Center for Environmental Medicine, Colorado State University, Fort Collins, CO, USA.
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
Aquat Toxicol. 2014 Nov;156:259-68. doi: 10.1016/j.aquatox.2014.09.003. Epub 2014 Sep 16.
California sea lions (CSLs) exposed to the marine biotoxin domoic acid (DA) develop an acute or chronic toxicosis marked by seizures and act as sentinels of the disease. Experimental evidence suggests that oxidative stress and neuroinflammation are important mechanisms underlying the seizurogenic potential of environmental toxicants but these pathways are relatively unstudied in CSLs. In the current study, we investigated the role of glutamate-glutamine changes and gliosis in DA-exposed CSLs to better understand the neurotoxic mechanisms occurring during DA toxicity. Sections from archived hippocampi from control and CSLs diagnosed with DA toxicosis were immunofluorescently stained for markers of gliosis, oxidative/nitrative stress and changes in glutamine synthetase (GS). Quantitative assessment revealed increasing loss of microtubule associated protein-2 positive neurons with elevations in 4-hydroxynonenal correlating with chronicity of exposure, whereas the pattern of activated glia expressing nitric oxide synthase 2 and tumor necrosis factor followed pathological severity. There was no significant change in the amount of GS positive cells but there was increased 3-nitrotyrosine in GS expressing cells and in neurons, particularly in animals with chronic DA toxicosis. These changes were consistently seen in the dentate gyrus and in the cornu ammonis (CA) sectors CA3, CA4, and CA1. The results of this study indicate that gliosis and resultant changes in GS are likely important mechanisms in DA-induced seizure that need to be further explored as potential therapies in treating exposed wildlife.
加利福尼亚海狮（CSL）暴露于海洋生物毒素软骨藻酸（DA）中会发展出一种以癫痫发作为特征的急性或慢性中毒，并充当疾病的“哨兵”。实验证据表明，氧化应激和神经炎症是环境毒物致痫潜力的重要机制，但这些途径在 CSL 中相对研究较少。在本研究中，我们研究了谷氨酸-谷氨酰胺变化和神经胶质增生在 DA 暴露的 CSL 中的作用，以更好地了解 DA 毒性过程中发生的神经毒性机制。对来自对照和被诊断为 DA 中毒的 CSL 存档海马体的切片进行了神经胶质增生、氧化/硝化应激和谷氨酰胺合成酶（GS）变化的免疫荧光染色。定量评估显示，微管相关蛋白-2 阳性神经元的丢失与 4-羟基壬烯醛的升高有关，这与暴露的慢性有关，而表达一氧化氮合酶 2 和肿瘤坏死因子的活化神经胶质的模式则与病理严重程度有关。GS 阳性细胞的数量没有显著变化，但在表达 GS 的细胞和神经元中，3-硝基酪氨酸增加，尤其是在慢性 DA 中毒的动物中。这些变化在齿状回和 Cornu ammonis（CA）的 CA3、CA4 和 CA1 区均可见。本研究的结果表明，神经胶质增生和由此产生的 GS 变化可能是 DA 诱导癫痫的重要机制，需要进一步探索作为治疗暴露野生动物的潜在疗法。
