The effect of the tachykinin NK2 receptor antagonist MEN11420 (nepadutant) on neurokinin A-induced bronchoconstriction in asthmatics

Schelfhout, Venessa; Velde, Veerle Van de; Maggi, Carlo Alberto; Pauwels, Romain; Joos, Guy

doi:10.1177/1753465809349741

Cited by 16 publications

(18 citation statements)

References 20 publications

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“…However, based on abstract, only seven studies appeared to meet the inclusion criteria and their full text was obtained (Figure 1). Therefore, we included 7 studies comprising the use of five tachykinin receptors antagonists: NK-2 in two [10-12], NK-1/NK-2 in four [11,13-15] and NK-1/NK-2/NK-3 in other one [16], referring to a total of 98 subjects (Table 1). All studies used different doses of tachykinin receptors antagonists.…”

Section: Resultsmentioning

confidence: 99%

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Tachykinin receptors antagonism for asthma: a systematic review

et al. 2011

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BackgroundTachykinins substance P, neurokinin A and neurokinin B seem to account for asthma pathophysiology by mediating neurogenic inflammation and several aspects of lung mechanics. These neuropeptides act mainly by their receptors NK1, NK2 and NK3, respectively which may be targets for new asthma therapy.MethodsThis review systematically examines randomized controlled trials evaluating the effect of tachykinins receptors antagonism on asthma. Symptoms, airway inflammation, lung function and airway inflammation were considered as outcomes. We searched the Cochrane Airways Group Specialized Register of Asthma Trials, Cochrane Database of Systematic Reviews, MEDLINE/PubMed and EMBASE. The search is as current as June 2010. Quality rating of included studies followed the Cochrane Collaboration and GRADE Profiler approaches. However, data were not pooled together due to different measures among the studies.ResultsOur systematic review showed the potential of NK receptor antagonist to decrease airway responsiveness and to improve lung function. However, effects on airway inflammation and asthma symptoms were poorly or not described.ConclusionThe limited available evidence suggests that tachykinin receptors antagonists may decrease airway responsiveness and improve lung function in patients with asthma. Further large randomized trials are still required.

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Section: Resultsmentioning

confidence: 99%

“…Regarding treatment dosages, 5 studies used single-doses [11-13,15,16] while in 2 studies doses of antagonists were given during 2 and 9 consecutive days [10,14]. Antagonists were administered by inhalation in 3 studies [10,15,16] and orally in 4 studies [11-14]. None of the studies reported changes in asthma symptoms as an outcome.…”

Section: Resultsmentioning

confidence: 99%

Tachykinin receptors antagonism for asthma: a systematic review

et al. 2011

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“…Therefore, release of tachykinins by the excitation of these nerve systems is thought to be involved in the pathogenesis of airway allergy in humans (14,15). Because those factors are produced in the airway tissues during inflammatory responses, developing therapy that blocks the tachykinin-dependent signaling cascade might be beneficial for the treatment of allergic inflammation (16)(17)(18).…”

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confidence: 99%

“…Recent articles indicated that SP regulates the function of various leukocytes, such as vascular endothelial growth factor secretion from mast cells (19), cytotoxicity of NK cells (20), cytokine production by monocytes and T cells (21,22), induction of chemokine or chemokine receptor of macrophages (23,24), and Ag presentation of dendritic cells (DCs) (25). In contrast, NKA is known to control various vital responses, such as airway contraction, vasodilatation, and vascular permeability, in humans (15,16,26). However, the function of NKA in the immune system is less-well defined compared with the role of SP.…”

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confidence: 99%

Neuropeptide Signaling Activates Dendritic Cell-Mediated Type 1 Immune Responses through Neurokinin-2 Receptor

Kitamura

Kobayashi

Wakita

et al. 2012

The Journal of Immunology

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Neurokinin A (NKA), a neurotransmitter distributed in the central and peripheral nervous system, strictly controls vital responses, such as airway contraction, by intracellular signaling through neurokinin-2 receptor (NK2R). However, the function of NKA–NK2R signaling on involvement in immune responses is less-well defined. We demonstrate that NK2R-mediated neuropeptide signaling activates dendritic cell (DC)-mediated type 1 immune responses. IFN-γ stimulation significantly induced NK2R mRNA and remarkably enhanced surface protein expression levels of bone marrow-derived DCs. In addition, the DC-mediated NKA production level was significantly elevated after IFN-γ stimulation in vivo and in vitro. We found that NKA treatment induced type 1 IFN mRNA expressions in DCs. Transduction of NK2R into DCs augmented the expression level of surface MHC class II and promoted Ag-specific IL-2 production by CD4+ T cells after NKA stimulation. Furthermore, blockade of NK2R by an antagonist significantly suppressed IFN-γ production by both CD4+ T and CD8+ T cells stimulated with the Ag-loaded DCs. Finally, we confirmed that stimulation with IFN-γ or TLR3 ligand (polyinosinic-polycytidylic acid) significantly induced both NK2R mRNA and surface protein expression of human PBMC-derived DCs, as well as enhanced human TAC1 mRNA, which encodes NKA and Substance P. Thus, these findings indicate that NK2R-dependent neuropeptide signaling regulates Ag-specific T cell responses via activation of DC function, suggesting that the NKA–NK2R cascade would be a promising target in chronic inflammation caused by excessive type 1-dominant immunity.

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“…The NK-2 receptor exhibits the highest affinity for neurokinin A. Neurokinin A is known to control various vital responses in humans, such as airway contraction, vasodilatation, and vascular permeability [137]. The function of neurokinin A in the immune system is less well defined compared with the role of substance P. One study reported that neurokinin A stimulation induced mRNA expression of type I interferons, upregulated expression of MHC class II molecules, and antigen presentation by DC, thereby enhancing DC function [138] and subsequently inducing CD4 + and CD8 + T cell responses.…”

Section: Regulation Of the Immune System By The Neuroendocrine Sysmentioning

confidence: 99%

Neuroendocrine Immunoregulation in Multiple Sclerosis

Deckx

Lee

Berneman

et al. 2013

Clinical and Developmental Immunology

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Currently, it is generally accepted that multiple sclerosis (MS) is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses that lead to damage of myelin. In this respect, intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress as well as a variety of other lifestyle interventions can influence the neuroendocrine system. On its turn, it has been demonstrated that the neuroendocrine system has immunomodulatory potential. Moreover, the neuroendocrine and immune systems communicate bidirectionally via shared receptors and shared messenger molecules, variously called hormones, neurotransmitters, or cytokines. Discrepancies at any level can therefore lead to changes in susceptibility and to severity of several autoimmune and inflammatory diseases. Here we provide an overview of the complex system of crosstalk between the neuroendocrine and immune system as well as reported dysfunctions involved in the pathogenesis of autoimmunity, including MS. Finally, possible strategies to intervene with the neuroendocrine-immune system for MS patient management will be discussed. Ultimately, a better understanding of the interactions between the neuroendocrine system and the immune system can open up new therapeutic approaches for the treatment of MS as well as other autoimmune diseases.

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The effect of the tachykinin NK2 receptor antagonist MEN11420 (nepadutant) on neurokinin A-induced bronchoconstriction in asthmatics

Abstract: In conclusion, the tachykinin NK(2) receptor antagonist nepadutant significantly inhibits bronchoconstriction induced by neurokinin A in patients with asthma.

Cited by 16 publications

References 20 publications

Tachykinin receptors antagonism for asthma: a systematic review

Tachykinin receptors antagonism for asthma: a systematic review

Neuropeptide Signaling Activates Dendritic Cell-Mediated Type 1 Immune Responses through Neurokinin-2 Receptor

Neuroendocrine Immunoregulation in Multiple Sclerosis

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