Airway Responses to Aerosolized Brevetoxins in an Animal Model of Asthma

Abstract

Florida red tide brevetoxins are sodium channel neurotoxins produced by the dinoflagellate Karenia brevis. When aerosolized, the toxin causes airway symptoms in normal individuals and patients with airway disease, but systematic exposures to define the pulmonary consequences and putative mechanisms are lacking. Here we report the effects of airway challenges with lysed cultures of Karenia brevis (crude brevetoxin), pure brevetoxin-2, brevetoxin-3, and brevetoxin-tbm (brevetoxin-2 minus the side chain) on pulmonary resistance and tracheal mucus velocity, a marker of mucociliary clearance, in allergic and nonallergic sheep. Picogram concentrations of toxin caused bronchoconstriction in both groups of sheep. Brevetoxin-tbm was the least potent, indicating the importance of the side chain for maximum effect. Both histamine H 1 -and cholinergic-mediated pathways contributed to the bronchoconstriction. A synthetic antagonist, β-naphthoyl-brevetoxin-3, and brevenal, a natural antagonist, inhibited the bronchoconstriction. Only crude brevetoxin and brevetoxin-3 decreased tracheal mucus velocity; both antagonists prevented this. More importantly, picomolar concentrations of the antagonists alone improved tracheal mucus velocity to the degree seen with mM concentrations of the sodium channel blocker amiloride. Thus, Karenia brevis, in addition to producing toxins that adversely affect the airways, may be a source of agents for treating mucociliary dysfunction. Keywords bronchoconstriction; mucus transport; natural therapiesFlorida red tide is a harmful algal bloom caused by the dinoflagellate Karenia brevis (previously Gymnodinium breve). K. brevis produces at least nine structurally-related polyether brevetoxins (PbTxs) (1-3), with PbTx-2 and PbTx-3 being the predominant forms (4,5). As a ) is included in the provisional patent application filed on behalf of the University of North Carolina at Wilmington by aaiPharma; A.J.B. has provisional patents filed with respect to treatment of mucociliary diseases for synthetic and natural products derived from cultured red tide, and has an interest in any licensing that might arise from patents and final patents that are not filed yet and, thus, have not been thoroughly reviewed by the U.S. Patent and Copyright Office; J.R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; I.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.G.B. has provisional patents filed with respect to treatment of mucociliary diseases for synthetic and natural products derived from cultured red tide, and has an interest in any licensing that might arise from patents and final patents not filed yet and, thus, ...

Osmotic stress triggers toxin production by the dinoflagellate Karenia brevis

“…tential for clearing mucus from the lungs, brevenal has been suggested as a potential treatment for cystic fibrosis (10). By manipulating the growth conditions for this alga through relatively simple salinity changes, we have shown that the yield of brevenal can be greatly enhanced.…”

“…In sheep, picomolar levels of brevenal have been shown to alleviate the bronchial constriction and wheezing response to brevetoxin (10). Because of the po- Brevetoxin cell quota increased rapidly within <3 h after hypoosmotic stress and reached a plateau after 24 h that continued to day 6, with a decrease noted at day 67.…”

“…The identification of a direct link between toxin production and environmental conditions adds a unique dimension to our understanding of HAB dynamics. Furthermore, the role of salinity in activating brevenal production may benefit commercial production of medical therapies (9,10).…”

Recent Applications of the Suzuki-Miyaura Cross-coupling to Complex Polycyclic Ether Synthesis

“…25 Importantly, it has been reported that brevenal signi cantly improves tracheal mucus velocity at picomolar concentrations in an animal model of asthma, making this substance a potential lead for the development of novel therapeutic agents for the treatment of mucociliary dysfunction associated with cystic brosis and other lung disorders. 26 More recently, Mattei and co workers reported that brevenal is a potent inhibitor of catecholamine secretion induced by ciguatoxin without affecting other secretagogue activities, such as nicotine or barium induced secretion of catecholamine. 27 These results suggest brevenal has potential as a naturally occurring potent inhibitor of ciguatoxin induced neurotoxic effects and for treatment of ciguatera seafood poisoning.…”

Oceans and human health: Emerging public health risks in the marine environment

“…In addition to the marine organisms and coral reefs, even the HAB toxins themselves may be of future therapeutic value for humans (Burja et al, 2001;Abraham et al, 2005). Finally, the marine animals themselves may serve as alternative models of human diseases and human physiology (such as the sea slug, aplysia, and the elucidation of the processes of memory).…”