1 Restorative Neuroscience Laboratory, Center for Integrated Research in Cognitive and Neural Sciences, Department of Psychology, Southern Illinois University , Carbondale, Illinois.
J Neurotrauma. 2014 May 15;31(10):961-75. doi: 10.1089/neu.2013.3119. Epub 2014 Jan 20.
The goal of this study was to compare the effects of minocycline and simvastatin on functional recovery and brain gene expression after a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in a rat model in the range obtained with clinically approved doses; minocycline 60 mg/kg q12h and simvastatin 10 mg/kg q12h for 72 h. Functional recovery was assessed using motor and spatial learning tasks and neuropathological measurements. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Gene Ontology analysis (GOA) was used to evaluate the effect on relevant biological pathways. Both minocycline and simvastatin improved fine motor function, but not gross motor or cognitive function. Minocycline modestly decreased lesion size with no effect of simvastatin. At 24 h post-CCI, GOA identified a significant effect of minocycline on chemotaxis, blood circulation, immune response, and cell to cell signaling pathways. Inflammatory pathways were affected by minocycline only at the 72 h time point. There was a minimal effect of simvastatin on gene expression 24 h after injury, with increasing effects at 72 h and 7 days. GOA identified a significant effect of simvastatin on inflammatory response at 72 h and 7 days. In conclusion, treatment with minocycline and simvastatin resulted in significant effects on gene expression in the brain reflecting adequate brain penetration without producing significant neurorestorative effects.
本研究旨在比较米诺环素和辛伐他汀对皮质挫伤（CCI）损伤后功能恢复和脑基因表达的影响。剂量方案旨在提供一种大鼠模型中血清浓度，其范围与临床批准剂量获得的浓度一致；米诺环素 60mg/kg q12h 和辛伐他汀 10mg/kg q12h 持续 72 小时。功能恢复通过运动和空间学习任务以及神经病理学测量来评估。基于微阵列的转录谱分析用于确定 24 小时、72 小时和 CCI 后 7 天对基因表达的影响。基因本体论分析（GOA）用于评估对相关生物途径的影响。米诺环素和辛伐他汀均改善精细运动功能，但不改善粗大运动或认知功能。米诺环素适度减少损伤大小，而辛伐他汀无此作用。在 CCI 后 24 小时，GOA 确定米诺环素对趋化作用、血液循环、免疫反应和细胞间信号通路有显著影响。炎症途径仅在 72 小时时受米诺环素影响。损伤后 24 小时，辛伐他汀对基因表达的影响最小，72 小时和 7 天时影响增加。GOA 确定辛伐他汀在 72 小时和 7 天时对炎症反应有显著影响。总之，米诺环素和辛伐他汀治疗对反映充分脑穿透的脑基因表达产生显著影响，而不会产生显著的神经修复作用。
