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)

The mechanism by which tolerance develops to the anticonvulsant effects of acetazolamide (AZM) was investigated in Swiss-Webster mice. The effects of single and six daily doses of 40 mg or 200 mg/kg AZM on electroshock seizure threshold (EST), maximal electroshock (MES) seizure pattern, and on the activity and total amount of carbonic anhydrase II (CAII) in various subcellular fractions (cytosol, microsomes, and myelin) of cerebral cortex, cerebellum, and brainstem were assessed. The activity of CAII was measured by microassay, and the total amount was measured by immunoassay methods developed in this laboratory. From the activity (units per microgram of protein) and total amount (nanograms per microgram protein) data, the specific activity (units per nanogram CAII) of the enzyme was calculated. With multiple doses, tolerance developed to both elevation of the EST and modification of the MES pattern noted with single doses of AZM. Accompanying the development of tolerance to the anticonvulsant effects of AZM was an increase in both the activity and specific activity of CAII in the various subcellular fractions and areas of the brain. The effects were dose dependent. Tolerance to the EST-elevating effects of AZM correlated with increases in the activity, total amount, and specific activity of CAII in the myelin fraction of the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of tolerance to the anticonvulsant effects of acetazolamide in mice: relation to the activity and amount of carbonic anhydrase in brain. 249 45

In the choroid plexus carbonic anhydrase II (CAII) supports the transport of bicarbonate ions, sodium ions, and water from blood to the CSF, and in the myelin sheath CAII supports compaction of myelin by stimulating cotransport of ions and water out from between the myelin membranes. In view of the latter, it is surprising that mutant mice deficient in CAII (Car-2n) have compact myelin. Since myelin basic protein also takes part in myelin compaction, we bred double CAII-deficient, myelin-deficient (Mld) mutant mice, in which the adults would have some compact myelin sheaths and a partial deficiency in myelin basic protein, with a view to examining oligodendrocytes and myelin sheaths in the double mutant. Like the parent Mld strain, the double mutants displayed tremors and seizures; however, the onset of seizures was delayed significantly in the double mutants, and the lifespan increased by several months. Like the brains of Car-2n mutants, those of double mutants (MldCar-2n) were deficient in mRNA and protein for CAII and showed upregulation of a different isozyme, CAIV. In the double mutants, oligodendrocytes were reduced in number, and the myelin sheaths and oligodendrocytes were swollen. The partial protection against seizures, which CAII deficiency conferred, suggests that acidosis in the central nervous system (CNS) of the Car-2n and MldCar-2n mice, due to absence of CAII from the choroid plexus, may downregulate the activity of NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of carbonic anhydrase II (CAII) deficiency on CNS structure and function in the myelin-deficient CAII-deficient double mutant mouse. 761 6

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

The seizure susceptibility of carbonic anhydrase II (CA) deficient mice and their normal littermates was determined and compared. In flurothyl-induced seizures, CA deficient mice displayed longer latencies to the onset of both clonic and tonic-clonic seizures. In pentylenetetrazole-induced seizures mutant mice exhibited a lower incidence of clonic seizures than did their normal littermates. Acetazolamide (a CA blocker) was used for the pretreatment of normal mice to compare them to CA deficient littermates. The pretreated mice displayed a lower incidence of flurothyl-induced tonic-clonic seizures and of both types of pentylenetetrazole seizures. The attempts to elicit audiogenic seizure did not reveal any difference between normal and mutant littermates. However, when the mice were primed by a loud sound during the critical period and retested for audiogenic seizures again at age 1.5 months, the CA deficient mice displayed a significantly lower incidence of seizures. The similarity between the anticonvulsant action of CA deficiency and the anticonvulsant action of acetazolamide suggests an important role of CA in seizures. The exact mechanism of anticonvulsant action by CA inhibition, however, remains to be elucidated.
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PMID:Reduced susceptibility to seizures in carbonic anhydrase II deficient mutant mice. 845 49

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

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

The prevalence of seizures in individuals with Down Syndrome (DS) is higher than in the general population. Rates of epilepsy in DS range from 1-13%. Forty percent of individuals develop seizures before 1 year of age and another 40% develop in their thirties or later. Boys have an earlier age of onset. The prevalence of epilepsy increases with age. Types of seizures are: 47% partial seizures, 32% infantile spasms and 21% generalized tonic-clonic seizures. Sex distribution for epilepsy in children with DS varies. Males have a younger age at onset. Trisomy 21 is common among epileptic children with DS but mosaicism or translocation has also been documented. The mechanisms underlying the increased seizure susceptibility in DS have not yet been completely explained. Seizures in infancy may be due to inherent structural brain abnormalities, like fewer inhibitory neurons, abnormal cortical lamination, persistent fetal dendritic morphology, underdeveloped synaptic profiles. Concentrations of carbonic anhydrase II are increased in the brains of young children with DS. It potentially increases seizure susceptibility. The pharmacological treatment of epilepsy in DS is same as that of other patients diagnosed with epilepsy. Individuals with DS have an unusually high number of side-effects from phenytoin. The diagnosis, classification and treatment of epilepsy in DS follow the guidelines applied to the general population. Review of literatures from 1960 to 2017 and electronically identified articles on epilepsy in Down syndrome in children in English are searched from internet and pub med to describe features of seizures in children with DS.
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PMID:Seizures in Down Syndrome: An Update. 3139 51