Colón Jennifer M, González Pablo A, Cajigas Ámbar, Maldonado Wanda I, Torrado Aranza I, Santiago José M, Salgado Iris K, Miranda Jorge D
University of Puerto Rico Medical Sciences Campus, Department of Physiology, San Juan, PR 00936, USA.
University of Puerto Rico Carolina Campus, Neuroregeneration Division, Neuroscience Research Laboratory, Natural Sciences Department, Carolina, PR 00984, USA.
Exp Neurol. 2018 Jan;299(Pt A):109-121. doi: 10.1016/j.expneurol.2017.10.006. Epub 2017 Oct 13.
No treatment is available for patients with spinal cord injury (SCI). Patients often arrive to the hospital hours after SCI suggesting the need of a therapy that can be used on a clinically relevant window. Previous studies showed that Tamoxifen (TAM) treatment 24h after SCI benefits locomotor recovery in female rats. Tamoxifen exerts beneficial effects in male and female rodents but a gap of knowledge exists on: the therapeutic window of TAM, the spatio-temporal mechanisms activated and if this response is sexually dimorphic. We hypothesized that TAM will favor locomotor recovery when administered up-to 24h after SCI in male Sprague-Dawley rats. Rats received a thoracic (T10) contusion using the MACSIS impactor followed by placebo or TAM (15mg/21days) pellets in a therapeutic window of 0, 6, 12, or 24h. Animals were sacrificed at 2, 7, 14, 28 or 35days post injury (DPI) to study the molecular and cellular changes in the acute and chronic stages. Immediate or delayed therapy (t=6h) improved locomotor function, increased white matter spared tissue, and neuronal survival. TAM reduced reactive gliosis during chronic stages and increased the expression of Olig-2. A significant difference was observed in estrogen receptor alpha between male and female rodents from 2 to 28 DPI suggesting a sexually dimorphic characteristic that could be related to the behavioral differences observed in the therapeutic window of TAM. This study supports the use of TAM in the SCI setting due to its neuroprotective effects but with a significant sexually dimorphic therapeutic window.
脊髓损伤（SCI）患者目前尚无有效治疗方法。患者常在脊髓损伤数小时后才被送往医院，这表明需要一种可在临床相关时间窗内使用的治疗方法。先前的研究表明，脊髓损伤后24小时给予他莫昔芬（TAM）治疗可促进雌性大鼠的运动功能恢复。他莫昔芬对雄性和雌性啮齿动物均有有益作用，但在以下方面仍存在知识空白：他莫昔芬的治疗时间窗、所激活的时空机制以及这种反应是否存在性别差异。我们假设，在雄性Sprague-Dawley大鼠脊髓损伤后长达24小时给予他莫昔芬将有利于运动功能恢复。大鼠使用MACSIS撞击器造成胸段（T10）挫伤，随后在0、6、12或24小时的治疗时间窗内给予安慰剂或他莫昔芬（15mg/21天）微丸。在损伤后2、7、14、28或35天（DPI）处死动物，以研究急性和慢性阶段的分子和细胞变化。即刻或延迟治疗（t = 6小时）可改善运动功能，增加白质保留组织和神经元存活。他莫昔芬可减少慢性阶段的反应性胶质增生，并增加Olig-2的表达。在2至28 DPI期间，雄性和雌性啮齿动物的雌激素受体α存在显著差异，这表明存在一种性别差异特征，可能与在他莫昔芬治疗时间窗内观察到的行为差异有关。本研究支持在脊髓损伤情况下使用他莫昔芬，因其具有神经保护作用，但存在显著的性别差异治疗时间窗。
