Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA.
Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA.
Brain Res. 2019 Nov 1;1722:146380. doi: 10.1016/j.brainres.2019.146380. Epub 2019 Aug 12.
Stroke poses a serious health and economic burden, and the lack of treatment options necessitates a viable therapy. Hypothermia represents a promising stroke therapy, yet side effects of full-body cooling, such as pneumonia, limit its clinical application. Selective endovascular cooling (SEC), via infusion of cold saline through the intraarterial artery, represents an attractive alternative by locally cooling the brain while preserving body temperature. However, the mechanisms underlying SEC are poorly understood. Brain-derived neurotrophic factor (BDNF) is a widely recognized promotor of neuroplasticity and biomarker of stroke outcomes, as well as its association with inflammation, such as IL-10. Stroke-induced neuroinflammation exacerbates damage and stems from peripheral organs, namely the spleen. The spleen has emerged as a therapeutic target for stroke, yet the effect of SEC on the splenic inflammatory response is unknown. Here, we aimed to elucidate the local and peripheral mechanisms driving SEC as a neuroprotective stroke therapy by examining brain BDNF and splenic IL-10 expression. Animals that received SEC prior to stroke displayed elevated brain BDNF expression ipsilaterally and contralaterally across the cortex, striatum, and hippocampus. SEC also upregulated splenic IL-10, suggesting alteration of the peripheral inflammatory response. The oxygen-glucose deprivation in vitro model of stroke further demonstrated that "cold" rat splenocytes protected rat primary neurons by upregulating BDNF and IL-10. Altogether these data support BDNF- and IL-10-based mechanisms underlying the neuroprotective potential of SEC therapy for stroke, and further advance the concept of exploiting the pathological link between brain and spleen as therapeutic targets.
中风会造成严重的健康和经济负担，而缺乏治疗选择需要一种可行的疗法。低温治疗代表了一种有前途的中风治疗方法，但全身降温的副作用，如肺炎，限制了其临床应用。通过动脉内输注冷盐水的选择性血管内冷却（SEC），通过局部冷却大脑而保持体温，代表了一种有吸引力的替代方法。然而，SEC 的机制尚未得到很好的理解。脑源性神经营养因子（BDNF）是神经可塑性的广泛认可促进剂和中风结果的生物标志物，以及其与炎症的关联，如 IL-10。中风引起的神经炎症会加重损伤，源自外周器官，即脾脏。脾脏已成为中风的治疗靶点，但 SEC 对脾脏炎症反应的影响尚不清楚。在这里，我们旨在通过检查大脑 BDNF 和脾脏 IL-10 的表达，阐明推动 SEC 作为神经保护中风治疗的局部和外周机制。在中风前接受 SEC 的动物显示出同侧和对侧大脑皮层、纹状体和海马中 BDNF 表达升高。SEC 还上调了脾脏 IL-10，表明外周炎症反应发生了改变。中风的体外氧葡萄糖剥夺模型进一步表明，“冷”大鼠脾细胞通过上调 BDNF 和 IL-10 来保护大鼠原代神经元。总之，这些数据支持 SEC 治疗中风的神经保护潜力的 BDNF 和 IL-10 为基础的机制，并进一步推进利用大脑和脾脏之间的病理联系作为治疗靶点的概念。
