Elsevier

Neuropharmacology

Volume 59, Issue 3, September 2010, Pages 180-189
Neuropharmacology

Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis

https://doi.org/10.1016/j.neuropharm.2010.05.005Get rights and content

Abstract

Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system (CNS). Due to disease complexity and heterogeneity, its pathogenesis remains unknown and despite extensive studies, specific effective treatments have not yet been developed. The factors behind the initiation of the inflammatory reactions in CNS have not been identified until now. MS is considered as a complex disease depending on genetic as well as environmental factors. Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Histamine [2-(4-imidazole) ethylamine] is a ubiquitous inflammatory mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems which can modulate immune responses. Histamine functions are mediated through four G-protein coupled receptors that are named H1–H4 receptor. Histamine is implicated as an important factor in pathophysiology of MS and EAE. It has been shown that histamine can change the permeability of blood brain barrier, which leads to elevation of infiltrated cells in CNS and neuroinflammation. In contrast, there are evidence that show the protective role of histamine in MS and its animal model, EAE. In this review, we try to clarify the role of histamine in pathogenesis of MS, as well as we evaluate the efficacy of histamine receptors agonists and antagonists in treatment of this disease.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) manifested morphologically by inflammation, demyelination, axonal loss and gliosis. The inflammatory lesions are characterized by high infiltration of various population of cellular and soluble mediators of the immune system, such as T cells, B cells, macrophages (MQs) and microglia, as well as a broad range of cytokines, chemokines, antibodies, complement and other toxic substances (Bruck, 2005, Mirshafiey, 2007). The cellular components involved in the neuroinflammation and neuroimmune activation in the cerebrospinal fluid (CSF) are brain microglial cells, ependymal cells, MQs, astrocytes and mast cells. Microglial cells which constitute around 10% of the CNS are the first to respond to neuronal injury (Kulkarni et al., 2004, Mirshafiey and Mohsenzadegan, 2009a).

Histamine is a potent mediator of immediate hypersensitivity reactions, and is stored primarily in mast cells and basophils. It exerts its pharmacologic effects through interaction with histamine H1, H2, H3 and H4 cell surface receptors (H1R–H4R), which promote changes in vascular permeability, levels of cyclic nucleotides, neutrophil and eosinophil chemotaxy, gastrointestional secretion and smooth muscle contraction (as described in Table 1) (Marquardt, 1983). Histamine seems to be primarily a pro-inflammatory agent through H1R mediated activities, whereas its physiological actions is exerted by H2Rs, and H3Rs for gastric acid production and CNS function, respectively (Repka-Ramirez and Baraniuk, 2002). The H4R is the newest identified member of the histamine receptors family (Tiligada et al., 2009). The H4R is involved in chemotaxy and inflammatory mediator release by eosinophils, mast cells, monocytes, dendritic cells and T cells (Huang and Thurmond, 2008).

Brain histamine is involved in a wide range of physiological functions such as regulation of sleep-wake cycle, arousal, appetite control, cognition, learning and memory mainly through the four receptors subtypes: H1, H2, H3 and H4.The neurons which produce histamine (histaminergic neurons), are exclusively located in the tubermammillary nucleus of the posterior hypothalamus that transmit histamine to almost all regions of the brain (Zhang et al., 2006).

It is suggested that, in the transmembrane region TM3, a conserved aspartic acid (amino acid position 107 in H1R, position 98 in H2R, position 114 in H3R and position 94 in H4R) is critical for binding of both histamine and its basic antagonists, presumably by providing a negative counter-ion for the protonated amine group of the ligand (Parsons and Ganellin, 2006). The affinity of histamine for binding to H3R and H4R is higher than its H1R and H2R (Lim et al., 2005, Sander et al., 2008).

Histamine has a long history of therapeutic use in many diseases, such as MS. Five possible mechanisms for histamine actions are postulated: 1) augmentation of subnormal cerebral tissue levels of histamine, 2) improved electrical function of demyelinated fibers, 3) increased cerebral blood flow, 4) suppression of autoimmune responses, and 5) stimulation of remyelination (Gillson et al., 1999). In contrast, it is reported the intravenous administration of histamine to MS patients has no significant effect in amelioration of disease (Smith and Schaller, 1953). Additionally, histamine can enhance microvascular permeability, leukocyte rolling, adhesion, and extravasation of inflammatory cells into the brain and spinal cord (Bebo et al., 1996a). It has been also demonstrated that, histamine, as biogenic amine with a broad range of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Microarray analysis shows that the H1R is overexpressed in the chronic plaques of MS patients. Moreover, mouse genetic studies have shown that histamine, H1R, and H2R play an important role in regulating encephalitogenic T cell responses and susceptibility to EAE (Teuscher et al., 2007, Ma et al., 2002, Musio et al., 2006, Pedotti et al., 2003, Theoharides and Konstantinidou, 2007). In addition, the expression of H1R and H2R on mononuclear cells in inflammatory regions of the brain in EAE model has been reported (Lock et al., 2002, Dimitriadou et al., 2000, Pedotti et al., 2001). The H3R is a recognized drug target for neuronal diseases, such as cognitive impairment, schizophrenia, sleep-wake disorders, epilepsy and neuropathic pain. A few number of the selective H3R antagonists have already passed some clinical phases II trials. Preclinical data robustly suggest the H4R therapeutic exploitation in allergy, inflammation, autoimmune disorders and possibly cancer (Tiligada et al., 2009, Kiss and Keseru, 2009)

Section snippets

Multiple sclerosis

MS, the principal inflammatory demyelinating disease of the CNS is believed to have an immunopathological etiology arising from gene–environment interactions, affecting approximately 0.1% of the population in the northern part of the world. The factors behind the initiation of the inflammatory response remain unknown. However, MS is considered as a complex disease depending on genetic as well as environmental factors (Mirshafiey et al., 2005). Among the genetic factors, some genes have a

Histamine

It is almost one century since Dale et al. isolated histamine from the mould ergot. In continue, they found that it had a stimulatory effect on smooth muscle of the gut and respiratory tract which resulted in vasodepression, stimulated cardiac contractility and induced a shock-like syndrome when injected into animals (Dale and Laidlaw, 1910, Dale and Laidlaw, 1919). For first time, Best et al. in 1927 succeeded to isolate histamine from samples of liver and lung (Best et al., 1927). Histamine

Histamine H1 receptor

The H1R plays an important role in wakefulness and inflammatory responses (Parsons and Ganellin, 2006). In the lung, H1Rs mediate functions such as bronchoconstriction, vasoconstriction and oedema formation (Parsons and Ganellin, 2006). The mice with disrupted H1R gene have a dysregulation in the normal circandian rhythm of locomotor activity and decreased exploratory behavior in a novel environment (Inoue et al., 1996). The gene that encodes human H1R is located on chromosome 3 and its

Histamine H2 receptor

The gene that encodes human H2R is located on chromosome 5 and its product is the seven transmembrane GPCR (Traiffort et al., 1995). H2Rs, expressed in the periphery and in the CNS couple to Gs proteins. In the periphery, the main role of the H2R is the regulation of gastric acid secretion in the parietal cells in the endothelium. Furthermore, the H2R mediates relaxation of airway and vascular smooth muscle. In the CNS, H2Rs are also mainly located postsynaptically and are widely expressed

Histamine H3 receptor

For first time, Arrang et al. in 1983 was discovered the H3R as the autoreceptor, which did regulate the secretion and generation of histamine (Arrang et al., 1983). The gene that encodes human H3R is located on chromosome 20 and produces seven transmembrane GPCR which contains 445 amino acids (Cogé et al., 2001a, Goodearl, 1999, Goodearl and Glucksman, 2000, Lovenberg et al., 1999; Lovenberg et al., 2000a, Lovenberg et al., 2000b, Lovenberg et al., 2002, Tardivel-Lacombe et al., 2001). In two

Histamine H4 receptor

Oda et al. for first time in 2000 identified the H4R (Oda et al., 2000). Surprisingly, it has been reported that H4R can interact with CCL16 chemokine, in addition to histamine, which leads to migration of mouse eosinophils from bone marrow to peripheral blood (Nakayama et al., 2004). H4R homology to H3R is 39% and to H1 and H2R only about 19% (Oda et al., 2000, Nakayama et al., 2004, Liu et al., 2001, Morse et al., 2001, Nakamura et al., 2000, Zhu et al., 2001). The gene that encodes human H4R

Multiple sclerosis and Histamine

The inflammatory features of histamine in the immune reactions, have made it as an important factor in pathogenesis of various allergic and autoimmune disease. Since years ago, researchers in various studies tried to detect the role of histamine in pathogenesis and/or treatment of MS (Smith and Schaller, 1953, Bramson, 1949, Jonez, 1948, Jonez, 1950a, Jonez, 1950b, Rieder et al., 1963, Bramson, 1948). In this field, determination of blood or CSF levels of histamine in MS patients could help

Conclusion

The correlation between histamine and MS was an interesting field for researchers since years ago. Several studies have been carried out for treating MS based on the use of histamine as therapeutic agent (Jonez, 1948, Jonez, 1950a, Jonez, 1950b, Rieder et al., 1963). The Dual effects of histamine in treating and/or worsening the MS disease and its animal model, EAE, is made a confusing question about its exact role in pathophysiology of MS: it is protective or deleterious? With regard to data

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