Brevenal Inhibits Pacific Ciguatoxin-1B-Induced Neurosecretion from Bovine Chromaffin Cells

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.

Review of Florida red tide and human health effects

“…~900) are lipid soluble, cyclic polyethers. In biological systems, they act to open voltage gated sodium (Na+) ion channels in cell membranes, leading to Na+ influx into the cell (Baden and Fleming 2007; LePage et al, 2003; Mattei et al, 2008; Twiner et al, 2007). There are over 10 different brevetoxins isolated in sea water blooms and K. brevis cultures in the laboratory, as well as multiple analogs and derivatives from the metabolism of shellfish and other organisms (Baden et al, 2005; Baden and Fleming 2007; Campbell et al, 2004; Michelliza et al, 2004 and 2007; Satake et al, 2008 and 2009).…”

Brevenal, a brevetoxin antagonist from Karenia brevis, binds to a previously unreported site on mammalian sodium channels

“…As seen with brevetoxins, brevenal also attenuates the effects of ciguatoxin in mammalian tissues. Brevenal was shown to inhibit neurosecretion in bovine chromaffin cells caused by pacific ciguatoxin 1b (P-CTX-1B) (Mattei et al , 2008). Inhibition data for brevenal in the presence of P-CTX-1B treatment were biphasic in nature, showing an initial affinity in the nanomolar range and subsequently, in the micromolar range.…”

Proteomic analysis of hepatic tissue of ciguatoxin (CTX) contaminated coral reef fish Cephalopholis argus and moray eel Gymnothorax undulatus

“…The opening of sodium channels causes membrane depolarisation, which in turn, elicits a tetrodoxin-sensitive increase of intracellular Ca 2+ that originates from both the external influx of Ca 2+ and the release of Ca 2+ from internal stores. Such rise in intracellular Ca 2+ in turn triggers a robust secretion of catecholamine (Mattei et al, 2008). The regulation of intracellular calcium levels may play a crucial part in toxin tolerance, and may require adjustments of the activities or protein levels of various Ca 2+ storage and Ca 2+ -responsive proteins (Sauviat et al, 2006).…”