Lamprecht Michael R, Morrison Barclay
Department of Biomedical Engineering, Columbia University , New York, New York.
J Neurotrauma. 2015 Sep 1;32(17):1361-8. doi: 10.1089/neu.2015.3912. Epub 2015 May 19.
Combination therapies are a promising therapeutic option for traumatic brain injury (TBI) owing to the clinical failure of monotherapy treatments, such as progesterone. Organotypic hippocampal slice cultures (OHSCs) from Sprague-Dawley rats were subjected to an in vitro TBI, and the neuroprotective effects of 17β-estradiol (E2) or memantine (MEM) monotherapies were quantified. Several combination treatments at different concentrations of both drugs were tested, with 100 pM of E2 and 10 μM of MEM statistically and significantly reducing cell death over either monotherapy when administered immediately after injury. This combination was also significantly neuroprotective when administered 1 h postinjury, possibly supporting future in vivo studies. Further, we hypothesized that this synergy could be the result of MEM blocking a potentially deleterious effect of E2, specifically E2 enhancement of N-methyl-D-aspartate (NMDA) currents. Evoked electrophysiological responses in OHSCs were potentiated by E2 treatment, whereas this potentiation was significantly reduced by MEM. In conclusion, a combination therapy of E2 and memantine was significantly more neuroprotective than both monotherapy treatments, and this synergy may be the result of MEM blocking a deleterious E2-mediated enhancement of NMDA receptors.
由于单一疗法（如孕酮）在临床上的失败，联合疗法成为创伤性脑损伤（TBI）一种很有前景的治疗选择。对来自Sprague-Dawley大鼠的器官型海马脑片培养物（OHSCs）进行体外创伤性脑损伤，并对17β-雌二醇（E2）或美金刚（MEM）单一疗法的神经保护作用进行量化。测试了两种药物不同浓度的几种联合治疗方案，结果显示，在损伤后立即给药时，100 pM的E2和10 μM的MEM联合使用在统计学上显著降低了细胞死亡，比单一疗法效果更好。这种联合疗法在损伤后1小时给药时也具有显著的神经保护作用，这可能为未来的体内研究提供支持。此外，我们推测这种协同作用可能是由于MEM阻断了E2的潜在有害作用，特别是E2增强N-甲基-D-天冬氨酸（NMDA）电流的作用。E2处理可增强OHSCs中的诱发电生理反应，而MEM可显著降低这种增强作用。总之，E2和美金刚联合疗法的神经保护作用明显优于两种单一疗法，这种协同作用可能是由于MEM阻断了E2介导的NMDA受体有害增强作用。
