Peterson Todd C, Hoane Michael R, McConomy Keith S, Farin Fred M, Bammler Theo K, MacDonald James W, Kantor Eric D, Anderson Gail D
1Department of Psychology, Southern Illinois University, Carbondale, Illinois.
2Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
J Neurotrauma. 2015 Jun 1;32(11):765-79. doi: 10.1089/neu.2014.3530. Epub 2015 Feb 26.
Neuroprotection, recovery of function, and gene expression were evaluated in an animal model of traumatic brain injury (TBI) after a combination treatment of nicotinamide (NAM) and progesterone (Prog). Animals received a cortical contusion injury over the sensorimotor cortex, and were treated with either Vehicle, NAM, Prog, or a NAM/Prog combination for 72 h and compared with a craniotomy only (Sham) group. Animals were assessed in a battery of behavioral, sensory, and both fine and gross motor tasks, and given histological assessments at 24 h post-injury to determine lesion cavity size, degenerating neurons, and reactive astrocytes. Microarray-based transcriptional profiling was used to determine treatment-specific changes on gene expression. Our results confirm the beneficial effects of treatment with either NAM or Prog, demonstrating significant improvements in recovery of function and a reduction in lesion cavitation, degenerating neurons, and reactive astrocytes 24 h post-injury. The combination treatment of NAM and Prog led to a significant improvement in both neuroprotection at 24 h post-injury and recovery of function in sensorimotor related tasks when compared with individual treatments. The NAM/Prog-treated group was the only treatment group to show a significant reduction of cortical loss 24 h post-injury. The combination appears to affect inflammatory and immune processes, reducing expression of a significant number of genes in both pathways. Further preclinical trials using NAM and Prog as a combination treatment should be conducted to identify the window of opportunity, determine the optimal duration of treatment, and evaluate the combination in other pre-clinical models of TBI.
在创伤性脑损伤（TBI）动物模型中，评估了烟酰胺（NAM）和孕酮（Prog）联合治疗后的神经保护作用、功能恢复及基因表达情况。动物在感觉运动皮层接受皮质挫伤损伤，分别用赋形剂、NAM、Prog或NAM/Prog联合治疗72小时，并与仅做开颅手术（假手术）的组进行比较。对动物进行了一系列行为、感觉以及精细和粗大运动任务的评估，并在损伤后24小时进行组织学评估，以确定损伤腔大小、变性神经元和反应性星形胶质细胞。基于微阵列的转录谱分析用于确定治疗特异性的基因表达变化。我们的结果证实了NAM或Prog治疗的有益效果，表明损伤后24小时功能恢复有显著改善，损伤腔形成、变性神经元和反应性星形胶质细胞减少。与单独治疗相比，NAM和Prog联合治疗在损伤后24小时的神经保护作用以及感觉运动相关任务的功能恢复方面均有显著改善。NAM/Prog治疗组是唯一在损伤后24小时显示皮质损失显著减少的治疗组。该联合似乎影响炎症和免疫过程，减少了两条途径中大量基因的表达。应进一步开展使用NAM和Prog联合治疗的临床前试验，以确定治疗时机、确定最佳治疗持续时间，并在TBI的其他临床前模型中评估该联合治疗。
