Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Brain. 2013 Jan;136(Pt 1):65-80. doi: 10.1093/brain/aws286. Epub 2013 Jan 4.
The recent public awareness of the incidence and possible long-term consequences of traumatic brain injury only heightens the need to develop effective approaches for treating this neurological disease. In this report, we identify a new therapeutic target for traumatic brain injury by studying the role of astrocytes, rather than neurons, after neurotrauma. We use in vivo multiphoton imaging and show that mechanical forces during trauma trigger intercellular calcium waves throughout the astrocytes, and these waves are mediated by purinergic signalling. Subsequent in vitro screening shows that astrocyte signalling through the 'mechanical penumbra' affects the activity of neural circuits distant from the injury epicentre, and a reduction in the intercellular calcium waves within astrocytes restores neural activity after injury. In turn, the targeting of different purinergic receptor populations leads to a reduction in hippocampal cell death in mechanically injured organotypic slice cultures. Finally, the most promising therapeutic candidate from our in vitro screen (MRS 2179, a P2Y1 receptor antagonist) also improves histological and cognitive outcomes in a preclinical model of traumatic brain injury. This work shows the potential of studying astrocyte signalling after trauma to yield new and effective therapeutic targets for treating traumatic brain injury.
最近公众对创伤性脑损伤的发病率和可能的长期后果的认识，只会加剧人们对开发治疗这种神经疾病的有效方法的需求。在本报告中，我们通过研究神经损伤后星形胶质细胞（而不是神经元）的作用，确定了创伤性脑损伤的一个新的治疗靶点。我们使用体内多光子成像技术，表明创伤过程中的机械力会引发星形胶质细胞内的细胞间钙波，而这些波是由嘌呤能信号介导的。随后的体外筛选表明，通过“机械半影”的星形胶质细胞信号会影响远离损伤中心的神经回路的活性，而减少星形胶质细胞内的细胞间钙波可在损伤后恢复神经活性。反过来，针对不同嘌呤能受体群体的靶向治疗可减少机械损伤器官型切片培养物中的海马细胞死亡。最后，我们的体外筛选中最有前途的治疗候选药物（MRS 2179，一种 P2Y1 受体拮抗剂）也可改善创伤性脑损伤的临床前模型中的组织学和认知结果。这项工作表明，研究创伤后星形胶质细胞信号的潜力可以为治疗创伤性脑损伤提供新的、有效的治疗靶点。
