Propranolol-induced seizures in mice: the role of noradrenaline

Amabeoku, G.J.; Syce, James

doi:10.1007/s000180050083

Cited by 6 publications

(1 citation statement)

References 19 publications

(14 reference statements)

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“…In experimental animals, administration at nearly lethal dose of propafenone (Fujihara et al, 1987;Mituzono et al, 1987) or disopyramide (Tanaka et al, 1971;Malavé et al, 1983) and high dose treatment with propranolol by i.p. administration (Amabeoku and Syce, 1997) induced seizures. In the present study, the seizure potential of propafenone, disopyramide or propranolol was not detected.…”

Section: Discussionmentioning

confidence: 92%

Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish

et al. 2014

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-As drug-induced seizures have severe impact on drug development, evaluating seizure induction potential of candidate drugs at the early stages of drug discovery is important. A novel assay system using zebrafish has attracted interest as a high throughput toxicological in vivo assay system, and we tried to establish an experimental method for drug-induced seizure liability on the basis of locomotor activity in zebrafish. We monitored locomotor activity at high-speed movement (> 20 mm/sec) for 60 min immediately after exposure, and assessed seizure liability potential in some drugs using locomotor activity. However this experimental procedure was not sufficient for predicting seizures because the potential of several drugs with demonstrated seizure potential in mammals was not detected. We, therefore, added other parameters for locomotor activity such as extending exposure time or conducting flashlight stimulation (10 Hz) which is a known seizure induction stimulus, and these additional parameters improved seizure potential detection in some drugs. The validation study using the improved methodology was used to assess 52 commercially available drugs, and the prediction rate was approximately 70%. The experimental protocol established in this present study is considered useful for seizure potential screening during early stages of drug discovery.Key words: Zebrafish, Locomotor activity, Seizure, Extending exposure time, Flashlight stimulation Correspondence: Naoteru Koseki (E-mail: naoteru-koseki@ds-pharma.co.jp) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.39, No.4, 579-600, 2014 Vol. 39 No. 4 579 through the blood-brain barrier (BBB). Since such assays are conducted with a focus on specific neural networks or cells associated with seizures, performing an evaluation using above alternative methods is direct and limited. On the basis of the aforementioned findings, a test system that can take pharmacokinetic effects into account and can be used to perform an evaluation under conditions closer to whole body is considered desirable. As such, an in vivo evaluation system using Caenorhabditis elegans (C. elegans), which is one of the nematodes with gamma-aminobutyratergic (GABAergic) neurons related to seizures, has been reported (Locke et al., 2006;Pandey et al., 2010), and an evaluation using behavioral assessment of such organism is expected. However, nematodes are very different from mammals in terms of the anatomical structure of central nervous system (CNS) or pharmacokinetics. Therefore, performing an assessment which approximates the evaluation of a conventional study using rodents is considered to be difficult.Zebrafish is a vertebrate and its genomic homology to humans is approximately 70% (Howe et al., 2013). In addition, zebrafish can be utilized in early stage drug screening in recent decades. For these reasons, an evaluation using zebrafish has recently been given attention as a novel in vivo evaluation system for safety assessment. Since zebrafish have tele...

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Section: Discussionmentioning

confidence: 92%

Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish

et al. 2014

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Management of Beta-Adrenergic Blocker Poisoning

Anderson

2008

Clinical Pediatric Emergency Medicine

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Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

Gaval-Cruz

Schroeder

Liles

et al. 2008

Pharmacology Biochemistry and Behavior

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The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine β-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh -/-mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh -/-mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh -/-mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh -/-mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.

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Propranolol-induced seizures in mice: the role of noradrenaline

Cited by 6 publications

References 19 publications

Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish

Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish

Management of Beta-Adrenergic Blocker Poisoning

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

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