Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury
Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury
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DOI：
10.1089/neu.2016.4636
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发表时间：
2017-04-01
影响因子：
4.2
通讯作者：
Crawford, Fiona
中科院分区：
文献类型：
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作者：
Ferguson, Scott;Mouzon, Benoit;Crawford, Fiona
创伤性脑损伤（TBI）具有慢性和长期的后果，目前尚无批准的药物治疗方法。我们之前已经描述了重复性轻度TBI （r-mTBI）小鼠模型在TBI后2年内的慢性神经行为和病理后遗症。尽管最初的损伤性质轻微，但继发性损伤过程涉及神经炎症和神经退行性通路，在损伤后持续数周和数月，为治疗干预提供了潜在的机会。在这项研究中，我们研究了一种新型抗炎化合物阿那他滨在改善TBI后预后方面的功效。我们的r-mTBI模型包括一系列5次轻度撞击（中线撞击速度为5米/秒，撞击深度为1mm，停留时间为200毫秒），间隔为48小时。阿那他滨在损伤后30分钟开始施用，并通过饮用水连续给药。在脑外伤后6个月，阿那他滨治疗改善了受伤小鼠的空间记忆。脑损伤后9个月，对一组小鼠实施安乐死进行病理分析，结果显示治疗后受伤动物的星形胶质细胞（胶质纤维酸蛋白，GFAP）和小胶质细胞（离子钙结合适配器分子1，IBA1）反应减少。然后对其余小鼠进行交叉治疗，以评估晚期治疗给药和治疗终止的影响。交叉治疗9个月后，其余小鼠的空间记忆没有受到损伤，而病理分析显示，延迟治疗的小鼠脑胼胝体IBA1有所改善，交叉治疗后服用安慰剂的r-mTBI小鼠脑胼胝体IBA1增加。这些数据表明，早期和晚期使用阿那他滨治疗对改善轻度TBI后的长期行为和病理结果都有疗效。未来的研究将描述治疗窗口，所需治疗的时间过程，以及在人体损伤后达到治疗水平所需的剂量。
Traumatic brain injury (TBI) has chronic and long-term consequences for which there are currently no approved pharmacological treatments. We have previously characterized the chronic neurobehavioral and pathological sequelae of a mouse model of repetitive mild TBI (r-mTBI) through to 2 years post-TBI. Despite the mild nature of the initial insult, secondary injury processes are initiated that involve neuroinflammatory and neurodegenerative pathways persisting and progressing for weeks and months post-injury and providing a potential window of opportunity for therapeutic intervention. In this study we examined the efficacy of a novel anti-inflammatory compound, anatabine, in modifying outcome after TBI.Our model of r-mTBI involves a series of five mild impacts (midline impact at 5 m/sec, 1mm strike depth, 200 msec dwell time) with an interval of 48 h. Anatabine treatment was administered starting 30 min after injury and was delivered continuously through drinking water. At 6 months after TBI, anatabine treatment improved spatial memory in injured mice. Nine months after TBI, a cohort of mice was euthanized for pathological analysis that revealed reductions in astroglial (glial fibrillary acid protein, GFAP) and microglial (ionized calcium-binding adapter molecule 1, IBA1) responses in treated, injured animals. Treatments for the remaining mice were then crossed-over to assess the effects of late treatment administration and the effects of treatment termination. Nine months following crossover the remaining mice showed no effect of injury on their spatial memory, and whereas pathological analysis showed improvements in mice that had received delayed treatment, corpus callosum IBA1 increased in post-crossover placebo r-mTBI mice.These data demonstrate efficacy of both early and late initiation of treatment with anatabine in improving long term behavioral and pathology outcomes after mild TBI. Future studies will characterize the treatment window, the time course of treatment needed, and the dose needed to achieve therapeutic levels of anatabine in humans after injury.