Role of histaminergic neurons in development of epileptic seizures in EL mice

Yawata, Izumi; Tanaka, Kazuaki; Nakagawa, Yoshifumi; Watanabe, Yasuo; Murashima, Yoshiya L.; Nakano, Kiwao

doi:10.1016/j.molbrainres.2004.08.019

Cited by 47 publications

(32 citation statements)

References 15 publications

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“…or i.c.v. administration induced seizures (Kamei et al, 2000;Kamei, 2001;Yokoyama, 2001;Yawata et al, 2004;Kukko-Lukjanov et al, 2010). In the present study, the seizure induction potential of diphenhydramine, promethazine, loratadine or fexofenadine could not be detected.…”

Section: Discussioncontrasting

confidence: 64%

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: Discussioncontrasting

confidence: 64%

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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“…The inhibitory effect of the histaminergic neuron system on seizures has been assigned in several studies (Scherkl et al, 1991;Yokoyama et al, 1992;Kamei, 2001;Yawata et al, 2004), but a possible neuroprotective effect of histaminergic neurons has attained less attention. In our study, the coculture system serves as an excellent model to study the effect of histaminergic neurons on neuronal damage in the hippocampus.…”

Section: Neuronal Degeneration In the Hippocampus Cultured Together Wmentioning

confidence: 99%

“…In different animal models of epileptic seizures, increased brain histamine levels elevate seizure threshold and reduce severity and duration of seizures (Scherkl et al, 1991;Yokoyama et al, 1992;Kamei, 2001;Yawata et al, 2004), whereas decreased histamine levels have the opposite effect (Yokoyama et al, 1992). Moreover, brain histamine levels are significantly lower in the genetically epilepsy-prone rats compared with normal rats Midzyanovskaya et al, 2002), which is in accordance with the clinical study in which histamine concentration is decreased in the cerebrospinal fluid of children with febrile convulsions compared with children without seizures (Kiviranta et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

Kukko‐Lukjanov

Soini²,

Taira³

et al. 2006

J. Neurosci.

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The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H 1 ) and histamine 3 (H 3 ) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (

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“…The pro-epileptic effect of carbachol was not observed in the isolated guinea-pig preparation (van der Linden and de Curtis, 1998;Dickson et al, 2000) and in hippocampal slices bathed with a 4.2 mM potassium solution (Fisahn et al, 1998;Gloveli et al, 1999). When BBB permeability is enhanced, potassium may leak into brain from the blood compartment, where its concentration is higher (Lux and Neher, 1973;Somjen, 1979 Histamine has an anticonvulsant action in the amygdaloid-kindled rats (Kamei et al, 1998), in a genetic model of temporal lobe epilepsy (Yawata et al, 2004). On the other hand, Yanovsky and Haas (1998) showed that, in vitro histamine application in the presence of 5 mM extracellular potassium has an excitatory effect mediated by H2 receptors.…”

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confidence: 99%

Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood–brain barrier permeability

et al. 2008

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Systemic application of the muscarinic agonist, pilocarpine, is commonly utilized to induce an acute status epilepticus that evolves into a chronic epileptic condition characterized by spontaneous seizures. Recent findings suggest that the status epilepticus induced by pilocarpine may be triggered by changes in the blood-brain barrier (BBB) permeability. We tested the role of the BBB in an acute pilocarpine model by using the in vitro model brain preparation and compared our finding with in vivo data. Arterial perfusion of the in vitro isolated guinea-pig brain with <1 mM pilocarpine did not cause epileptiform activity, but rather reduced synaptic transmission and induced steady fast (20-25 Hz) oscillatory activity in limbic cortices. These effects were reversibly blocked by co-perfusion of the muscarinic antagonist atropine sulfate (5 μM). Brain pilocarpine measurements in vivo and in vitro suggested modest BBB penetration. Pilocarpine induced epileptiform discharges only when perfused with compounds that enhance BBB permeability, such as bradykinin (n=2) or histamine (n=10). This pro-epileptic effect was abolished when the BBB-impermeable muscarinic antagonist atropine methyl bromide (5 μM) was co-perfused with histamine and pilocarpine. In the absence of BBB permeability enhancing drugs, pilocarpine induced epileptiform activity only after arterial perfusion at concentrations >10 mM. Ictal discharges correlated with a high intracerebral pilocarpine concentration measured by high pressure liquid chromatography.We propose that acute epileptiform discharges induced by pilocarpine treatment in the in vitro isolated brain preparation are mediated by a dose-dependent, atropine-sensitive muscarinic effect promoted by an increase in BBB permeability. Pilocarpine accumulation secondary to BBB permeability changes may contribute to in vivo ictogenesis in the pilocarpine epilepsy model. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2009 November 9. Published in final edited form as:Neuroscience. Pilocarpine is a non-selective muscarinic agonist (Maslanski et al., 1994) with a relatively high affinity for CNS muscarinic receptors (Hedlund and Bartfai, 1981) commonly utilized to develop an experimental model of temporal lobe epilepsy (Turski et al., 1989;Cavalheiro et al., 2006; but see Sloviter, 2005). In different animal species, i.p. injection of pilocarpine induces a convulsive status epilepticus (SE; i.e. sub-continuous generalized seizures that recur for several hours), followed within 2 weeks by a chronic epileptic condition that mimics human temporal lobe epilepsy (Cavalheiro et al., 2006). The initial SE is thought to be triggered by a cholinergic activation of excitatory neurons in specific brain regions that include limbic cortices. Such an effect is supposedly mediated by micro-molar concentrations of pilocarpine, since this drug shows a relatively poor brain penetration (Omori et al., 2004). Although studies directly assessing pilocarpine penetration across the ...

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Role of histaminergic neurons in development of epileptic seizures in EL mice

Cited by 47 publications

References 15 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

Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood–brain barrier permeability

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