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)

ADCI (5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine), a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonist, is a broad-spectrum anticonvulsant with a favorable side-effect profile. In the present study, we sought to determine if tolerance develops to the anticonvulsant activity of ADCI, using the maximal electroshock (MES) test to assess seizure protection. Mice were treated with three daily injections of a 2 x ED50 dose for MES protection (18 mg/kg, intraperitoneally, i.p.) or vehicle for 7 or 14 days. On the day after the chronic treatment protocol, all animals received a challenge dose of ADCI (18 mg/kg) and 15 min later were evaluated in the MES test. In control animals, 83-94% of animals were protected and the ADCI plasma levels immediately after the MES test were 5.5-9.7 micrograms/ml. In treated animals, 29 and 0% of animals were protected at 7 and 14 days, respectively, and the ADCI plasma levels were 77 and 52% of the control values. [3H]Dizocilpine binding to brain NMDA receptors was unaltered by the chronic drug treatment. In subsequent experiments, we determined that 14-day chronically treated animals could be completely protected by increased doses of ADCI (ED50 28.9 mg/kg). In both naive and chronically treated animals receiving a challenge dose of ADCI, plasma drug levels decreased in two phases, the first with a time constant of approximately 55 min and the second with a much slower rate. The estimated plasma concentrations of ADCI reflecting threshold (3-5 micrograms/ml) and 50% protection (5-7.5 micrograms/mg) were similar in naive and chronic animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticonvulsant efficacy of ADCI (5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) after acute and chronic dosing in mice. 755 68

Ten calcium channel blockers were evaluated in mice after intraperitoneal (i.p.) administration for prevention of seizures induced by various convulsants. The dihydropyridines (class II calcium antagonists, i.e., nisoldipine, nitrendipine, nicardipine, nifedipine, and nimodipine) selectively prevented seizures elicited by administration of pentylenetetrazol (PTZ), N-methyl-D,L-aspartate (NMDLA) and the dihydropyridine calcium channel agonist BAY K 8644. With regard to prevention of NMDLA-induced seizures and the subsequent mortality, these compounds were similar in potency to the noncompetitive NMDA receptor antagonist MK801. Unlike MK801 (IC50 = 0.014 microM), the dihydropyridines did not inhibit in vitro binding of MK801 to synaptic membrane fractions prepared from rat cerebrohippocampal tissue. The dihydropyridines did not influence seizures elicited by maximal electroshock (MES). Flunarizine (diphenyl-alkylamine, class IV) was selectively active in the MES test, considerably less potent against NMDLA-induced convulsions/mortality, exhibited weak noncompetitive NMDA antagonism in vitro (IC50 = 28 microM), and was inactive in the PTZ and BAY K 8644 testing paradigms. Diltiazem, a class III benzothiazepine, possessed relatively weak broad spectra of activity against MES, PTZ, NMDLA, and BAY K 8644 test situations. It was inactive in vitro as a noncompetitive NMDA antagonist. The class I compound verapamil (phenylalkylamine) displayed only moderate inhibition of NMDLA-evoked seizures/mortality. Prenylamine (class V) was moderately active against convulsions produced by MES and NMDLA while retaining a degree (IC50 = 16 microM) of noncompetitive NMDA antagonism. Lidoflazine (class VI) was inactive in all tests. The Ca2+ channel blockers and MK801 were inconsistent in their ability to prevent bicuculline (BIC)-elicited convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticonvulsant properties of calcium channel blockers in mice: N-methyl-D-,L-aspartate- and Bay K 8644-induced convulsions are potently blocked by the dihydropyridines. 768 Oct 2

To define their efficacy and mechanism of action, the possible antagonistic effects of intravenously administered dextrorphan and dizocilpine, non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists, on tonic convulsions and death in a variety of experimental mice models were compared. Dextrorphan not only produced dose-dependent protection against the tonic convulsions caused by an intracerebroventricular injection of NMDA, but also showed a broad spectrum of anticonvulsant activities against tonic convulsions caused by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), bicuculline, pentylenetetrazole or electroconvulsive shock. The anticonvulsant action of dizocilpine was found to be more efficacious for any type of tonic convulsions and was 20- to 70-fold more potent than that of dextrorphan. Dizocilpine, unlike dextrorphan, impaired motor function at doses showing its anticonvulsant activity. Bay k-8644 (a Ca2+ channel agonist)-induced seizures were not antagonized by dextrorphan. Dextrorphan and dizocilpine were characteristically selective for protective functions against death, especially with three subtypes of glutamate receptors, as death caused by NMDA but not by AMPA and KA was selectively and markedly inhibited by both dextrorphan and dizocilpine. In view of these results, the efficacy of dextrorphan and dizocilpine as antagonists of convulsant effects appears to be consistent with the interpretation that a variety of convulsants cause tonic convulsions via direct or indirect interaction with the NMDA receptor complex. Furthermore, it is suggested that influx of Ca(2+) and intracellular Ca(2+) activity, such as the Bay k-8644-modulated activation of Ca(2+) binding proteins, are not directly modified by the administration of dextrorphan, itself.
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PMID:Antagonism of various tonic convulsions in mice by dextrorphan and dizocilpine. 768 6

4-Aminopyridine, a voltage-dependent potassium channel blocker, causes tonic-clonic and electrographic seizures in vivo and evokes epileptiform activity and release of glutamate, aspartate and GABA in vitro. This study examined the effects of 4-aminopyridine (4AP) on de novo synthesis of neuroactive amino acids and a subsequent response to various anticonvulsant compounds (phenytoin, carbamazepine, phenobarbital, valproate, ethosuximide, diazepam, lamotrigine, felbamate, losigamone, U54494A, CPP, MK801 and CNQX) using a hippocampal slice preparation. 4-Aminopyridine had a minimal effect on total tissue concentrations of glutamate, aspartate, and GABA, but caused a significant increase in their de novo synthesis. Phenytoin, carbamazepine, lamotrigine, losigamone and U54494A were the only compounds which were effective in blocking the 4AP-induced increase in all newly synthesized amino acids. It appears that these compounds inhibit 4AP effects in this paradigm by blocking depolarization, probably at use-dependent voltage-sensitive sodium channels. Therefore, this paradigm may be useful in selectively identifying anticonvulsants which act by blocking depolarization.
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PMID:The effects of anticonvulsant compounds on 4-aminopyridine-induced de novo synthesis of neurotransmitter amino acids in rat hippocampus in vitro. 775 May 7

This study investigates the possible involvement of opioid receptors in the action of a variety of anticonvulsant agents. The opioid antagonist naloxone (0.3, 1 mg/kg IP) and the selective mu-opioid antagonist cyprodime (3 mg/kg IP) significantly inhibited the increase in electroshock seizure threshold induced by phenytoin (3 mg/kg IP) in mice. The anticonvulsant effects of ethanol (1 g/kg IP) were also significantly antagonised by naloxone (1 mg/kg IP) but not by a 0.3 mg/kg IP dose or by cyprodime (3 mg/kg IP). The results with naloxone were confirmed using higher doses of phenytoin (10 mg/kg IP) and ethanol (1.5 g/kg IP). In contrast to the above findings, naloxone (0.3, 1 mg/kg IP) had no effect on the increase in seizure threshold induced by sodium valproate (200 mg/kg IP) or dizocilpine (MK801, 0.5 mg/kg IP) and paradoxically potentiated the increase in seizure threshold produced by phenobarbitone (15 mg/kg IP); carbamazepine (10 mg/kg IP) and the benzodiazepine agonist loprazolam (1 mg/kg IP), clearly differentiating these compounds from phenytoin and ethanol. These findings suggest that the anticonvulsant effects of phenytoin and ethanol (as assessed by their ability to prevent tonic hindlimb extension in the mouse electroshock model) may be mediated, at least in part, by the release of endogenous opioids and subsequent activation of opioid receptors (mu, in the case of phenytoin, but non-mu, in the case of ethanol) although direct activity at opioid receptors cannot be precluded.
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PMID:Investigation of the involvement of opioid receptors in the action of anticonvulsants. 787 Sep 91

1. The competitive antagonists at the N-methyl-D-aspartate (NMDA) receptor, CGP39551 and CGP37849, protected against the barbiturate withdrawal syndrome in mice, as measured by ratings of convulsive behaviour on handling. 2. The effective doses of these compounds were lower than those required to prevent seizures due to NMDA in naive animals; these were in turn lower than those needed to prevent the convulsive effects of the alpha-aminobutyric acid (GABA) antagonist, bicuculline. 3. The NMDA-receptor antagonists did not alter the increase in the incidence of convulsions due to the GABAA antagonist, bicuculline, that is seen during barbiturate withdrawal, although the latencies to these convulsions during barbital withdrawal were significantly increased after CGP39551. 4. Barbiturate withdrawal did not affect the convulsive actions of NMDA, whether measured by the incidence of convulsions or by intravenous infusion. 5. The Bmax for [3H]-dizocilpine ([3H]-MK801) binding was significantly increased by chronic barbital treatment in cerebrocortical but not in hippocampal tissues, while the Kd remained unaltered in either case. 6. At 1 h and 24 h after administration of a single dose of barbitone, the Bmax for [3H]-dizocilpine binding was unaltered in cerebrocortical tissue. Acute addition of barbitone in vitro did not alter [3H]-dizocilpine binding or the displacement of binding of thienylcyclohexylpyridine.
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PMID:Possible involvement of NMDA receptor-mediated transmission in barbiturate physical dependence. 791 57

1. We previously reported that volatile anaesthetics produce incidences of a transient opisthotonus in mice, a sign of CNS stimulation. This study was performed to investigate mechanisms by which enflurane-induced opisthotonus (EIO) occurs. 2. The effects of pretreatment of N-methyl-D-aspartate (NMDA) antagonists dizocilpine (MK-801; DIZ) and ketamine (KET), GABAA antagonists picrotoxin (PIC), pentylenetetrazol (PTZ) and glycine antagonist strychnine (STR) on the incidence of EIO were determined. Prior to exposure to 2.0% enflurane in air, male ddN mice were given intraperitoneal injections of 0.2 mL saline (control), 0.5-5.0 mg/kg DIZ, 20-80 mg/kg KET, 2.9 mg/kg PIC, 40.0 mg/kg PTZ and 0.75 mg/kg STR. After the injection, the behavioural state of the mice was observed for 20 min (the pre-enflurane period). During the exposure to enflurane the time for immobilization, that is, anaesthetic induction time (IT), and the incidence of EIO were measured. 3. Dizocilpine (1.0-5.0 mg/kg) and KET (80 mg/kg) significantly (P < 0.01) reduced both the incidence of EIO and IT in a dose-dependent manner. During the pre-enflurane period DIZ produced incidences (5-40%) of transient seizures in a dose-dependent manner, while KET did not induce them at all. The two GABAA antagonists had no detectable effect on the EIO. Strychnine significantly enhanced the EIO. These CNS stimulants resulted in a 3-10% incidence of transient seizure and/or opisthotonus during the pre-enflurane period, but there was no correlation between DIZ-induced seizure and EIO. 4. These results suggest that the EIO is mediated by the NMDA and the STR-sensitive glycine receptors, but not the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible participation of NMDA and glycine receptors but not GABAA receptors in enflurane-induced opisthotonus in mice. 798 80

Seizures may be induced in mice in response to stimulation of subtypes of glutamate receptors by kainic acid or inhibition of certain voltage-dependent potassium channels by 4-aminopyridine (4-AP). The anti-seizure efficacy of intraperitoneally administered anticonvulsants and Ca++ antagonists to CF-1 mice was tested using these models. The order of potency for prevention of kainate convulsions and the subsequent lethality was: dihydropyridine Ca++ antagonists (nicardipine, nisoldipine > nitrendipine > nifedipine > nimodipine) followed by verapamil > prenylamine > diltiazem > flunarizine > remacemide HCl > ethosuximide > valproate. In the 4-AP model the order of potency to prevent hind limb tonic extension was: MK801(+/-) > lamotrigine > phenytoin, phenobarbital > carbamazepine > FPL 12495AA (the desglycine metabolite of remacemide HCl), remacemide HCl > flunarizine > prenylamine >>> valproate. Therefore, compounds that limit activation of kainate receptors and voltage-operated linked calcium channels are active in the kainate model. Agents effective against maximal electroshock appear to be effective in the 4-AP model.
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PMID:Kainic acid and 4-aminopyridine seizure models in mice: evaluation of efficacy of anti-epileptic agents and calcium antagonists. 815 36

Mice selectively bred to be Withdrawal Seizure-Prone (WSP) or Seizure-Resistant (WSR) after chronic ethanol administration have been reported to be differentially sensitive to the anticonvulsant and proconvulsant effects on alcohol withdrawal of drugs interacting with glutamate receptors. Several behavioral effects of the noncompetitive glutamate receptor antagonist, dizocilpine, were determined in WSP and WSR mice to see whether their differential sensitivity generalized to effects unrelated to seizures, and to see whether it was only apparent during ethanol withdrawal. Dizocilpine potentiated the loss of righting reflex induced by ethanol, and dose-dependently stimulated habituated and nonhabituated open field activity. WSP and WSR mice were equally sensitive to these effects of dizocilpine. Pretreatment with dizocilpine increased the transcorneal amperage necessary to produce maximal electroshock seizures: WSR mice were more sensitive than WSP to this effect. Ethanol withdrawal (i.e., testing 6 h after a 24-h exposure to ethanol vapor) and dizocilpine had several effects on mice tested in the hole-in-wall apparatus. Several differences between WSP and WSR mice were also found, but in no case did dizocilpine differentially affect ethanol-withdrawing WSP and WSR mice. Across these experiments, differences between WSP and WSR mice in response to dizocilpine were rather specific. For some responses, WSP and WSR mice were equally sensitive, but only in the seizure-related measure assessed were naive WSR mice more sensitive than WSP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of dizocilpine in withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice. 820 61

Both clinical and laboratory studies are being undertaken to investigate the deleterious neurologic and developmental effects associated with cardiopulmonary bypass, hypothermia, and circulatory arrest in the neonate and infant. A prospective, randomized clinical study of 171 neonates and young infants compared circulatory arrest with low-flow bypass (50 mL.kg-1.min-1). Circulatory arrest was associated with a higher incidence of early postoperative seizures as well as greater release of creatine kinase-BB. There was a strong correlation between duration of circulatory arrest and seizures (p = 0.004). The late consequences of these findings will be known at the completion of developmental assessment of all patients at 1 and 4 years of age. Laboratory studies have used a miniature piglet model that closely replicates clinical circulatory arrest. High-energy phosphate stores determined by magnetic resonance spectroscopy were maintained in animals undergoing 1 hour of low-flow bypass but became undetectable after 32 minutes of a 1-hour period of circulatory arrest. However, they returned to baseline within 3 hours of reperfusion as did cerebral blood flow and metabolism determined by microsphere studies. Piglets undergoing 1 hour of circulatory arrest showed more rapid recovery of cerebral adenosine triphosphate content and intracellular pH when managed with the pH-stat strategy during hypothermic bypass than with the more alkaline alpha-stat strategy. Other laboratory studies have examined pharmacologic methods of reducing cerebral injury associated with circulatory arrest including aprotinin, anti-CD18, neuronal receptor antagonists (MK801, NBQX), and blockade of glutamate release with adenosine in a cerebroplegia solution. These studies have suggested a number of promising approaches to improving the technique of circulatory arrest.
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PMID:Review of current research at Boston Children's Hospital. 826 70


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