Abstract
Traumatic brain injury (TBI) is a major cause of death and disability. Despite progress in neurosurgery and critical care, patients still lack a form of neuroprotective treatment that can counteract or attenuate injury progression. Inflammation after TBI is a key modulator of injury progression and neurodegeneration, but its spatiotemporal dissemination is only partially known. In vivo approaches to study post-traumatic inflammation longitudinally are pivotal for monitoring injury progression/recovery and the effectiveness of therapeutic approaches. Here, we provide a minimally invasive, highly sensitive in vivo molecular magnetic resonance imaging (MRI) characterization of endothelial activation associated to neuroinflammatory response after severe TBI in mice, using microparticles of iron oxide targeting P-selectin (MPIOs-α-P-selectin). Strong endothelial activation was detected from 24 h in perilesional regions, including the cortex and hippocampus, and peaked in intensity and diffusion at two days, then partially decreased but persisted up to seven days and was back to baseline 15 days after injury. There was a close correspondence between MPIOs-α-P-selectin signal voids and the P-selectin stained area, confirming maximal endothelial activation at two days. Molecular MRI markers of inflammation may thus represent a useful tool to evaluate in vivo endothelial activation in TBI and monitoring the responses to therapeutic agents targeting vascular activation and permeability.
Highlights
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity across all ages in all countries, with a bimodal distribution between young adults (13–20 years old) and older adults (>60 years old) [1].The primary injury resulting from the biomechanical impact directly damages brain tissue by tearing, shearing, and stretching forces
We tested whether ultra-sensitive molecular magnetic resonance imaging (MRI) could be an integrative approach in combination with conventional T2-weighted MRI to detect endothelial activation over time in a mouse model of severe TBI
Mice subjected to TBI were intravenously injected with MPIOs coupled to either a control immunoglobulin or to an antibody directed against P-selectin, and scanned at different times after injury for up to two weeks (Figure 2A–D)
Summary
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity across all ages in all countries, with a bimodal distribution between young adults (13–20 years old) and older adults (>60 years old) [1].The primary injury resulting from the biomechanical impact directly damages brain tissue by tearing, shearing, and stretching forces. Traumatic brain injury (TBI) is a leading cause of mortality and morbidity across all ages in all countries, with a bimodal distribution between young adults (13–20 years old) and older adults (>60 years old) [1]. Evidence from animal models and imaging/autopsy studies in humans indicates lasting inflammatory changes and blood-brain barrier (BBB) dysfunction in determining the post-TBI outcome [5]. Many aspects of the spatial and temporal inflammatory changes in vivo in the human traumatized brain await clarification. Routine imaging techniques (such as computed tomography (CT) and magnetic resonance imaging (MRI)) help clinicians plan surgery and manage complications to secondary injury [6,7] but cannot yet evaluate neuroinflammation.
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