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 influence of chronic administration of antidepressants on cyclic AMP-dependent protein kinase activity was examined in rat frontal cortex. Chronic administration of imipramine, tranylcypromine, or electroconvulsive seizures decreased cyclic AMP-dependent protein kinase activity in soluble fractions by approximately 25%, whereas enzyme activity was increased in the particulate fractions by approximately 20%. In contrast, enzyme activity in crude homogenates was not altered. This effect appears to be specific to antidepressant drugs, because representatives of several other classes of psychotropic drugs-namely, haloperidol, morphine, and diazepam--failed to alter either soluble or particulate levels of cyclic AMP-dependent protein kinase activity in this brain region following chronic administration. When the total particulate fraction was subfractionated, it was found that chronic imipramine treatment significantly increased the activity of cyclic AMP-dependent protein kinase in crude nuclear fractions but not in crude synaptosomal or microsomal fractions. Taken together, the data raise the possibility that chronic antidepressant treatments may stimulate the translocation of cyclic AMP-dependent protein kinase from the cytosol to the nucleus. This effect would represent a novel action of antidepressants that could contribute to the long-term adaptive changes in brain thought to be essential for the clinical actions of these treatments.
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PMID:Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. 279 22

(Na+, K+)-ATPase (E.C.3.6.1.3) was partially purified from the cerebral cortex of audiogenic DBA/2 mice, from the primary and secondary epileptogenic foci of cats with a freeze lesion and from normal and epileptic human cortices. No differences in the specific activities of the microsomal enzyme were observed between normal and epileptic cortex. The influence of K+ ions and phenytoin, a potent antiepileptic drug, was then studied on the phosphorylation level of (Na+, K+)-ATPase alpha(+) (neuronal) and alpha(-) (non-neuronal) catalytic subunits resolved by SDS-gel electrophoresis. In normal cortex, the apparent affinity of the non-neuronal enzyme to K+ ions was reduced compared to the affinity of the neuronal enzyme. Phenytoin decreased the phosphorylation level of (Na+, K+)-ATPase purified from non-epileptogenic cortex of control C57/BL mice, cats and human patients. In fact, the drug induced the dephosphorylation of the (Na+, K+)-ATPase catalytic subunits, mainly of its alpha(-), non-neuronal subtype. In the cortex of audiogenic DBA/2 mice, K+ ions induced the dephosphorylation of (Na+, K+)-ATPase, with the same affinity as in control C57/BL mice. The dephosphorylating influence of phenytoin was however much decreased. In the primary and secondary foci of lesioned cats, both K+ and phenytoin dephosphorylating influences were decreased. Those changes were especially valid for the alpha(-), non-neuronal subunit. In human epileptic cortex, the (Na+, K+)-ATPase catalytic subunit had a decreased affinity to K+, as well as it lost its sensitivity to phenytoin dephosphorylation. Those results confirm the existence of two molecular forms of (Na+, K+)-ATPase in animal and human brain cortex. Those two forms, the neuronal and the non-neuronal or glial (Na+, K+)-ATPases, differ at least by their K+ regulation and their phenytoin sensitivity. Phenytoin studies also suggest that the drug stimulates the cortical (Na+, K+)-ATPase, mainly its glial form, providing central nervous system with an enhanced ability to regulate extracellular K+. In epileptic cortex, (Na+, K+)-ATPase and especially its glial form is altered in its K+ regulation and phenytoin sensitivity. That deficiency of glial (Na+, K+)-ATPase in focal epileptogenic cortex could be responsible for ictal transformation and seizure spread (Acta neurol. belg., 1988, 88, 257-280).
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PMID:Brain cortical (Na+ K+)-ATPase in epilepsy. A biochemical study in animals and humans. 285 92

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 possibility of tolerance development from chronic administration of felbamate (FBM) was investigated in mice and rats. Chronic administration (15 days) of FBM (150 mg/kg i.p.) in mice had no significant effect on either intravenous pentylenetetrazol (PTZ) seizure threshold or hexobarbital sleep time; however, hexobarbital sleep time was significantly increased after a single dose. Chronic administration (5-7 days) of FBM (48 or 95 mg/kg orally) in rats also had no significant effect on either maximal electroshock seizure activity or hexobarbital sleep time. Chronic administration of FBM at 238 mg/kg slightly decreased anti-subcutaneous PTZ activity in chronically treated rats (one of eight protected) as compared with those receiving only a single dose (three of eight protected), but there was no significant change in hexobarbital sleep time. Chronic treatment of rats for 7 days with 48 mg/kg had no significant effect on any hepatic parameters. However, 95 or 238 mg/kg of FBM significantly increased p-nitroanisole O-demethylase activity. It is concluded that the increased hexobarbital sleep time induced by an acute dose of FBM reflects the CNS-depressant effect of the substance. The increased p-nitroanisole O-demethylase activity observed after chronic administration may be indicative of some liver microsomal induction. Overall, FBM in doses ranging from 48 to 238 mg/kg appears to have minimal potential for tolerance development.
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PMID:The effect of chronic felbamate administration on anticonvulsant activity and hepatic drug-metabolizing enzymes in mice and rats. 310 74

Enzymatic production of prostaglandins (PGs) from exogenous arachidonic acid was studied in brain microsomal fractions prepared from mice following pentylenetetrazol (PTZ)-induced convulsions. Prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) measured either by radioimmunoassay or after incubation with [1-14C]arachidonic acid (AA) was significantly increased in microsomes from the convulsed animals. Pretreatment of the mice with the anticonvulsant ethosuximide prevented the enhanced PG production. The increased PG synthesis could not be attributed to an increased substrate availability nor to an activated phospholipase nor to a direct effect of the convulsant on the fatty acid cyclooxygenase. Evidence that a modification of the cyclooxygenase had occurred with seizure activity was obtained from kinetic analysis; the apparent Km for the AA was lowered from 30 +/- 3 microM in the controls to 12 +/- 1 microM in the PTZ-treated mice. Further evidence for a modification of the fatty acid cyclooxygenase was obtained from incubations of the microsomes with catalase to reduce peroxide formation. Limiting peroxide levels did not decrease the microsomal cyclooxygenase activity in the PTZ-treated mice to control levels. Seizure activity induced by picrotoxin and strychnine also increased the microsomal capacity of the convulsed animals to synthesize PGs. The increased brain fatty acid cyclooxygenase activity may result from a biochemical modification of the enzyme induced by seizure activity.
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PMID:Evidence for increased activity of mouse brain fatty acid cyclooxygenase following drug-induced convulsions. 310 89

A 33-year-old female presented for elective excision of a posterior fossa tumour following two generalized seizures six months earlier. The patient had been asymptomatic on phenytoin 300 mg/day. Two h pre-operatively, a 300-mg dose of phenytoin was administered, general anesthesia induced and pancuronium bromide given to achieve neuro-muscular paralysis. Respiration was supported and anesthesia maintained with isoflurane and nitrous oxide in oxygen. Thirty min into the operation a further 2-mg dose of pancuronium bromide was administered. One h later, the patient coughed. A peripheral nerve stimulator was applied to the right common peroneal nerve with surface electrodes. Over the next 75 min a total of 15 mg of pancuronium bromide was required. With each dose there was a complete loss of response to peripheral nerve stimulation, followed by a rapid return of full train-of-four response, accompanied by coughing and cerebral engorgement. At this point, metocurine iodide was administered with full sustained paralysis for 45 min. Blood samples collected during a second operation indicated the patient had an extremely short pancuronium elimination half-life and a small volume of distribution. Several explanations are offered including phenytoin induction of hepatic microsomal enzymes responsible for the biotransformation of pancuronium, alterations in tissue or protein binding and/or alterations in myoneuronal junctional response.
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PMID:Pancuronium-phenytoin interaction: a case of decreased duration of neuromuscular blockade. 322 Jun 9

Progabide (PGB) is a gamma-aminobutyric acid (GABA)-agonist drug undergoing clinical evaluation for the treatment of spasticity, movement disorders, and epilepsy. Drug interactions were studied during a randomized, double-blind, crossover trial of the efficacy and toxicity of PGB in patients with partial seizures taking phenytoin (PHT) and carbamazepine (CBZ). In twenty-two of 32 patients (69%) receiving PGB, PHT dosage was reduced, while only four patients (12%) had their dosage reduced during placebo treatment (p less than 0.001). Carbamazepine dosage was decreased in five of 32 patients (16%) during the active treatment, while two patients (6%) had a dosage reduction when receiving placebo (p greater than 0.75). The mean PHT concentrations at the end of baseline, PGB, and placebo treatments were significantly different: 17.5, 20.4, and 16.8 mg/L, respectively (p less than 0.05). Nevertheless, careful adjustment of PHT dosage maintained serum concentration within +/- 25% of target values in both the PGB and placebo periods. Among patients who first received PGB and then placebo, PHT concentrations remained elevated relative to dose suggesting that PGB exerts a prolonged effect on PHT disposition. The addition of PGB to regimens including PHT results in a significant increase in serum PHT concentrations. This drug interaction most likely occurs as a result of PGB mediated inhibition of hepatic microsomal enzymes.
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PMID:Effect of progabide on serum phenytoin and carbamazepine concentrations. 342 61

Synthesis of arachidonoyl CoA and docosahexaenoyl CoA in homogenates and microsomes from cerebrum, cerebellum, and brain stem and in synaptic plasma membranes from cerebrum of control rats and rats undergoing bicuculline-induced status epilepticus were studied. Arachidonoyl CoA synthesis was 3-5 times higher than docosahexaenoyl CoA in homogenates and microsomes. The synaptic plasma membranes showed only 1.5- to 2.5-fold higher activity. The presence of Triton X-100 (0.1%) in the incubation medium did not alter the activity of arachidonoyl CoA synthesis but did increase the synthesis of docosahexaenoyl CoA in homogenates, microsomes, and especially in synaptic plasma membranes. The synthesis of these polyenoic fatty acyl CoAs were 4-6 times higher in microsomes than in homogenates. Synaptic plasma membranes exhibited about the same amount of activity as homogenates in the synthesis of docosahexaenoyl CoA, but only half the activity of the latter in arachidonoyl CoA synthesis. The synthesis of arachidonyl CoA and docosahexaenoyl CoA in cerebral homogenates and microsomes was higher than that of cerebellum and brain stem. The apparent Km values for labeled arachidonic acid (17 microM) and docosahexaenoic acid (12 microM) in synaptic plasma membranes were lower than the values for microsomes isolated from different brain regions. The Vmax values were also 4-10 times lower. Microsomes from different regions did not differ in their apparent Km values, but did show variations in apparent Vmax values. Cerebellar microsomes showed lower Vmax values than the other two regions. The presence of Triton X-100 caused a significant decrease in the apparent Km values with little change in the Vmax values. Bicuculline-induced seizures did not alter the kinetic properties of arachidonoyl CoA and docosahexaenoyl CoA synthesis, except there was a significant decrease in the apparent Km and Vmax values for cerebellar microsomal docosahexaenoyl CoA synthesis. In conclusion, there were marked differences in the activation of polyenoic fatty acids in different parts of the brain and in subcellular fractions. Although bicuculline-induced convulsions accumulate free polyenoic fatty acids in the brain, no changes were detected when the fatty activation was assayed with exogenous cofactors, except in cerebellum.
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PMID:Synthesis of arachidonoyl coenzyme A and docosahexaenoyl coenzyme A in synaptic plasma membranes of cerebrum and microsomes of cerebrum, cerebellum, and brain stem of rat brain. 398 82

DBA/2J mice are susceptible to audiogenic seizures (ASs) in an age-dependent manner, susceptibility being maximal at 21 days of age and declining thereafter. DBA, as compared with AS-resistant C57BL/6J (C57) mice, had higher carbonic anhydrase (CA) activity in cerebral cortex, brainstem, and cerebellum homogenates at 21 days of age. CA activity was also increased in cytosolic (82%), microsomal (167%), and myelin (68%) subcellular fractions from cerebral cortex, and in cytosolic (51%) and mitochondrial (102%) fractions from brainstem of DBA mice at 21 days of age. In addition, DBA mice had a higher Na+, K+-ATPase activity in myelin from cerebral cortex, and a lower HCO3--ATPase activity in mitochondria from brainstem. The differences in CA activity in the cerebral cortex and in HCO3--ATPase were not present at 110 days of age, when DBA mice are no longer susceptible to ASs. Because CA and HCO3--ATPase are involved in maintaining a proper ionic environment for neuronal function, these data suggest that alterations in activity of these enzymes are related to the age-dependent changes in AS susceptibility in DBA mice.
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PMID:Subcellular distribution of carbonic anhydrase and Na+, K+- and HCO3--ATPases in brains of DBA and C57 mice. 623 73

The exposure in humans to ethanol or barbiturates during prenatal or neonatal development is common. There are indications that the magnitude of the resulting symptoms may be genetically determined. In the present article, an animal model was established for the study of the genetic determination of the neurosensitivity to ethanol and barbiturates administered during prenatal and/or neonatal development. Inbred C57BL/10 (C57) and DBA/1 (DBA) mice were employed in the ethanol studies and these strains and the outbred HS/Ibg (HS) were used in the barbiturate studies. Early ethanol administration induced a long lasting increase in the susceptibility to audiogenic seizures in both strains but to a greater degree in C57. Neuropharmacological studies implicated the serotonergic but not the noradrenergic system as mediating the early ethanol induced changes in audiogenic seizures. Open field activity was decreased but only in C57. Male agonistic behavior and predatory behavior were greatly reduced by early ethanol administration but mainly in DBA. Long term induction of the activity of the hepatic enzymes, alcohol dehydrogenase and microsomal ethanol oxidizing system, occurred in both strains after early exposure to ethanol. After early exposure to phenobarbital HS mice had long lasting increases in the susceptibility to audiogenic seizures and in the hippocampus related behaviors, spontaneous alternations and eight arm maze performance. The hepatic microsomal drug oxidizing system was induced in adult HS mice with early phenobarbital (PhB) exposure. Early PhB exposure also caused long term decreased sensitivity to ethanol narcosis and an accelerated acquisition to barbiturate tolerance, possibly mediated via a change in the sensitivity of the post synaptic dopamine receptors. Changes in the PhB treated offspring also included a reduction in the levels thyroid hormone. Early exposure to PhB resulted in a long term deficit in the area of brain layers, number of neurons, dendritic spines and the ultrastructure. Strain comparison suggested that DBA was less neurosensitive to early PhB administration than both HS and C57. It was concluded that genotype-environment interaction exists in the effect of drugs on the developing CNS.
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PMID:Genetic factors in drug neuroteratogenicity. 635 25


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