Journal
MOLECULAR IMMUNOLOGY
Volume 111, Issue -, Pages 118-127Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2019.04.008
Keywords
Phenothiazine antipsychotics; Pseudo-allergic reactions; MRGPRX2; H-1 receptor antagonist; Mast cell
Categories
Funding
- National Natural Science Foundation of China [81230079, 81227802]
Ask authors/readers for more resources
Phenothiazines are a class of antipsychotics that share the same tricyclic structure and are widely used in clinical settings. Adverse reactions from these drugs, however, have been regularly reported, with allergic skin reactions noted in some cases. Nevertheless, the mechanisms underlying anaphylaxis by these drugs have not been described. In the present study, we found that phenothiazine antipsychotics increased calcium mobilization and activated mast cells to release beta-hexosaminidase, histamine, and tumor necrosis factor-alpha via Mas-related G-protein-coupled receptor member X2 (MRGPRX2) in vitro. In addition, they induced histamine release in serum via Mrgprb2 in C57BL/6 mice without Evans blue extravasation or paw swell. Further experiments indicated these drugs had good interaction with the histamine H-1 receptor (H1R) and show an anti-calcium mobilization effect on H1R-HEK293 cells, which confirmed a potential antagonist effect of these drugs on the H1R. The molecular docking and activity experiments indicated that the N-methyl substitution on the side chain of these drugs played a significant role in activating MRGPRX2, while the phenothiazine tricyclic ring was associated with the inhibiting effect on the H1R. Therefore, due to their dual properties of increasing histamine levels without obvious allergic symptoms, clinicians should be highly vigilant for damage from histamine accumulation and long-term inflammatory reactions during the clinical use of phenothiazine antipsychotics.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available