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Transcranial amelioration of inflammation and cell death after brain injury.
Open accessAbstract
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.
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“Cx3cr1+ meningeal macrophages are observed dying within 30 min of injury induction, leading to formation of a “honeycomb” network of microglia at the glial limitans, likely preventing the spread of reactive oxygen species from the leptomeninges into the brain parenchyma”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Roth et al., 2013
In the citing paper
“For example, damage to the glia limitans superficialis after TBI results in a profound morphological transformation of the underlying microglia that depends on ATP release by surface-associated astrocytes and subsequent detection by microglial purinergic receptors (126).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
In the citing paper
“Real-time imaging studies revealed that microglia transform into honeycomb- and jellyfish-like morphologies that provide barrier support and debris clearance (126).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
In the citing paper
“TBI can disrupt vascular integrity in the meninges and brain parenchyma, resulting in leakage of materials from the blood supply into CNS (Fig. 4) (125-127).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
In the citing paper
“In the absence of this transformation, the glia limitans leaked profoundly.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
In the citing paper
“In the minutes following TBI, microglia are recruited via purinergic signaling to clear necrotic debris and adopt a phagocytic state [100,107,108].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [107]
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Retracted
Metadata
- Authors
- Roth, T. L., Nayak, D., Atanasijevic, T., Koretsky, A. P., Latour, L. L., & McGavern, D. B.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- McGavern, Dorian B.
- Venue
- Nature
- Published
- 2013-12-08
- Volume
- 505
- Issue
- 7482
- Pages
- 223-228
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3930079
- OpenAlex
- W2055797258
- Cited by
- 574
- References
- 27
- Citations by year
- 2026: 30 · 2025: 46 · 2024: 45 · 2023: 42 · 2022: 62 · 2021: 50 · 2020: 49 · 2019: 51 · 2018: 48 · 2017: 39 · 2016: 50 · 2015: 38 · 2014: 24
- FWCI
- 23.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (ZIANS003112)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
- Physical Sciences › Engineering › Biomedical Engineering › Automotive and Human Injury Biomechanics
- Keywords
- traumatic brain injury, meningeal inflammation, purinergic receptor antagonists, glutathione, reactive oxygen species, microglia, neutrophils, vascular injury, neuroinflammation, intravital microscopy
- MeSH terms
- Administration, Topical, Animals, Antioxidants, Astrocytes, Brain, Brain Injuries, Disease Models, Animal, Encephalitis, Glutathione, Humans, Male, Meninges, Neutrophils, Skull, Glasgow Coma Scale, Cell Death, Rats, Sprague-Dawley, Reactive Oxygen Species, Microglia, Receptors, Purinergic P2, Neuroprotective Agents, Intracranial Hemorrhages, Mice, Rats, Receptors, Purinergic P2X7, Purinergic P2 Receptor Antagonists
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