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  • br Conclusion Leukocytes adhesion to endothelial cells is


    Conclusion Leukocytes adhesion to endothelial cells is one of the most critical event in the inflammatory response. In presented paper using a relevant model of adhesion we have demonstrated that histamine influence eosinophils adhesion to endothelium. This effect appears to be mediated by H4 histamine receptor, while H1, H2 and H3 histamine receptors are not involved.
    Conflict of interest
    Acknowledgements This work was supported by the NCN grant: “Research on human eosinophils as a potential therapeutic target” DEC/2014/13/N/NZ7/00897, “Histamine H3/H4 receptors as an attractive target for the search of biologically active compounds” DEC/2011/02/A/NZ4/00031, and European Regional Development Fund under the Innovative Economy Programme (grant coordinated by JCET-UJ, NoPOIG.01.01.02-00-069/09).
    Introduction The brain's histaminergic (HA) modulatory system has received less attention as a locus of pathology and potential therapeutic target than the monoaminergic systems (Haas et al., 2008, Panula and Nuutinen, 2013). However, its anatomical organization has much in common with the more extensively studied dopaminergic, serotonergic, and noradrenergic systems. Histaminergic neurons are clustered in the posterior hypothalamus, from which they project broadly throughout the central nervous system. Acting on four G-protein coupled receptors, H1R–H4R, they have diverse modulatory effects throughout the brain. Given this capacity for widespread modulation of neuronal information processing, alterations in HA neurotransmission are likely to contribute to disruptions in prostaglandin endoperoxide synthase function and thus to neuropsychiatric disease. There has long been interest in brain histamine receptors, especially the H3 receptor, as potential therapeutic targets (Sander et al., 2008, Schwartz, 2011). In recent years the role of HA dysregulation as a pathophysiological contributor to a range of illnesses has begun to come into sharper focus (Ercan-Sencicek et al., 2010, Shan et al., 2015a). Importantly, these two lines of work need not converge – histaminergic modulation may prove to be therapeutically useful even in conditions in which HA dysregulation is not central to pathophysiology. H3 antagonists are particularly promising in the treatment of narcolepsy and extensive daytime sleepiness, as reviewed below; investigations are ongoing in a range of other conditions. This remains an area of rapid development and significant therapeutic promise.
    Dysregulation in histamine signaling in Tourette syndrome Motor and vocal tics occur in approximately 5% of the population; Tourette syndrome represents the most severe end of a spectrum of tic disorders and affects ∼0.3–1.0% (Scahill et al., 2013). Many cases improve with age, but severe cases can persist and cause profound morbidity (Bloch et al., 2013). Available therapies are of limited efficacy and are often limited by side effects (Bloch, 2008, Eddy et al., 2011). A landmark genetic study in 2010 identified a rare, dominant-acting mutation in the histidine decarboxylase (Hdc) gene, which encodes the enzyme required for the conversion of histidine into histamine, as a putative cause of Tourette syndrome in a single family with an exceptionally high incidence of the disorder (Ercan-Sencicek et al., 2010). This represents the first time that abnormalities in histaminergic neurotransmission have been clearly implicated as causative in any neuropsychiatric condition. The implicated nonsense mutation truncates the protein and produces a mutant enzyme that is unable to convert histidine into histamine; in vitro, it functions as a dominant negative, interfering with the ability of wild-type protein to produce histamine (Ercan-Sencicek et al., 2010). This mutation is, thus far, unique to the index family. However, subsequent genetic studies have provided evidence that other abnormalities in histaminergic signaling may also increase risk for TS. A candidate gene study by Karagiannidis and colleagues examined polymorphisms in the Hdc gene and found overtransmission of two single nucleotide polymorphisms (SNPs) and the associated haplotypes in TS patients (Karagiannidis et al., 2013). While candidate gene studies have a poor track record in neuropsychiatric disease and such findings should thus be treated with caution (Fernandez et al., 2015), this finding, if replicated, suggests that common polymorphisms, not just the high-penetrance but rare mutation described initially, can contribute to TS risk in the population. A recent study of copy number variation (CNVs) provide further support for abnormalities in HA signaling in TS patients beyond the original family (Fernandez et al., 2012). Importantly, it was not the Hdc gene itself that was implicated by this CNV study, but rather signaling through the H1R and H2R pathways. While further studies in larger cohorts of patients are needed, this CNV study provides convergent evidence for dysregulation of histaminergic signaling as an important causal factor in at least some cases of TS.