Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA; Center for Visual and Neurocognitive Rehabilitation Atlanta, VA Medical Center, Decatur, GA, 30033, USA.
Neurochem Int. 2017 Dec;111:82-92. doi: 10.1016/j.neuint.2017.03.017. Epub 2017 Mar 28.
Previous investigations suggest that DL-3-n-butylphthalide (NBP) is a promising multifaceted drug for the treatment of stroke. It is not clear whether NBP can treat traumatic brain injury (TBI) and what could be the mechanisms of therapeutic benefits. To address these issues, TBI was induced by a controlled cortical impact in adult male mice. NBP (100 mg/kg) or saline was intraperitoneally administered within 5 min after TBI. One day after TBI, apoptotic events including caspase-3/9 activation, cytochrome c release from the mitochondria, and apoptosis-inducing factor (AIF) translocation into the nucleus in the pericontusion region were attenuated in NBP-treated mice compared to TBI-saline controls. In the assessment of the nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway, NBP ameliorated the p65 expression and the p-IκB-α/IκB-α ratio, indicating reduced NF-κB activation. Consistently, NBP reduced the upregulation of proinflammatory cytokines such as tumor necrotizing factor-alpha (TNF-α) and interleukin-1beta (IL-1β) after TBI. In sub-acute treatment experiments, NBP was intranasally delivered once daily for 3 days. At 3 days after TBI, this repeated NBP treatment significantly reduced the contusion volume and cell death in the pericontusion region. In chronic experiments up to 21 days after TBI, continues daily intranasal NBP treatment increased neurogenesis, angiogenesis, and arteriogenesis in the post-TBI brain, accompanied with upregulations of regenerative genes including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), endothelial-derived nitric oxide synthase (eNOS), and matrix metallopeptidase 9 (MMP-9). The NBP treatment significantly improved sensorimotor functional recovery and reduced post-TBP depressive behavior. These new findings demonstrate that NBP shows multiple therapeutic benefits after TBI.
先前的研究表明，DL-3-正丁基苯酞（NBP）是一种有前途的多效药物，可用于治疗中风。目前尚不清楚 NBP 是否可以治疗创伤性脑损伤（TBI），以及其治疗益处的机制是什么。为了解决这些问题，我们在成年雄性小鼠中通过皮层控制撞击诱导 TBI。在 TBI 后 5 分钟内，通过腹腔内注射 NBP（100mg/kg）或生理盐水。在 TBI 后 1 天，与 TBI-生理盐水对照组相比，NBP 治疗的小鼠在挫伤区，细胞凋亡事件包括 caspase-3/9 激活、线粒体细胞色素 c 释放和凋亡诱导因子（AIF）向核内易位均减弱。在核因子 kappa-轻链增强子的 B（NF-κB）通路的评估中，NBP 改善了 p65 表达和 p-IκB-α/IκB-α 比值，表明 NF-κB 激活减少。一致地，NBP 降低了创伤性脑损伤后促炎细胞因子如肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的上调。在亚急性治疗实验中，NBP 每天经鼻给药 1 次，连续 3 天。在 TBI 后 3 天，这种重复的 NBP 治疗显著减少了挫伤区的挫伤体积和细胞死亡。在 TBI 后 21 天的慢性实验中，连续每天经鼻给予 NBP 治疗增加了 TBI 后脑内的神经发生、血管生成和血管生成，同时增加了再生基因的表达，包括脑源性神经营养因子（BDNF）、血管内皮生长因子（VEGF）、内皮衍生型一氧化氮合酶（eNOS）和基质金属蛋白酶 9（MMP-9）。NBP 治疗显著改善了感觉运动功能恢复，减少了 TBP 后的抑郁行为。这些新发现表明，NBP 在 TBI 后具有多种治疗益处。
