Abstract
Ciguatoxins and brevetoxins are neurotoxic cyclic polyether compounds produced by dinoflagellates, which are responsible for ciguatera and neurotoxic shellfish poisoning (NSP) respectively. Recently, brevenal, a natural compound was found to specifically inhibit brevetoxin action and to have a beneficial effect in NSP. Considering that brevetoxin and ciguatoxin specifically activate voltage-sensitive Na+ channels through the same binding site, brevenal has therefore a good potential for the treatment of ciguatera. Pacific ciguatoxin-1B (P-CTX-1B) activates voltage-sensitive Na+ channels and promotes an increase in neurotransmitter release believed to underpin the symptoms associated with ciguatera. However, the mechanism through which slow Na+ influx promotes neurosecretion is not fully understood. In the present study, we used chromaffin cells as a model to reconstitute the sequence of events culminating in ciguatoxin-evoked neurosecretion. We show that P-CTX-1B induces a tetrodotoxin-sensitive rise in intracellular Na+, closely followed by an increase in cytosolic Ca2+ responsible for promoting SNARE-dependent catecholamine secretion. Our results reveal that brevenal and β-naphtoyl-brevetoxin prevent P-CTX-1B secretagogue activity without affecting nicotine or barium-induced catecholamine secretion. Brevenal is therefore a potent inhibitor of ciguatoxin-induced neurotoxic effect and a potential treatment for ciguatera.
Highlights
Ciguatera is the most widespread human syndrome of marine poisoning that occurs following consumption of fish from tropical and subtropical pacific regions contaminated with ciguatoxins that accumulate through the marine food chain [1]
The Na+ channel blocker tetrodotoxin (TTX, 1 mM) potently inhibited P-CTX-1B-evoked Na+ increase (Figure 1C), indicating that voltage-sensitive Na+ channel activation is directly involved in this increase
These results indicate that P-CTX-1B induced a marked rise of cytosolic Na+ in chromaffin cells through an activation of voltage-sensitive Na+ channels
Summary
Ciguatera is the most widespread human syndrome of marine poisoning that occurs following consumption of fish from tropical and subtropical pacific regions contaminated with ciguatoxins that accumulate through the marine food chain [1]. It is mainly characterised by neurological, gastrointestinal and cardiovascular disturbances [2]. Ciguatera is a significant public heath issue in endemic areas with up to 50,000 cases recorded annually [3]. It is becoming a widespread health problem with the globalisation of the fishing industry importing ciguateric fish from endemic regions [3]. Research with the toxic dinoflagellate that produces brevetoxins, Karenia brevis, has resulted in the discovery of natural and chemically modified compounds that may have the potential for the treatment of ciguatera
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