High mobility group box protein 1 in paediatric traumatic brain injury
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-01-29.
© 2018 Dr. Kyria Webster
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity for children and young adults. Accumulating research suggests that children may be more vulnerable to poor long-term outcomes after TBI compared to adults, including a higher risk of developing post traumatic epilepsy (PTE). The neuroinflammatory response, known to contribute to neuropathology after TBI and the development of PTE, has been reported to differ depending upon age at the time of injury, though the time course and key factors in this response have not been well-characterized. One of the major initiators of the inflammatory cascade, high mobility group box protein 1 (HMGB1), shows age-dependent expression under basal conditions, and its elevation after TBI has been associated with worsened outcomes in young patients. This thesis therefore aims to characterize the acute time course of key neuroinflammatory cells and HMGB1 after paediatric and adult TBI, using an experimental mouse model. It further aims to evaluate the effect of acute inhibition of HMGB1 on the acute and long-term outcomes after paediatric TBI. To investigate this, we used a controlled cortical impact model in C57Bl/6 mice with a 3-week age-of-injury to represent a paediatric age and an 8- to 10-week age-of-injury to represent early adult age. Western Blot (WB) revealed a temporal profile of Iba1, GFAP and HMGB1 across the time course post-injury, which showed earlier and more robust expression in the paediatric than the adult cohort. . HMGB1 extracellular release was confirmed at 3 d post-injury by immunofluorescence. An increase in peripheral HMGB1 was found in serum from paediatric TBI mice, which was not evident in adult serum. Acute inhibition of HMGB1 with Glycyrrhizin (Gly) showed reduced oedema with a pre-treatment paradigm but a reduction of gliosis only with a post-treatment paradigm, suggesting that Gly actions were dependent upon the timing of treatment initiation after paediatric TBI. In a more chronic study, acute inhibition of HMGB1 improved some long-term cognitive deficits and reduced persistent microglia activation in the hippocampus but did not improve PTE outcomes or lesion size. Together, these findings demonstrate that the post-injury inflammatory cascade is influenced by age at the time of insult, which may be an important consideration for treatment strategies aiming to ameliorate this response after TBI. They also demonstrate that pharmacological inhibition of HMGB1 is both time-dependent and age-dependent after TBI. Therefore, HMGB1 is involved in secondary damage after paediatric TBI and may represent an important therapeutic target.
Keywordsneuroscience; developmental neuroscience; post traumatic epilepsy; inflammation; traumatic brain injury
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- Medicine (RMH) - Theses