D'Mello Fiona, Braidy Nady, Marçal Helder, Guillemin Gilles, Rossi Fanny, Chinian Mirielle, Laurent Dominique, Teo Charles, Neilan Brett A
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia.
Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, The University of New South Wales, Sydney, Australia.
Neurotox Res. 2017 Feb;31(2):245-258. doi: 10.1007/s12640-016-9678-5. Epub 2016 Oct 29.
Toxins produced by cyanobacteria and dinoflagellates have increasingly become a public health concern due to their degenerative effects on mammalian tissue and cells. In particular, emerging evidence has called attention to the neurodegenerative effects of the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA). Other toxins such as the neurotoxins saxitoxin and ciguatoxin, as well as the hepatotoxic microcystin, have been previously shown to have a range of effects upon the nervous system. However, the capacity of these toxins to cause neurodegeneration in human cells has not, to our knowledge, been previously investigated. This study aimed to examine the cytotoxic effects of BMAA, microcystin-LR (MC-LR), saxitoxin (STX) and ciguatoxin (CTX-1B) on primary adult human astrocytes. We also demonstrated that α-lipoate attenuated MC-LR toxicity in primary astrocytes and characterised changes in gene expression which could potentially be caused by these toxins in primary astrocytes. Herein, we are the first to show that all of these toxins are capable of causing physiological changes consistent with neurodegeneration in glial cells, via oxidative stress and excitotoxicity, leading to a reduction in cell proliferation culminating in cell death. In addition, MC-LR toxicity was reduced significantly in astrocytes-treated α-lipoic acid. While there were no significant changes in gene expression, many of the probes that were altered were associated with neurodegenerative disease pathogenesis. Overall, this is important in advancing our current understanding of the mechanism of toxicity of MC-LR on human brain function in vitro, particularly in the context of neurodegeneration.
由于蓝藻和甲藻产生的毒素对哺乳动物组织和细胞具有退化作用，它们日益成为公共卫生关注的问题。特别是，新出现的证据已引起人们对蓝藻毒素β-N-甲基氨基-L-丙氨酸（BMAA）神经退行性影响的关注。其他毒素，如神经毒素石房蛤毒素和雪卡毒素，以及肝毒性微囊藻毒素，此前已被证明对神经系统有一系列影响。然而，据我们所知，这些毒素在人类细胞中引起神经退行性变的能力此前尚未得到研究。本研究旨在检测BMAA、微囊藻毒素-LR（MC-LR）、石房蛤毒素（STX）和雪卡毒素（CTX-1B）对原代成人星形胶质细胞的细胞毒性作用。我们还证明了α-硫辛酸可减轻原代星形胶质细胞中MC-LR的毒性，并对这些毒素可能在原代星形胶质细胞中引起的基因表达变化进行了表征。在此，我们首次表明，所有这些毒素都能够通过氧化应激和兴奋性毒性作用，在神经胶质细胞中引起与神经退行性变一致的生理变化，导致细胞增殖减少，最终导致细胞死亡。此外，在经α-硫辛酸处理的星形胶质细胞中，MC-LR的毒性显著降低。虽然基因表达没有显著变化，但许多发生改变的探针与神经退行性疾病发病机制有关。总体而言，这对于推进我们目前对MC-LR体外对人类脑功能毒性机制的理解非常重要，特别是在神经退行性变的背景下。
