A Pilot, Open Label, Clinical Trial Using Hydroxyzine in Multiple Sclerosis

Logothetis, I.; Mylonas, I. A.; Baloyannis, Stavros; Pashalidou, M.; Orologas, A.; Zafeiropoulos, A.; Kosta, Vasiliki; Theoharides, Theoharis C.

doi:10.1177/039463200501800421

Cited by 43 publications

(33 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Epidemiological data indicate that use of sedating H 1 R antagonists is associated with decreased MS risk (13). In a small pilot study, patients with relapsing-remitting or relapsing-progressive MS given the H 1 R antagonist hydroxyzine remained stable or improved neurologically (14). Microarray analysis revealed that the H 1 R was overexpressed in the chronic plaques of MS patients (15).…”

Section: H Istamine [2-(4-imidazole) Ethylamine] (Ha) Is a Ubiquitousmentioning

confidence: 99%

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Teuscher

Subramanian

Noubade

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Histamine (HA), a biogenic amine with a broad spectrum of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. HA exerts its effect through four G protein-coupled receptors designated HA receptor H 1, H2, H3, and H4. We report here that, compared with wild-type animals, mice with a disrupted HA H 3 receptor (H3RKO), the expression of which is normally confined to cells of the nervous system, develop more severe disease and neuroinflammation. We show that this effect is associated with dysregulation of bloodbrain barrier permeability and increased expression of MIP-2, IP-10, and CXCR3 by peripheral T cells. Our data suggest that pharmacological targeting of the H 3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease.blood-brain barrier ͉ experimental allergic encephalomyelitis ͉ multiple sclerosis H istamine [2-(4-imidazole) ethylamine] (HA) is a ubiquitous mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems (1). HA is a potent mediator of inflammation and a regulator of innate and adaptive immunity (2). HA exerts its effect through four G proteincoupled receptors [H 1 , H 2 , H 3 , and H 4 receptor, designated according to the chronological order of their discovery (1)].HA is implicated in the pathophysiology of multiple sclerosis (MS) and its animal models, collectively termed experimental allergic encephalomyelitis (EAE). HA and agents causing the release of HA from mast cells, the primary source of HA in the body (3), alter blood-brain barrier (BBB) permeability. Tissue levels of HA correlate with the onset of EAE (4-6). Inhibitors of mast cell degranulation and H 1 R and H 2 R antagonists modify EAE severity (7)(8)(9)(10)(11)(12). Epidemiological data indicate that use of sedating H 1 R antagonists is associated with decreased MS risk (13). In a small pilot study, patients with relapsing-remitting or relapsing-progressive MS given the H 1 R antagonist hydroxyzine remained stable or improved neurologically (14). Microarray analysis revealed that the H 1 R was overexpressed in the chronic plaques of MS patients (15). Moreover, mouse genetic studies have shown that HA, H 1 R, and H 2 R play an important role in regulating encephalitogenic T cell responses and susceptibility to EAE (16-18). The role of H 3 R and H 4 R in EAE and MS has not been studied.H 3 R is not normally expressed by hematopoietic cells; rather, it is expressed presynaptically where it is an inhibitory autoreceptor (inhibits release of HA from histaminergic neurons) and heteroreceptor (inhibits release of other neurotransmitters such as acetylcholine, noradrenaline, dopamine, and 5-HT from nonhistaminergic neurons) (19). Absence of presynaptic inhibition results in failure to limit neurotransmitter rel...

show abstract

Section: H Istamine [2-(4-imidazole) Ethylamine] (Ha) Is a Ubiquitousmentioning

confidence: 99%

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Teuscher

Subramanian

Noubade

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…H 1 R protein and mRNA are highly expressed in MS lesions (17), and H 1 antihistamines reduce EAE in mice and rats (17,18). In patients with MS, the use of sedating H 1 antihistamines is correlated with decreased disease incidence and amelioration of symptoms (19,20). Our laboratory has shown that susceptibility to Bphs and EAE requires expression of Hrh1, the gene encoding H 1 R (21).…”

mentioning

confidence: 99%

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Lu¹,

Diehl²,

Noubade³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertussis-induced histamine sensitization (Bphs) T he blood-brain barrier (BBB) involves endothelial cells that line the blood vessels of the central nervous system (CNS) and the tight junction protein complexes between these endothelial cells. The BBB thereby acts as a physical and metabolic barrier by separating the vasculature from the parenchyma of the CNS (1). Breakdown of the BBB is associated with the onset and pathogenesis of multiple sclerosis (MS), a degenerative, demyelinating, inflammatory disease of the CNS (2). In MS and its autoimmune model, experimental autoimmune encephalomyelitis (EAE), activated T cells cross the BBB into the perivascular space of the CNS, causing damage to neurons (2). Surveillance of the CNS by T cells does occur (3), but the paucity of leukocytes found in the CNS under noninflammatory conditions suggests that extravasation of cells across the BBB is tightly regulated. Therefore, identifying factors that modulate BBB permeability may be of therapeutical value in treating inflammatory demyelinating diseases of the CNS.Bordetella pertussis-induced hypersensitivity to histamine (Bphs/ Bphs) is a genetically controlled intermediate phenotype associated with susceptibility to EAE (4). Bphs is a state wherein mice are rendered highly susceptible to histamine after a preceding injection of B. pertussis toxin (PTX) (5). Bphs-susceptible strains of mice die within 30 min after histamine challenge, presumably attributable to hypotensive and hypovolemic shock. The cells targeted during Bphs are not known. Histamine has also been implicated in the pathophysiology of MS and EAE. Increased tissue levels of histamine correlate with the onset of EAE (6-8). Mast cells, the major source of histamine (9), are present in MS lesions (10-12), and evidence of mast cell activation is found in the cerebrospinal fluid (CSF) of patients who have MS (13). In mice, mast cells (14) and their activation (15) are required for early EAE onset and maximal disease severity.The effects of histamine are mediated by four surface histamine receptors: H 1 R, H 2 R, H 3 R, and H 4 R (16). H 1 R protein and mRNA are highly expressed in MS lesions (17), and H 1 antihistamines reduce EAE in mice and rats (17,18). In patients with MS, the use of sedating H 1 antihistamines is correlated with decreased disease incidence and amelioration of symptoms (19,20). Our laboratory has shown that susceptibility to Bphs and EAE requires expression of Hrh1, the gene encoding H 1 R (21).Expression of H 1 R on T cells is required for their full encephalitogenic potential (22), but the contribution of H 1 R signaling in other cell types to the pathogenesis of EAE has not been formally addressed. In this study, w...

show abstract

“…These facts, as well as the finding that elevated concentrations of mast cell specific protease is present in the cerebrospinal fluid of MS patients [11], and the increase in mast cell transcripts within and outside MSlesions [23], supports the importance of mast cells for the onset and/or maintenance of MS. The report that histamine-1 receptor antagonist hydroxyzine, which partially inhibits brain mast cells, may reduce MS symptoms in females and males [24] further emphasises the importance of mast cells in MS.…”

Section: Discussionmentioning

confidence: 95%

“…The possible immediate treatment of MS, based on the assumption that mast cells have some key-role, would be the application of mast cell blockers, to inhibit secretion of histamine and proteases and/or antihistamines as recently designed by others [24] to inhibit the histamineinduced oedema formation and protease induced demyelination. Local down-regulation of the blood-brain barrier leads to enhanced mediator access onto the perivascular mast cells.…”

Section: Discussionmentioning

confidence: 99%

Mast cells and multiple sclerosis in females and males

Krüger¹,

Mörk²

2012

WJNS

View full text Add to dashboard Cite

Mast cells were observed in autopsies from 11 females and 8 males. We confirm earlier observations that mast cells are more frequent in close vicinity to MSplaques. In these plaque-border zone areas, defined as the area within 1 mm distance of the actual plaques, the average number of mast cells was 2.34/mm 2 in males and 4.77/mm 2 in females, which in average is appr. 10 times more than earlier observed in MS. The difference in number of mast cells between females and males is significant (p < 0.005) and is of interest since females are more inclined to developing MS than males. Mast cells were rare in areas without visible plaques. The mast cells were preferably located close to capillaries and venules. A mechanism for the probable role of mast cells, based on diet-factors and mast cell mediators in the pathogenesis of MS is discussed.

show abstract

A Pilot, Open Label, Clinical Trial Using Hydroxyzine in Multiple Sclerosis

Cited by 43 publications

References 37 publications

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Mast cells and multiple sclerosis in females and males

Contact Info

Product

Resources

About

A Pilot, Open Label, Clinical Trial Using Hydroxyzine in Multiple Sclerosis

Cited by 43 publications

References 37 publications

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Endothelial histamine H 1 receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis

Mast cells and multiple sclerosis in females and males

Contact Info

Product

Resources

About

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Endothelial histamine H ₁ receptor signaling reduces blood–brain barrier permeability and susceptibility to autoimmune encephalomyelitis