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

Abstract

BACKGROUND AND PURPOSEBetahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H3 receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H4 receptor) to influence vestibular system function, using a selective H4 receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584. EXPERIMENTAL APPROACHRT-PCR was used to assess the presence of H4 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 H4 receptor modulation in the rat vestibular system. KEY RESULTSThe transcripts of H4 and H3 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 H4 receptor agonist 4-methylhistamine. Thioperamide, a H3/H4 receptor antagonist, exerted effects similar to those of H3 and H4 receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 mM. H4 receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects. CONCLUSIONS AND IMPLICATIONSH4 receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H4 receptors as pharmacological targets for the treatment of vestibular disorders. Abbreviations

The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature

“…Moreover, JNJ 10191584 and JNJ 7777120 ameliorated the symptoms in two different rat models of vestibular deficits (3,3 0 -iminodipropionitrile injection and kainate-induced unilateral excitotoxic insult) (Desmadryl et al, 2012). Furthermore, H 4 R mRNA was detected in the vestibular ganglion of rats by RT-PCR (Desmadryl et al, 2012).…”

“…A publication by Desmadryl et al (2012) attracted some interest, because it reported that the selective H 4 R antagonists JNJ 10191584 and JNJ 7777120 reduced the electrically evoked discharge volley of primary vestibular neurons in a reversible, 4-MH-sensitive and concentration-dependent manner (Desmadryl et al, 2012). Moreover, JNJ 10191584 and JNJ 7777120 ameliorated the symptoms in two different rat models of vestibular deficits (3,3 0 -iminodipropionitrile injection and kainate-induced unilateral excitotoxic insult) (Desmadryl et al, 2012).…”

“…First, a suited knockout model would be needed to ensure target-specific action of the H 4 R antagonists. Second, expression of H 4 R was only determined by conventional RT-PCR and required a second amplification step (nested PCR), indicating very low mRNA concentrations (Desmadryl et al, 2012). Third, the results were not yet reproduced by independent research groups.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…mRNA expression of both the full-length H 4 receptor and one of the deletion forms has also been detected in a rat brain endothelial cell line using reversetranscription polymerase chain reaction and sequencing (Karlstedt et al, 2013). The H 4 receptor may also be involved in the vestibular system, because expression of the receptor has been reported in vestibular nucleus neurons and ganglia in rats (Desmadryl et al, 2012;Zhang et al, 2013). Overall, the presence of the H 4 receptor in afferent pathways including dorsal root ganglion, spinal cord dorsal horn, and thalamus, as well as in other CNS areas, appears to be entirely consistent with a role in sensory signaling.…”

“…In whole cell clamp recordings of layer IV somatosensory cortex cells from mice, H 4 receptor-induced hyperpolarization has been reported with a single H 4 receptor agonist, antagonist, and respective dose (Connelly et al, 2009); confirmation is required with multiple ligands and a full concentration range. In rat vestibular neurons, treatment H 4 receptor antagonist led to inhibitory effects on the action potential (Desmadryl et al, 2012). In addition it has been shown that the receptor also mediated action potential discharge in human submucosal neurons (Breunig et al, 2007).…”