Histaminergic mechanisms in amygdaloid-kindled seizures in rats

Kamei, Chiaki; Ishizawa, Keisuke; Kakinoki, Hiroshi; Fukunaga, Masafumi

doi:10.1016/s0920-1211(98)00005-9

Cited by 74 publications

(50 citation statements)

References 13 publications

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“…221) Rodent studies report that elevated brain histamine levels, evoked by administration of histamine, the HMT inhibitor metoprine or L-histidine suppress epileptic discharges. [222][223][224][225][226] Consequently, the histidine decarboxylase inhibitor a-fluoromethylhistidine reduces seizure threshold. The anticonvulsive effect of central histamine is attenuated by H 1 R antagonists, while no changes have been observed after co-administration of H 2 R and H 3 R antagonists.…”

Section: )mentioning

confidence: 99%

“…The anticonvulsive effect of central histamine is attenuated by H 1 R antagonists, while no changes have been observed after co-administration of H 2 R and H 3 R antagonists. [223][224][225] With respect to the anticonvulsive effects of H 3 R antagonists various studies report the beneficial use in distinct seizure models, e.g. electrically induced convulsions, 227,228) kindling, 229,230) and pentylenetetrazole-(PTZ) induced seizures.…”

Section: )mentioning

confidence: 99%

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Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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INTRODUCTIONThe biogenic amine histamine, 2-(1H-imidazol-4-yl)-ethanamine, is produced by decarboxylation of L-histidine and is implicated in a wide range of physiological and pathophysiological functions. It is metabolised by histamine N tmethyltransferase (HMT) and mono-or diaminoxidase. Histamine is mainly acting via four distinct metabotropic histamine receptor subtypes (H 1 R-H 4 R), which have meanwhile all been cloned. Whereas antagonists for H 1 R and H 2 R subtypes have been blockbusters in therapy of allergy and ulcer, respectively, antagonists for H 3 R and H 4 R subtypes are not on the market. The recently described H 4 R seems to be involved in inflammatory and immunomodulatory processes. H 3 Rs play a central role in neurotransmission of histamine and in control of many other neurotransmitters. Several antagonists are in preclinical and some in clinical stage of development. PHARMACOLOGICAL BACKGROUND Auto-and HeteroreceptorThe H 3 R was first described in 1983 as a presynaptic autoreceptor, which mediates synthesis of histamine and inhibition of its release from histaminergic neurons in slices of rat cerebral cortex. 1) Localisation studies in rodents show a predominance in distinct regions of the central nervous system (CNS) as the H 3 R is mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, and hypothalamus 2-5) ( Fig. 1). In addition, it is expressed in the peripheral nervous system, e.g. in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.In mammalian brain histaminergic neurons originate in the tuberomammillary nucleus (TMN) spreading into above mentioned brain regions, where they control histamine levels by regulation of synthesis and liberation rates 27) and modulate different neuronal systems. 28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2). Interneuron cross-talk and adaptive processes seem to be important factors in H 3 Rmediated signalling. Molecular AspectsThe human histamine H 3 receptor (hH 3 R) cDNA firstly described 1999 encodes a 445 amino acid protein and belongs to the his...

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Section: )mentioning

confidence: 99%

Section: )mentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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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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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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“…We have found in a previous study that histidine, a precursor of histamine, and metoprine, an inhibitor of histamine N-methyltransferase, inhibited amygdala kindled seizures in rats at doses causing an increase in histamine contents of the brain and these effects were antagonized by histamine H 1 antagonists, diphenhydramine and chlorpheniramine. 17) Tuomisto and Tacke also showed that metoprine raised brain histamine concentrations and inhibited maximal electroshock seizures in rats. 18) These reports suggest that histaminergic mechanisms play an important role in the inhibition of seizures through histamine H 1 receptors.…”

Section: Discussionmentioning

confidence: 94%

Influences of Histamine H1 Receptor Antagonists on Maximal Electroshock Seizure in Infant Rats

Ishikawa

Takechi

Rahman

et al. 2007

Biological & Pharmaceutical Bulletin

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The influences of histamine H 1 receptor antagonists on maximal electroshock seizure were studied using infant rats. In this study, electroconvulsion was induced by stimulating rats using ear-clip electrodes, and the durations of electroencephalogram (EEG) seizure, tonic extensor (TE) seizure and clonic (CL) seizure induced by maximal electroshock were measured. Diphenhydramine, chlorpheniramine, cyproheptadine and ketotifen caused a dose-dependent and significant prolongation of both EEG seizure and TE seizure induced by maximal electroshock. On the other hand, epinastine and fexofenadine caused no such effects, even at a dose of 50 mg/kg. All drugs used in this study showed no significant effect on CL seizure induced by maximal electroshock. From these findings, it is suggested that epinastine and fexofenadine may cause no harmful influence on epilepsy, even when used in a little child.

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Histaminergic mechanisms in amygdaloid-kindled seizures in rats

Cited by 74 publications

References 13 publications

Histamine H3 Receptor Antagonists Go to Clinics

Histamine H3 Receptor Antagonists Go to Clinics

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

Influences of Histamine H1 Receptor Antagonists on Maximal Electroshock Seizure in Infant Rats

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