Abstract
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 14C-sucrose and 99mTc-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 14C-sucrose that persisted in specific brain regions from 0.25 to 72 hours. However, 99mTc-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.
Highlights
Mild traumatic brain injury associated with blast exposure is the most prevalent form of injury among military personnel who have served in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OF/OND), with at least 300,000 personnel being subject to at least one exposure[1,2,3,4,5]
For the smaller sucrose molecules, blood-brain barrier (BBB) disruption persisted for at least 72 h, while aberrant BBB permeability to the larger albumin molecules was restored to normal levels within 24 h
In keeping with other reports[21,23,52], we found that a single blast exposure provokes rapid, transient BBB disruption, permitting aberrant entry of both sucrose and albumin radiotracers into multiple brain regions
Summary
Mild traumatic brain injury (mTBI) associated with blast exposure is the most prevalent form of injury among military personnel who have served in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OF/OND), with at least 300,000 personnel being subject to at least one exposure[1,2,3,4,5]. Vascular injury, including disruption of the blood-brain barrier (BBB), may be an important initiating mechanism by which mTBI could trigger long-term pathophysiological cascades promoting neurodegeneration, including Alzheimer’s-like disorders and other neurodegenerative proteinopathies that include chronic traumatic encephalopathy[14,15,16,17,18,19]. BBB disruption has been examined in a number of pre-clinical models of blast-induced traumatic brain injury (TBI)[20,21,22,23,24,25,26,27]. We used a sensitive and highly quantifiable blood-borne radiolabeled tracer approach to assess the time course and magnitude of BBB disruption in multiple brain regions after blast-induced mTBI in mice. We assessed the effects of blast on tight junction integrity and the roles of nitric oxide and prostaglandin in mediating blast-induced BBB disruption
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