School of Nursing, College of Health and Human Services, University of North Carolina Wilmington, Wilmington, NC 28403, USA.
SeaTox Research Inc., Wilmington, NC 28409, USA.
Mar Drugs. 2022 Mar 29;20(4):233. doi: 10.3390/md20040233.
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.
短沟对虾毒素是一组海洋神经毒素，可激活细胞膜中的电压门控钠离子通道（VGSCs），高剂量时通道持续激活会导致毒性。相比之下，较低剂量已被证明可引发神经再生。因此，短沟对虾毒素已被提议作为中风患者的一种新的治疗方法，因为神经元的再生和修复对于恢复至关重要。然而，环境暴露的研究结果表明，短沟对虾毒素可能会引起炎症，因此，考虑到神经炎症的潜在风险，短沟对虾毒素作为中风治疗方法存在一定的争议。在这项研究中，我们研究了几种短沟对虾毒素类似物的炎症特性，包括那些与 VGSCs 结合强和弱的类似物，因为结合经典地表明了毒性。我们发现，几种类似物对单核细胞有毒，而其他类似物则没有，并且毒性程度与 VGSC 结合无关。相反，结果表明，含有醛基的短沟对虾毒素更可能引起免疫毒性，而与 VGSC 的结合亲和力无关。我们的研究结果表明，不同的短沟对虾毒素家族成员可以通过单核细胞中多种可能的作用机制引发细胞凋亡和坏死。因此，在将“短沟对虾毒素”作为一个统一的群体进行治疗时应谨慎，特别是在中风治疗研究中。
