Delayed white matter loss in concussive head injuries and its treatment

抽象的。 一半的创伤性脑损伤会导致脑白质完整性的改变。鉴于目前正在取得的进展 了解导致急性轴索损伤的机制，治疗药物的需求尚未得到满足 预防迟发性神经元损伤，恢复神经功能。我们最近证明了急性 鼻腔给药(IN)细胞因子白血病抑制因子(LIF)减少胶质细胞增生，保存 大脑皮质皮质髓鞘化、新皮质体积保留和感觉运动行为改善 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)模型中，我们展示了 延迟的LIF Rx可防止感觉运动功能下降，并减少焦虑 恢复6周。因此，我们的总体假设是，鼻腔LIF Rx可以降低神经功能 预防迟发性白质损伤和抑制轴突再生促进脑损伤后脑组织损伤 Sarm1激活。明确表明干预措施正在减缓退化过程，并 滋养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演变 并刺激再生。因此，我们建议利用高分辨率的多通道活体动物 磁共振成像以确定对IN LIF Rx反应的结构和功能变化。我们 将补充体内成像和体外扩散张量成像研究，并将相互关联 组织学和神经功能分析的发现。这些研究将为未来的发展铺平道路 可以评估类似放射标志物以预防迟发性脑白质损伤的临床试验。 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