title: Transcranial amelioration of inflammation and cell death after brain injury.
abstract: Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function. 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.
authors: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Theodore L
authors: TL
authors: Roth
authors: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Debasis
authors: D
authors: Nayak
authors: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Tatjana
authors: T
authors: Atanasijevic
authors: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Alan P
authors: AP
authors: Koretsky
authors: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Lawrence L
authors: LL
authors: Latour
authors: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Dorian B
authors: DB
authors: McGavern
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control*; D015600:Glasgow Coma Scale; D005978:Glutathione / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D020300:Intracranial Hemorrhages / Q000150:complications / Q000175:diagnosis; D008297:Male; D008578:Meninges / Q000187:drug effects / Q000473:pathology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D012886:Skull / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D058919:Purinergic P2 Receptor Antagonists; D017382:Reactive Oxygen Species; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D005978:Glutathione