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  • Histamine H and H receptor


    Histamine H2 and H3 receptor expression is altered in the gap27 of Hdc mice (Chepkova et al, 2012, Fitzsimons and et al, 2001). Because these mice lack HA, expression of HA receptors might be thought to be irrelevant. This is not the case in Hdc heterozygotes, however, or in patients with a heterozygous abnormality in the Hdc gene (Ercan-Sencicek et al., 2010) or in some other component of histaminergic signaling (Fernandez et al., 2012). Furthermore, developing insights into the function of the H3R histamine receptor, described elsewhere in this volume (CITE ARIAS-MONTANO, THIS VOLUME), suggest its potential to influence cellular events even in the absence of HA. H3R expression is restricted to the central nervous system. It is a G-protein-coupled receptor that is typically coupled to Gαi. Unlike most G-protein-coupled receptors, H3R has a high basal activity, meaning it may produce significant basal Gαi activity, as well as corresponding activity by Gβ/γ subunits, even in Hdc knockout animals (Morisset and et al., 2000). Furthermore, H3R has recently been shown to heterodimerize with both D1R and D2R dopamine receptors and to modulate their coupling to intracellular signaling cascades in the striatum in complex ways (Ferrada et al, 2008, Ferrada et al, 2009, Moreno et al, 2011, Moreno et al, 2014). Expression of H3Rs is elevated in the basal ganglia in the Hdc knockout model of TS (M. Rapanelli and C Pittenger, unpublished); even in the absence of HA tone, such receptor dysregulation may alter intracellular signaling. Such observations, together with the fact that H3R is largely specific to the central nervous system and therefore may be pharmacologically targeted with little concern about peripheral side effects, has led to considerable interest in this receptor as a potential therapeutic target in TS (Hartmann et al., 2012). A controlled initial efficacy trial of the H3R antagonist AZD5213 in adolescents with TS recently completed data collection (NCT01904773); results have yet to be reported.
    Conclusion The histaminergic system was slower to be appreciated as a potential player in the pathophysiology and treatment of neuropsychiatric disease than other aminergic modulatory systems, but it is well positioned to modulate a range of clinically important neural systems and behavioral functions. Evidence for a pathophysiological role is strongest in Tourette syndrome, thanks to a pair of important genetic studies and subsequent analysis of the Hdc knockout mouse as a pathophysiologically grounded model of the disorder. Preclinical studies suggest a role for HA in arousal and cognitive function. H3R antagonism has been particularly closely studied; this receptor is expressed primarily or exclusively in the central nervous system, and therefore it can be pharmacologically targeted with minimal concern about peripheral side effects. There is preclinical evidence suggesting potential benefit from H3R antagonism in several disorders; clinically, pilot studies have been disappointing in schizophrenia and attention deficit disorder but quite promising in narcolepsy and other conditions characterized by hypersomnia.
    Introduction Atherosclerotic cardiovascular disease (ASCD) is the leading cause of morbidity and mortality in the United States [1]. Currently, 3-hydroxy-3-methyl-glutaryl- (HMG) coenzyme A reductase inhibitors (statins) targeting low-density lipoprotein cholesterol (LDL-C) are the cornerstone for treatment of ASCD, though significant residual risk remains [2]. One important element of prevention may be therapies targeting high-density lipoprotein cholesterol (HDL-C), the levels of which are inversely correlated with ASCD [3, 4]. This has been examined in several clinical trials with drugs that enhance HDL-C levels, including niacin [5, 6] and cholesteryl ester transfer protein (CETP) inhibitors [7, 8]. However, these studies, with the exception of one, have failed in attaining their primary endpoints and several were halted for their futility. Importantly, several genetic studies have also failed to demonstrate that individuals with high HDL-C levels are protected from developing ASCD [9, 10] prompted a revision of the “HDL hypothesis” to consider HDL functionality instead. One approach to counter this is to develop drugs that target de novo apolipoprotein A-I (apo A-I) synthesis [11, 12]. About 70% of plasma apo A-I is derived from the liver while 30% is from the small intestine. Apo A-I gene transcription is regulated by several factors including hormones such as cortisol and retinoids, fatty acids including several endogenous peroxisome proliferator receptor α (PPARα) ligands, and some pro-inflammatory mediators such as tumor necrosis factor α (TNF α) and interleukin-1β (IL-1β) [13]. While the former stimuli induce apo A-I gene expression, TNF α and IL-1β suppress apo A-I gene transcription by interfering with PPARα function [13]. Newly synthesized nascent HDL-C has been shown to be the preferred substrate for cholesterol efflux from macrophages onto HDL-C or apo A-I by the ATP binding cassette protein A1 (ABCA1) expressed in macrophages [14], the first step in the process of reverse cholesterol transport. Both fibrates and statins have been shown to induce apo A-I expression by stimulating PPARα [15, 16]. Another drug that targets apo A-I gene transcription, RVX-208 [17], is currently in clinical trials though initial results have been somewhat disappointing [18, 19]. Furthermore, fibrates, statins, and RVX-208 have only modest effects on HDL-C levels in vivo. Therefore, there is a strong need to understand and identify novel regulators of apo A-I gene expression.