Department of Biomedical Engineering, University of Arkansas, Fayetteville AR 72701, USA.
Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson AR 72079, USA.
Sci Rep. 2016 Sep 14;6:33330. doi: 10.1038/srep33330.
Non-penetrating or mild traumatic brain injury (mTBI) is commonly experienced in accidents, the battlefield and in full-contact sports. Astrocyte cellular edema is one of the major factors that leads to high morbidity post-mTBI. Various studies have reported an upregulation of aquaporin-4 (AQP4), a water channel protein, following brain injury. AZA is an antiepileptic drug that has been shown to inhibit AQP4 expression and in this study we investigate the drug as a therapeutic to mitigate the extent of mTBI induced cellular edema. We hypothesized that mTBI-mediated astrocyte dysfunction, initiated by increased intracellular volume, could be reduced when treated with AZA. We tested our hypothesis in a three-dimensional in vitro astrocyte model of mTBI. Samples were subject to no stretch (control) or one high-speed stretch (mTBI) injury. AQP4 expression was significantly increased 24 hours after mTBI. mTBI resulted in a significant increase in the cell swelling within 30 min of mTBI, which was significantly reduced in the presence of AZA. Cell death and expression of S100B was significantly reduced when AZA was added shortly before mTBI stretch. Overall, our data point to occurrence of astrocyte swelling immediately following mTBI, and AZA as a promising treatment to mitigate downstream cellular mortality.
非穿透性或轻度创伤性脑损伤（mTBI）在事故、战场和全接触运动中很常见。星形胶质细胞细胞水肿是导致 mTBI 后高发病率的主要因素之一。各种研究报告称，脑损伤后水通道蛋白-4（AQP4）表达上调。AZA 是一种抗癫痫药物，已被证明能抑制 AQP4 的表达，在这项研究中，我们将该药物作为一种治疗方法，以减轻 mTBI 诱导的细胞水肿的程度。我们假设，当用 AZA 治疗时，mTBI 介导的星形胶质细胞功能障碍，由细胞内体积增加引发，可能会减少。我们在体外 mTBI 星形胶质细胞三维模型中测试了我们的假设。样本未拉伸（对照）或仅进行一次高速拉伸（mTBI）损伤。mTBI 后 24 小时 AQP4 表达明显增加。mTBI 在 mTBI 后 30 分钟内导致细胞肿胀显著增加，而在 AZA 存在下显著减少。当在 mTBI 拉伸前添加 AZA 时，细胞死亡和 S100B 的表达显著降低。总的来说，我们的数据表明 mTBI 后立即发生星形胶质细胞肿胀，以及 AZA 作为减轻下游细胞死亡率的有前途的治疗方法。
