Abstract
Current therapies for Traumatic brain injury (TBI) focus on stabilizing individuals and on preventing further damage from the secondary consequences of TBI. A major complication of TBI is cerebral edema, which can be caused by the loss of blood brain barrier (BBB) integrity. Recent studies in several CNS pathologies have shown that activation of latent platelet derived growth factor-CC (PDGF-CC) within the brain can promote BBB permeability through PDGF receptor α (PDGFRα) signaling, and that blocking this pathway improves outcomes. In this study we examine the efficacy for the treatment of TBI of an FDA approved antagonist of the PDGFRα, Imatinib. Using a murine model we show that Imatinib treatment, begun 45 min after TBI and given twice daily for 5 days, significantly reduces BBB dysfunction. This is associated with significantly reduced lesion size 24 h, 7 days, and 21 days after TBI, reduced cerebral edema, determined from apparent diffusion co-efficient (ADC) measurements, and with the preservation of cognitive function. Finally, analysis of cerebrospinal fluid (CSF) from human TBI patients suggests a possible correlation between high PDGF-CC levels and increased injury severity. Thus, our data suggests a novel strategy for the treatment of TBI with an existing FDA approved antagonist of the PDGFRα.
Highlights
The Centers for Disease Control estimate that every year in the United States approximately 2.5 million people sustain a Traumatic brain injury (TBI)
In our previous studies of ischemic stroke we have found that the protease tissue-type plasminogen activator induces opening of the blood brain barrier (BBB) through proteolysis of latent platelet derived growth factor-CC (PDGF-CC), generating an active form of PDGF-CC that binds to the PDGF receptor α (PDGFRα) and induces cell signaling (Su et al, 2008)
Consistent with our hypothesis, we found that compared to vehicle-treated controls, Imatinib treatment significantly reduced Evans blue (EB) leakage in the ipsilateral hemisphere 24 h after TBI (Figures 1A,B >70%)
Summary
The Centers for Disease Control estimate that every year in the United States approximately 2.5 million people sustain a Traumatic brain injury (TBI). There are approximately 53,000 TBI related deaths and 283,000 hospitalizations annually, with many patients suffering permanent disability (Frieden et al, 2014). TBI is a contributing factor in nearly a third of all injury-related deaths in the United States and is a leading cause of death in North America for individuals between the ages of 1–45 (Rutland-Brown et al, 2006; Hemphill and Phan, 2013b; Byrnes et al, 2014). The pathophysiology of TBI is complex and involves both primary and secondary insults (Hemphill and Phan, 2013b; Finnie, 2014). Secondary injury development includes multifaceted biochemical and physiological processes that are initiated by the primary insult and manifest over a period of hours to days and even months (Cernak, 2005; Finnie, 2014; Logsdon et al, 2015)
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