Ambroxol is a widely used secretolytic agent originally developed from
vasicine, a natural
alkaloid found in Adhatoda vasica, extracts of which have been used to treat
bronchitis,
asthma, and
rheumatism. We previously reported that
ambroxol inhibits
IgE-dependent mediator secretion from human mast cells and basophils, key effector cells of allergic
inflammation. Here, the mechanisms involved in the inhibitory properties of
ambroxol were assessed in comparison to other secretolytic analogues (e.g.
vasicine,
bromhexine,
sputolysin). The results show that, in comparison to
ambroxol, which reduced
IgE-dependent histamine release from basophils
at 10 microM-1 mM, the release of the
amine was only moderately reduced by
sputolysin and
vasicine at 1 mM. In contrast, above 10 microM,
bromhexine was found to be toxic to basophils in vitro as evidenced by induction of histamine release and reduced cell viability. In contrast, the inhibitory actions of
ambroxol at concentrations below 1 mM were not toxic and entirely reversible.
Ambroxol was also more potent than either
sputolysin or
vasicine in attenuating basophil
IL-4 and
IL-13 secretions, whereas
bromhexine-induced suppression of de novo
cytokine synthesis was due to toxic effects. Additionally,
ambroxol reduced
IgE-dependent
p38 MAPK phosphorylation in basophils, unlike
bromhexine,
sputolysin and
vasicine. These results clearly show that
ambroxol is both more potent and effective at inhibiting
IgE-dependent basophil mediator release and
p38 MAPK activity than the other secretolytic analogues employed. The therapeutic potential of
ambroxol as an
anti-allergic agent is further underlined by these data.