Michigan State University College of Human Medicine, Grand Rapids, MI, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
Prostaglandins Other Lipid Mediat. 2013 Jul-Aug;104-105:18-24. doi: 10.1016/j.prostaglandins.2012.07.005. Epub 2012 Aug 16.
After traumatic brain injury (TBI), arachidonic acid (ArA) is released from damaged cell membranes and metabolized to many bioactive eicosanoids, including several epoxyeicosatrienoic acids (EETs). Soluble epoxide hydrolase (Ephx2, sEH) appears to be the predominant pathway for EET metabolism to less active dihydroxyeicosatrienoates (DHETs). Prior studies indicate that brain levels of EETs increase transiently after TBI and EETs have antiinflammatory and neuroprotective activities which may benefit the injured brain. If the net effect of increased EET levels in the injured brain is beneficial to recovery, then Ephx2 gene disruption would be expected to enhance elevated EET levels and improve recovery in the injured brain. Thus, Ephx2-KO (Ephx2(-/-) bred onto pure C57Bl/6 background) mice were compared to wild-type controls in a unilateral controlled cortical impact model of TBI. Before injury, animals behaved comparably in open field activity and neurologic reflexes. Interestingly, the Ephx2-KO mice showed improved motor coordination on a beam walk task, yet showed indications of defective learning in a test of working spatial memory. After surgery, brain-injured Ephx2-KO mice again had less of a deficit in the beam walk than wild-type, and the difference in latency (post-pre) showed a trend of protection for Ephx2-KO mice after TBI. Brain-injured mice showed no genotype differences in working memory. Surprisingly, sham-operated Ephx2-KO mice exhibited an injured phenotype for working memory, compared to sham-operated wild-type mice. Brain eicosanoid levels were measured using liquid chromatography with tandem mass spectrometry. Of the 20 eicosanoids evaluated, only 8,9-EET was elevated in the Ephx2-KO cerebral cortex (37 d post-surgery, in both sham and injured). Tissue DHET levels were below the limit of quantification. These results reflect a significant contribution of sEH deficiency in coordination of ambulatory movements and working spatial memory in the mouse. Further investigation of differential sEH expression and EET levels at earlier time points and across other brain regions may shed light on these behavioral differences.
创伤性脑损伤（TBI）后，花生四烯酸（ArA）从受损的细胞膜中释放出来，并代谢为许多生物活性的类二十烷酸，包括几种环氧二十碳三烯酸（EETs）。可溶性环氧化物水解酶（Ephx2，sEH）似乎是 EET 代谢为较少活性的二羟二十碳三烯酸（DHETs）的主要途径。先前的研究表明，TBI 后大脑中的 EET 水平短暂增加，EET 具有抗炎和神经保护作用，这可能有益于受伤的大脑。如果受伤大脑中 EET 水平升高的净效应对恢复有益，那么 Ephx2 基因缺失预计会增强升高的 EET 水平并改善受伤大脑的恢复。因此，在单侧控制皮质撞击模型的 TBI 中，将 Ephx2-KO（Ephx2(-/-) 繁殖到纯 C57Bl/6 背景上）小鼠与野生型对照进行比较。在受伤之前，动物在开放场活动和神经反射方面表现相似。有趣的是，Ephx2-KO 小鼠在横梁行走任务中表现出更好的运动协调能力，但在工作空间记忆测试中表现出学习缺陷的迹象。手术后，受伤的 Ephx2-KO 小鼠在横梁行走任务中的缺陷再次少于野生型，潜伏期（术后-术前）的差异表明 Ephx2-KO 小鼠在 TBI 后具有保护趋势。受伤的小鼠在工作记忆方面没有表现出基因型差异。令人惊讶的是，与假手术的野生型小鼠相比，假手术的 Ephx2-KO 小鼠表现出工作记忆的损伤表型。使用液相色谱-串联质谱法测量脑类二十烷酸水平。在评估的 20 种类二十烷酸中，只有 8,9-EET 在 Ephx2-KO 大脑皮层中升高（手术后 37 天，在假手术和受伤组中）。组织 DHET 水平低于定量下限。这些结果反映了 sEH 缺乏在协调小鼠的步行运动和工作空间记忆方面的重要贡献。进一步研究早期时间点和其他脑区的差异 sEH 表达和 EET 水平可能揭示这些行为差异的原因。
