Brevenal Is a Natural Inhibitor of Brevetoxin Action in Sodium Channel Receptor Binding Assays

Abstract

Summary1. Florida red tides produce profound neurotoxicity that is evidenced by massive fish kills, neurotoxic shellfish poisoning, and respiratory distress. Red tides vary in potency, potency that is not totally governed by toxin concentration. The purpose of the study was to understand the variable potency of red tides by evaluating the potential for other natural pharmacological agents which could modulate or otherwise reduce the potency of these lethal environmental events.2. A synaptosome binding preparation with 3-fold higher specific brevetoxin binding was developed to detect small changes in toxin binding in the presence of potential antagonists. Rodent brain labeled in vitro with tritiated brevetoxin shows high specific binding in the cerebellum as evidenced by autoradiography. Synaptosome binding assays employing cerebellum-derived synaptosomes illustrate 3-fold increased specific binding. 3.A new polyether natural product from Florida's red tide dinoflagellate Karenia brevis, has been isolated and characterized. Brevenal, as the nontoxic natural product is known, competes with tritiated brevetoxin for site 5 associated with the voltage-sensitive sodium channel (VSSC). Brevenal displacement of specific brevetoxin binding is purely competitive in nature.4. Brevenal, obtained from either laboratory cultures or field collections during a red tide, protects fish from the neurotoxic effects of brevetoxin exposure.5. Brevenal may serve as a model compound for the development of therapeutics to prevent or reverse intoxication in red tide exposures.

Osmotic stress triggers toxin production by the dinoflagellate Karenia brevis

“…Brevenal, the recently discovered beneficial compound produced by K. brevis, acts as a brevetoxin antagonist by binding to the sodium channel receptor (9). In sheep, picomolar levels of brevenal have been shown to alleviate the bronchial constriction and wheezing response to brevetoxin (10).…”

“…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).…”

“…In addition to brevetoxins, K. brevis produces a nontoxic polyether compound that inhibits brevetoxin from binding to sodium channels known as brevenal (8). Competition between brevetoxins and brevenal for sodium channels has been shown to increase fish survival (9). In addition, the unique ability of brevenal to compete with brevetoxin suggests that it may serve as a solution to aerosolized brevetoxins, and it has also been implicated as a therapy for cystic fibrosis (10).…”

The Biosynthesis of Polyketide Metabolites by Dinoflagellates

“…The structure of brevenal is distinct from, but somewhat reminiscent of, the hemi-brevetoxins that were reported by Shimizu in 1989 (Prasad andShimizu et al, 1989). Brevenal appears not to share the sodium channel activity of the brevetoxins, but surprisingly acts as a brevetoxin antagonist (Bourdelais et al, 2004). Several new side-chain variants of brevetoxin B have been isolated from K. brevis .…”

Aerosolized Florida Red Tide Toxins and Human Health Effects

“…Furthermore, they are highly pertinent because they are conducted with environmentally relevant concentrations of individual toxigenic agents and/ or natural brevetoxins (Abraham et al, 2005a. To complicate matters further, K. brevis also produces its own natural antagonist-brevenal (Bourdelais et al, 2004). Brevenal has been identified in collected field air samples , and when aerosolized, brevenal can block the constrictor effects of crude brevetoxins, PbTx-2, and PbTx-3 (Abraham et al, 2005a).…”