Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-29341-6
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Funding
- VA Puget Sound Health Care System Seed Grant
- Department of Veterans Affairs Office of Research and Development Medical Research Service RDIS [0005]
- Veterans Affairs Rehabilitation Research and Development Service Merit Review Grant [B77421]
- University of Washington Friends of Alzheimer's Research
- University of Washington Royalty Research Fund
- Northwest Network Mental Illness Research Education and Clinical Center
- [R01AG046619]
- [T32AG052354]
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Mild blast-induced traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption. However, the mechanisms whereby blast disrupts BBB integrity are not well understood. To address this issue BBB permeability to peripherally injected C-14-sucrose and Tc-99m-albumin was quantified in ten brain regions at time points ranging from 0.25 to 72 hours. In mice, repetitive (2X) blast provoked BBB permeability to C-14-sucrose that persisted in specific brain regions from 0.25 to 72 hours. However, Tc-99m-albumin revealed biphasic BBB disruption (open-closed-open) over the same interval, which was most pronounced in frontal cortex and hippocampus. This indicates that blast initiates interacting BBB disruption and reparative processes in specific brain regions. Further investigation of delayed (72 hour) BBB disruption revealed that claudin-5 (CLD5) expression was disrupted specifically in the hippocampus, but not in dorsal striatum, a brain region that showed no blast-induced BBB permeability to sucrose or albumin. In addition, we found that delayed BBB permeability and disrupted CLD5 expression were blocked by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). These data argue that latent nitric oxide-dependent signaling pathways initiate processes that result in delayed BBB disruption, which are manifested in a brain-region specific manner.
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