Tang Huiling, Hua Fang, Wang Jun, Yousuf Seema, Atif Fahim, Sayeed Iqbal, Stein Donald G
a Department of Emergency Medicine , Emory University , Atlanta , GA , USA.
Brain Inj. 2015 Sep;29(10):1165-1174. doi: 10.3109/02699052.2015.1035330. Epub 2015 Jun 17.
Inflammation is an important component of the response to traumatic brain injury (TBI). Progesterone has been shown to inhibit neuroinflammation following (TBI) and may do so through Toll-like receptor (TLR)-mediated pathways. In vitro studies indicate that 1,25-dihydroxyvitamin D(3) (VDH) may also modulate the inflammatory response through the TLR4 pathway. This study tested the hypothesis that PROG and VDH would exert additive and synergistic neuroprotective effects compared with individual treatment by modulating TLR4/NF-κB-mediated inflammation pathways after TBI in rats.
Bilateral medial frontal cortical impact injury was induced in young adult Sprague-Dawley rats. Progesterone (i.p., 16 mg kg body weight) and VDH (1 µg kg body weight) were injected separately or combined at 1 and 6 hours after surgery. Rats were killed 24 hours post-surgery and peri-contusional brain tissue harvested for immunostaining and protein measurement.
TLR4, phosphorylation of NF-κB, neuronal loss and astrocyte activation were significantly reduced with combination treatment after TBI compared to each agent given individually.
At 24 hours after TBI, combination therapy shows greater efficacy in reducing neuroinflammation compared to progesterone and VDH given separately, and does so by modulating the TLR4/NF-κB signalling pathway.
炎症是创伤性脑损伤（TBI）反应的重要组成部分。已表明孕酮可抑制TBI后的神经炎症，且可能通过Toll样受体（TLR）介导的途径发挥作用。体外研究表明，1,25-二羟维生素D（3）（VDH）也可能通过TLR4途径调节炎症反应。本研究检验了以下假设：与单独治疗相比，孕酮（PROG）和VDH通过调节大鼠TBI后TLR4/NF-κB介导的炎症途径，将发挥相加和协同的神经保护作用。
在年轻成年Sprague-Dawley大鼠中诱导双侧内侧额叶皮质撞击损伤。在手术后1小时和6小时分别或联合注射孕酮（腹腔注射，16mg/kg体重）和VDH（1μg/kg体重）。术后24小时处死大鼠，收集挫伤周围脑组织进行免疫染色和蛋白质测量。
与单独给予每种药物相比，TBI后联合治疗显著降低了TLR4、NF-κB磷酸化、神经元损失和星形胶质细胞活化。
在TBI后24小时，与单独给予孕酮和VDH相比，联合治疗在减轻神经炎症方面显示出更大的疗效，并且通过调节TLR4/NF-κB信号通路实现这一效果。
