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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Topical
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Animals
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Antioxidants / administration & dosage
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Antioxidants / therapeutic use
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Astrocytes / pathology
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Brain / drug effects
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Brain / pathology
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Brain Injuries / complications*
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Brain Injuries / diagnosis
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Brain Injuries / drug therapy
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Brain Injuries / pathology*
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Cell Death / drug effects
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Disease Models, Animal
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Encephalitis / complications
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Encephalitis / drug therapy
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Encephalitis / pathology*
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Encephalitis / prevention & control*
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Glasgow Coma Scale
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Glutathione / administration & dosage
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Glutathione / therapeutic use
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Humans
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Intracranial Hemorrhages / complications
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Intracranial Hemorrhages / diagnosis
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Male
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Meninges / drug effects
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Meninges / pathology
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Mice
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Microglia / cytology
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Microglia / drug effects
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Microglia / physiology
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / therapeutic use
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Neutrophils / drug effects
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Neutrophils / physiology
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Purinergic P2 Receptor Antagonists / administration & dosage
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Purinergic P2 Receptor Antagonists / pharmacology
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Purinergic P2 Receptor Antagonists / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
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Receptors, Purinergic P2 / metabolism
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Receptors, Purinergic P2X7 / metabolism
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Skull / metabolism
Substances
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Antioxidants
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Neuroprotective Agents
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Purinergic P2 Receptor Antagonists
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Reactive Oxygen Species
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Receptors, Purinergic P2
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Receptors, Purinergic P2X7
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Glutathione