Delayed white matter loss in concussive head injuries and its treatment

抽象的。 一半的脑外伤会导致白色物质完整性的改变。尽管在以下方面取得了进展， 了解导致急性轴突损伤的机制后，对治疗剂的需求仍未得到满足， 预防迟发性神经元损伤，恢复神经功能。我们最近证明，急性 鼻内（IN）给予细胞因子白血病抑制因子（LIF）可减少神经胶质增生， 胼胝体髓鞘形成，保留新皮质体积和改善感觉运动行为， 新生儿缺氧缺血性脑损伤在这里，在小鼠闭合性头部损伤（CHI）TBI模型中，我们表明， 延迟IN LIF Rx可预防感觉运动功能下降，并在开始IN LIF Rx时减少焦虑， 6周恢复期因此，我们的总体假设是，鼻内LIF Rx可以减少神经功能， 通过防止迟发性白色物质损伤和通过抑制轴突再生来促进轴突再生， SARM 1激活。毫不含糊地表明干预正在减缓退化过程， 培育再生需要随着时间的推移进行监测，以表明它可以防止组织损伤的发展 并刺激再生因此，我们建议利用高分辨率多模态活体动物 磁共振成像以确定响应于IN LIF Rx的结构和功能变化。我们 将用离体扩散张量成像研究补充体内成像，并将 结果与组织学和神经功能分析。这些研究将为未来的研究铺平道路。 临床试验，其中可以评估类似的放射学标记物以预防迟发性白色损伤。 1

Abstract. Half of all traumatic brain injuries cause changes in white matter integrity. Whereas progress is being made in understanding the mechanisms that lead to acute axonal injury, there is an unmet need for therapeutics to prevent delayed neuronal injury and restore neurological function. We recently demonstrated that the acute intranasal (IN) administration of the cytokine Leukemia Inhibitory factor (LIF) reduced gliosis, preserved corpus callosal myelination, preserved neocortical volumes and improved sensorimotor behavior in a neonatal hypoxic-ischemic brain injury. Here, in a mouse closed head injury (CHI) TBI model, we show that delayed IN LIF Rx prevents sensorimotor functional decline and reduces anxiety when IN LIF Rx is initiated at 6 wks of recovery. Therefore, our overall hypothesis is that intranasal LIF Rx can decrease neurological deficits after TBI by preventing delayed white matter injury and nurturing axonal regeneration by inhibiting SARM1 activation. Unequivocally demonstrating that an intervention is slowing a degenerative process and nurturing regeneration requires monitoring over time to show that it prevents the evolution of tissue damage and stimulates regeneration. Therefore, we propose to utilize high resolution multiple modality live animal magnetic resonance imaging to determine the structural and functional changes in response to IN LIF Rx. We will complement the in vivo imaging with ex-vivo diffusion tensor imaging studies and will correlate the findings with histological and neurological functional analyses. These studies will pave the way for future clinical trials where similar radiological markers can be assessed to prevent delayed white matter injury. 1