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Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability.

ABSTRACT: BACKGROUND AND PURPOSE:Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H(3) receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H(4) receptor) to influence vestibular system function, using a selective H(4) receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584. EXPERIMENTAL APPROACH:RT-PCR was used to assess the presence of H(4) receptors in rat primary vestibular neurons. In vitro electrophysiological recordings and in vivo behavioural approaches using specific antagonists were employed to examine the effect of H(4) receptor modulation in the rat vestibular system. KEY RESULTS:The transcripts of H(4) and H(3) receptors were present in rat vestibular ganglia. Application of betahistine inhibited the evoked action potential firing starting at micromolar range, accompanied by subsequent strong neuronal depolarization at higher concentrations. Conversely, reversible inhibitory effects elicited by JNJ 10191584 and JNJ 7777120 began in the nanomolar range, without inducing neuronal depolarization. This effect was reversed by application of the selective H(4) receptor agonist 4-methylhistamine. Thioperamide, a H(3) /H(4) receptor antagonist, exerted effects similar to those of H(3) and H(4) receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100?µM. H(4) receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects. CONCLUSIONS AND IMPLICATIONS:H(4) receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H(4) receptors as pharmacological targets for the treatment of vestibular disorders.

SUBMITTER: Desmadryl G

PROVIDER: S-EPMC3575788 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability.

Desmadryl G G Gaboyard-Niay S S Brugeaud A A Travo C C Broussy A A Saleur A A Dyhrfjeld-Johnsen J J Wersinger E E Chabbert C C

British journal of pharmacology 20121001 4

<h4>Background and purpose</h4>Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H(3) receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H(4) receptor) to influence vestibular system function, using a selective H(4) receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584.<h4>Experimental approach</h4>RT-PCR was used to assess the presence of H(4) receptors in rat primary ve ...[more]

PMID: 22624822

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Project description:The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into clinical efficacy in humans.

Dataset Information

Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability.

Publications

Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability.

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