Transcranial amelioration of inflammation and cell death after brain injury

Using long-term intravital photography to explore the cellular changes after compression-induced traumatic brain injury in a murine model, it is shown that parenchymal and meningeal inflammation as well as cell death can be modulated by topical treatment with purinergic receptor antagonists and glutathione. Traumatic brain injury, often a consequence of road accidents, is a major killer and cause of neurological disorders. This study describes a closed-skull mouse model with a pathology resembling mild traumatic brain injury in humans. The authors use long-term intravital microscopy to study the dynamics of the injury response from its inception. Using the model they show that parenchymal and meningeal cell death can be reduced by topical treatment with purinergic receptor antagonists and the antioxidant glutathione. Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function1,2. At present, no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain insights into TBI pathogenesis, we developed a novel murine closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic-receptor-dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We also show that the skull bone is permeable to small-molecular-weight compounds, and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results shed light on the acute cellular response to TBI and provide a means to locally deliver therapeutic compounds to the site of injury.