Administration of tamoxifen regulates changes in gene expression during the acute phase of traumatic spinal cord injury

Traumatic spinal cord injury (SCI) may induce irreversible damage leading to severe incapacity. Molecular mechanisms underlying SCI are not fully understood, preventing the development of novel therapeutic resources. Tamoxifen has demonstrated to be a promising therapy. Our aim was to elucidate the molecular mechanisms involved in the beneficial effect of TMX administered after SCI. We use a rat model of SCI, Tamoxifen was administred intraperitoneal 30 min after injury. Four groups were organized, 1) Non-injured without TMX (Sham/TMX-), 2) Non-injured with TMX (Sham/TMX+), 3) Injured without TMX (SCI/TMX-), and 4) Injured with TMX (SCI/TMX+). From the comparison between Sham/TMX- and SCI/TMX-, 708 genes showed differential expression. Among the relevant genes Anxa1 was upregulated, this gene’s product is a promising marker of injury severity. Enriched pathways were the spinal cord injury pathway and pathways related to inflammatory response. When comparing SCI/TMX- versus SCI/TMX+, only 30 genes showed differential expression. Our results reinforce the key role of inflammatory response in SCI and Tamoxifen seem to be able to regulate this response by suppressing changes in gene expression. Our data also support the potential of previously described severity markers.创伤性脊髓损伤（SCI）可引发不可逆损伤，进而导致严重残疾。目前学界尚未完全阐明脊髓损伤的分子机制，这阻碍了新型治疗手段的开发。他莫昔芬（Tamoxifen）已被证实是一种颇具潜力的治疗药物。本研究旨在阐明脊髓损伤后给予他莫昔芬（TMX）所发挥的有益作用背后的分子机制。本研究采用脊髓损伤大鼠模型，于损伤后30分钟对大鼠进行腹腔注射他莫昔芬（TMX）。实验共设置四组：1）未损伤且未给予他莫昔芬组（Sham/TMX-）；2）未损伤但给予他莫昔芬组（Sham/TMX+）；3）损伤且未给予他莫昔芬组（SCI/TMX-）；4）损伤且给予他莫昔芬组（SCI/TMX+）。对比Sham/TMX-组与SCI/TMX-组的基因表达谱，共鉴定出708个差异表达基因。在相关差异基因中，Anxa1基因呈上调表达，其编码产物是颇具潜力的损伤严重程度标志物。富集分析显示，差异基因显著富集于脊髓损伤通路以及炎症反应相关通路。对比SCI/TMX-组与SCI/TMX+组，则仅发现30个差异表达基因。本研究结果进一步证实了炎症反应在脊髓损伤中的核心作用，同时表明他莫昔芬可通过抑制异常基因表达变化来调节该炎症应答。本研究数据同时证实了此前报道的损伤严重程度标志物的应用潜力。