Immune Modulating Brevetoxins: Monocyte Cytotoxicity, Apoptosis, and Activation of M1/M2 Response Elements Is Dependent on Reactive Groups

Abstract

Brevetoxins are a suite of marine neurotoxins that activate voltage-gated sodium channels (VGSCs) in cell membranes, with toxicity occurring from persistent activation of the channel at high doses. Lower doses, in contrast, have been shown to elicit neuroregeneration. Brevetoxins have thus been proposed as a novel treatment for patients after stroke, when neuron regrowth and repair is critical to recovery. However, findings from environmental exposures indicate that brevetoxins may cause inflammation, thus, there is concern for brevetoxins as a stroke therapy given the potential for neuroinflammation. In this study, we examined the inflammatory properties of several brevetoxin analogs, including those that do and do not bind strongly to VGSCs, as binding has classically indicated toxicity. We found that several analogs are toxic to monocytes, while others are not, and the degree of toxicity is not directly related to VGSC binding. Rather, results indicate that brevetoxins containing aldehyde groups were more likely to cause immunotoxicity, regardless of binding affinity to the VGSC. Our results demonstrate that different brevetoxin family members can elicit a spectrum of apoptosis and necrosis by multiple possible mechanisms of action in monocytes. As such, care should be taken in treating “brevetoxins” as a uniform group, particularly in stroke therapy research.

Marine natural products

“…Rather, aldehyde-containing BTXs are more immunotoxic, with the conclusion from the study being that different BTX pharmacophores can elicit different toxicity profiles. 319 Another study has evaluated the levels of paralytic shellfish toxins (PSTs; in saxitoxin equivalents) in Arctic food webs during the anomalously warm 2019 period. Notably, high levels of PSTs in benthic clams and the Pacific walruses who predate upon them were detected, at levels high enough to cause observable physiological effects if consumed by humans in comparable amounts.…”

Effects of marine biotoxins on drug-metabolizing cytochrome P450 enzymes and their regulation in mammalian cells

“…Furthermore, Hilderbrand et al showed elevated levels of IL-6 in mouse bone marrow-derived mast cells after exposure to PbTx (Hilderbrand et al 2011 ). However, McCall and co-workers recently found no significant effect on IL-1β, IL-6 and TNF-α in human THP-1 cells, but elevated levels of anti-inflammatory IL-4 (McCall et al 2022 ).…”

Karenia brevis Extract Induces Cellular Entry through Distinct Mechanisms in Phagocytic RAW 264.7 Macrophages versus Non-Phagocytic Vero Cells

“…An important component missing from these studies is a precise mechanistic understanding of how K. brevis extracts, other than brevetoxins, interact directly with target cells. In fact, new studies have come to light showing that canonical mechanisms of brevetoxin interaction with sodium channels may not be the only pathway of cellular effect [13][14][15][16].…”