Dictamnine is an effective anti‐anaphylactoid compound acting via the MrgX2 receptor located on mast cells

Abstract

Anaphylactoid reactions are potentially fatal allergic diseases caused by mast cells (MCs), which release histamine and lipid mediators under certain stimuli. Therefore, there is an urgent need to develop new drug candidates to treat anaphylactoid reactions. The MrgX2 receptor mediates anaphylactoid reactions that cause inflammatory diseases. Cortex dictamni is a Chinese herb used for treating allergy‐related diseases; however, its active compound is still unknown and its mechanism of action has not yet been reported. The aim of this study was to screen the anti‐anaphylactoid compound from C. dictamni extracts. An MrgX2/CMC‐HPLC method was established for screening MrgX2‐specific compounds retained from the alcohol extract of C. dictamni. A mouse model of hindpaw extravasation was used to evaluate the anti‐anaphylactoid effect of this ingredient. Intracellular Ca2+ mobilization was assessed using a calcium imaging assay. Enzyme immunoassays were performed to measure cytokine and chemokine release levels. The molecular signaling pathways were explored by western blotting. As a result, dictamnine was identified as an effective compound using the MrgX2/CMC method, which remarkably suppressed MC intracellular Ca2+ mobilization and the release of de novo degranulated substances, and inhibited PKC‐PLCγ‐IP3R‐associated protein signaling molecules. Hence, dictamnine is a novel therapeutic candidate for anaphylactoid reactions via MrgX2.

Anti‐inflammatory effect of dictamnine on allergic rhinitis via suppression of the LYN kinase‐mediated molecular signaling pathway during mast cell activation

“…In both AR and dermatitis models, dictamnine suppresses pruritus in mice and inhibits MC infiltration and activation in lesions (Yang et al, 2023). Dictamnine inhibits the calcium flux of neuronal cells activated by both chloroquine and allyl isothiocyanate in the atopic dermatitis model, which is consistent with the inhibitory effect of dictamnine on intracellular calcium flux in MCs triggered by IgE or C48/80 (Liu et al, 2021). The mechanism by which dictamnine inhibits pruritus in atopic dermatitis is thought to involve the inhibition of the MrgprA3‐TRPA1 mediated histamine‐independent itch pathway (Yang et al, 2023).…”

“…Dictamnine has been reported to ameliorate dermatitis symptoms and inflammatory cytokine expression in dermatological diseases, such as atopic dermatitis (Dubinin et al, 1987). Dictamnine ameliorates chronic itch in dinitrofluorobenzene (DNFB)‐induced atopic dermatitis mice (Yang et al, 2023), inflammation in oxazolone‐induced mouse dermatitis (Lin et al, 2021), and inhibits anaphylactoid reactions via MRGPRX2 (Liu et al, 2021). In the present study, we investigated the anti‐AR effects of dictamnine by inhibiting MC activity and its underlying mechanisms.…”

“…It also has antiviral, antifungal (Yang & Chen, 2008), antiangiogenic, and anticancer properties (Gao et al, 2011). A previous study described the suppressive effect of dictamnine on the C48/80-induced anaphylactoid reaction, revealing that dictamnine can inhibit MC degranulation (Liu et al, 2021). However, few studies have explored the anti-allergic effects of dictamnine in regulating AR.…”

Modulation of the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2) by Xenobiotic Compounds and Its Relevance to Human Diseases

“…Exogenous ligands of MRGPRX2 include the cationic polymer compound 48/80 (C48/80), which is commonly used in receptor functional assays, and a variety of drugs approved by the Food and Drug Administration (FDA), such as fluoroquinolones (e.g., ciprofloxacin), neuromuscular blocking agents (e.g., rocuronium, atracurium), opioids (e.g., morphine), and many others [ 4 , 9 , 28 ]. MRGPRX2 can also be activated or inhibited by other exogenous agents, such as bacterial quorum sensing proteins, insect venoms [ 3 , 29 , 30 ], or many different plant xenobiotics ( Figure 1 ) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]; representatives of which are described in the following part of this review.…”

Furoquinoline Alkaloids: Insights into Chemistry, Occurrence, and Biological Properties

“…Dictamnine ( 1 ) demonstrated anti-anaphylactoid activity in a mouse model of hind paw extravasation. It is suggested that dictamnine may act through the MrgX2 receptor located on mast cells, making it a promising candidate for an effective anti-anaphylactic compound [ 55 ].…”