title: P2X7 receptor antagonist activity of the anti-allergic agent oxatomide.
abstract: Activation of the P2X7 receptor by extracellular ATP is associated with various immune responses including allergic inflammation. Anti-allergic agents, such as H1-antihistamines, are known to inhibit the effects of different chemical mediators such as acetylcholine and platelet-activating factor. Therefore, we hypothesized that some anti-allergic agents might affect P2X7 receptor function. Using N18TG2 and J774 cells, which express functional P2X7 receptors, the effects of several anti-allergic agents on P2X7 receptor function were investigated by monitoring the ATP-induced increase in intracellular Ca(2+) concentrations ([Ca(2+)]i). Among the various agents tested, oxatomide significantly inhibited P2X7 receptor-mediated [Ca(2+)]i elevation in a concentration-dependent manner without affecting the P2Y2 receptor-mediated response in both N18TG2 and J774 cells. Consistently, oxatomide inhibited P2X7 receptor-mediated membrane current and downstream responses such as mitogen-activated protein kinase activation, inflammation-related gene induction, and cell death. In addition, oxatomide inhibited P2X7 receptor-mediated degranulation in mouse bone marrow-derived mast cells. Whole cell patch clamp analyses in HEK293 cells expressing human, mouse, and rat P2X7 receptors revealed that the inhibitory effect of oxatomide on ATP-induced current was most prominent for the human P2X7 receptor and almost non-existent for the rat P2X7 receptor. The potent inhibitory effects of oxatomide on human P2X7 receptor-mediated function were confirmed in RPMI8226 human B cell-like myeloma cells, which endogenously express the P2X7 receptor. Our results demonstrated that the antihistamine oxatomide also acts as a P2X7 receptor antagonist. Future studies should thus evaluate whether P2X7 receptor antagonism contributes to the anti-allergic effects of oxatomide.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunma 370-0033, Japan. Electronic address: 0721094@takasaki-u.ac.jp.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunma 370-0033, Japan. Electronic address: mito@takasaki-u.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunma 370-0033, Japan. Electronic address: isao@takasaki-u.ac.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsuoka
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*
chemical_list: D018926:Anti-Allergic Agents; D054426:Chemokine CXCL2; D010879:Piperazines; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D017455:Receptors, IgE; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; C015408:oxatomide; D002118:Calcium
keywords: ATP; Anti-allergy; Antihistamine; Membrane current; Oxatomide; Oxatomide (PubChem CID: 4615); P2X7 receptor