 30 min-recovery periods in between. Hippocampal slices from mutant, CA II-deficient mice, were more resistant to all periods of hypoxia tested than slices from normal littermates. In a separate set of mutant and normal slices, there were no differences in LTP of population spike amplitude. The relative resistance of CA II-deficient mice to hypoxia-induced damage may be a consequence of severe interstitial acidosis. The sustained influence of increased extracellular proton concentrations may change the characteristics of NMDA receptors resulting in an increased resistance of synaptic transmission in CA II-deficient mice to hypoxia compared to controls.
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PMID:Resistance of hippocampal synaptic transmission to hypoxia in carbonic anhydrase II-deficient mice. 774 11

Carbonic anhydrase (CA) II is the major CA isozyme in the brain, where it participates in acid-base homeostasis, fluid transport, and myelin synthesis. The CA II deficiency [CA(II)D] mutation in the mouse results in structural changes in the glial cells in the CNS and in decreased susceptibility to seizures, but no detectable changes in myelin yield and ultrastructure. We compared the CA isozymes in brain and spinal cord fractions, as well as in purified myelin, between CA(II)D and control mice. CA(II)D resulted in a much lower total CA specific activity in all tissues examined but in higher CA IV specific activities in soluble and membrane-associated fractions and pure myelin. Western blots of purified myelin showed a band corresponding to CA IV in CA(II)D mice. This band was weak or undetectable in myelin samples from normal mice. Immunocytochemical staining demonstrated CA IV in oligodendrocytes and myelinated tracts in normal mouse brains and stronger staining of the same structures in brains of CA(II)D mutants. We conclude that CA(II)D mutation in the mouse up-regulates CNS CA IV. We speculate that this up-regulation could mitigate the effect of CA(II)D on myelin formation and maintenance.
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PMID:Up-regulation of carbonic anhydrase isozyme IV in CNS myelin of mice genetically deficient in carbonic anhydrase II. 820 39

Mice deficient in carbonic anhydrase II (CA II) were tested along with their normal littermates for susceptibility to seizures induced by flurothyl and loud sound at ages 10-180 days. In the flurothyl seizure model, CA II-deficient mice displayed increased resistance to clonic seizures from 32 to 90 days of age, whereas tonic-clonic seizures were suppressed at all ages. The mortality of CA II-deficient mice was significantly decreased at ages 19-40 days. The incidence of sound-induced seizures was very low and no difference between CA II-deficient and normal mice was found. The anticonvulsant effect of CA II deficiency appears to be dependent on seizure model and seizure type and to have age-specific characteristics.
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PMID:Developmental changes in seizure susceptibility in carbonic anhydrase II-deficient mice and normal littermates. 848 54

In this paper we review our data from in vivo and in vitro experiments with mutant, carbonic anhydrase II (CA II) deficient mice (Car2n/Car2n mutants) compared to their nonmutant littermates (Car2n/+ or +/+). In vivo, mutant mice were more resistant to flurothyl-, pentylenetetrazol, and loud sound-induced seizures than normal littermates. The increased resistance to flurothyl seizures was age dependent for clonic seizures, occurring after 19 days of age and disappearing after 90 postnatal days. In in vitro experiments, synaptic transmission in hippocampal slices from mutant mice were more resistant to hypoxia than synaptic transmission in slices from normal littermates. There was almost no difference in hippocampal CA1 long-term potentiation of synaptic transmission between mutants and nonmutants. However, studying in vitro epileptogenesis, we found hippocampal slices from mutants to be more prone to seizures in the low Mg2+ environment than slices from normal littermates. This striking difference between in vivo and in vitro seizures susceptibility in CA II-deficient mutants suggests and existence of an anticonvulsant factor present in conditions in vivo, but not in vitro. We suggest that extracellular proton concentrations (extracellular pH) acting as N-methyl-D-aspartate (NMDA) receptor antagonist may be such a factor. Mutant mice suffer from severe systemic acidosis that can decrease NMDA receptor function and thus be anticonvulsant in vivo. However in vitro, the steady pH of perfusing solution is relatively alkalinic for mutant mouse slices enhancing the thus NMDA receptor conductance and leading to proconvulsant effects. Thus, the anticonvulsant action of CA inhibition in vivo may be mediated by acidotic extracellular pH rather than an accumulation of CO2 as suggested previously.
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PMID:Anticonvulsant action of carbonic anhydrase inhibition. 871 46

Brain pH is thought to be an influential factor in determining susceptibility to seizures. We compared the susceptibility of brain slices from carbonic anhydrase II (CA II)-deficient mice to epileptiform activity induced by low extracellular [Mg2+], with slices from normal littermates, both bathed in artificial cerebrospinal fluid at pH 7.3. In both entorhinal cortex and hippocampal field CA1, epileptiform activity started earlier in CA II-deficient slices. Raising extracellular [CO2] (20%; extracellular pH, 6.7) reversibly blocked the epileptiform activity in normal, but not in CA II-deficient, slices. The data, combined with previous in vivo findings showing an increased resistance of mutants to seizures, suggest the presence of in vivo anticonvulsant acidosis with long-term compensatory changes that lead to in vitro 'proconvulsant' behavior in CA II-deficient slices clamped at pH 7.3.
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PMID:Increased susceptibility of brain slices from carbonic anhydrase II-deficient mice to low [Mg2+]O-induced seizures. 872 70

Carbonic anhydrases (CAs) are important enzymes in the central nervous system (CNS), where they participate in regulating cerebrospinal fluid (CSF) secretion, blood-brain barrier and glial cell function. Using RT-PCR we found CA XII mRNA in rat and mouse brain. Cloning of rat CA XII revealed 94% homology with the mouse CA XII. To map the putative functional roles of different CAs, we studied the expression and localization of CA II, CA IV, CA VII, CA-related protein (CA-RP) VIII and CA XII mRNAs in rat brain after kainic acid induced epileptic seizures using Northern blot analysis and in situ hybridization. The expression of CA IV, CA VII and CA-RP VIII was somewhat similar: they were expressed in the cortex, hippocampus and midbrain structures and their expression did not change after the kainic acid treatment. The expression of CA II was concentrated in the white matter structures, which is in line with the preferential expression of CA II in the oligodendrocytes. High levels of CA II mRNA were also detected in the choroid plexus. Surprisingly, CA II was induced 3-12 h after seizures in the vulnerable CA1 region. CA XII was expressed in dentate granule cells, cortex and choroid plexus. Kainic acid stimulated CA XII expression throughout the cortical layer I. The observed hippocampal induction of CA II may indicate a pro-apoptotic and/or epileptogenic role of CA II after prolonged seizures. The physiological significance of the observed cortical induction of CA XII remains obscure. Cytosolic CA II is known to participate in CSF secretion, and the high expression of CA XII in the choroid plexus suggests an analogous role for this membrane-bound isozyme.
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PMID:Expression of carbonic anhydrases II, IV, VII, VIII and XII in rat brain after kainic acid induced status epilepticus. 1627 2

By using a proteomic approach, we found increased levels of carbonic anhydrase II (CA II) in the brain of Ts65Dn mice, a mouse model for Down syndrome (DS). Further immunoblot analyses showed that the levels of CA II are increased not only in the brain of adult Ts65Dn mice but also in the brain of infants and young children with DS. Cellular localization of the enzyme in human brain, predominantly in the oligodendroglia and primitive vessels in fetal brain and in the oligodendroglia and some GABAergic neurons postnatally, was similar in DS subjects and controls. Given the role of CA II in regulation of electrolyte and water balance and pH homeostasis, up-regulation of CA II may reflect a compensatory mechanism mobilized in response to structural/functional abnormalities in the developing DS brain. However, this up-regulation may also have an unfavorable effect by increasing susceptibility to seizures of children with DS.
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PMID:Increased levels of carbonic anhydrase II in the developing Down syndrome brain. 1808 50

Brain carbonic anhydrases (CAs) are known to modulate neuronal signalling. Using a novel CA VII (Car7) knockout (KO) mouse as well as a CA II (Car2) KO and a CA II/VII double KO, we show that mature hippocampal pyramidal neurons are endowed with two cytosolic isoforms. CA VII is predominantly expressed by neurons starting around postnatal day 10 (P10). The ubiquitous isoform II is expressed in neurons at P20. Both isoforms enhance bicarbonate-driven GABAergic excitation during intense GABAA-receptor activation. P13-14 CA VII KO mice show behavioural manifestations atypical of experimental febrile seizures (eFS) and a complete absence of electrographic seizures. A low dose of diazepam promotes eFS in P13-P14 rat pups, whereas seizures are blocked at higher concentrations that suppress breathing. Thus, the respiratory alkalosis-dependent eFS are exacerbated by GABAergic excitation. We found that CA VII mRNA is expressed in the human cerebral cortex before the age when febrile seizures (FS) occur in children. Our data indicate that CA VII is a key molecule in age-dependent neuronal pH regulation with consequent effects on generation of FS.
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PMID:Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures. 2388 Oct 97


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