Pathophysiology and therapeutic strategies for the treatment of traumatic brain injury: investigating the role of erythropoietin
thesisposted on 29.11.2016 by Hellewell, Sarah Claire
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Traumatic brain injury (TBI) is a leading cause of death and disability in the industrialised world, and predominantly strikes young people in the prime of their lives. Diffuse brain injury may derive from numerous mechanisms, such as rapid rotation, acceleration/deceleration of the head, or a traumatic impact, often resulting in diffuse axonal injury (DAI) which has been reported to occur in up to 70% of all TBI patients. Characterised by damage in the vulnerable white matter tracts of the brain, DAI is a debilitating injury that may often go unnoticed in imaging due to the lack of overt tissue damage. Patients who suffer DAI also frequently present with respiratory impairment due to associated chest injury, TBI-induced loss of respiratory control, or cerebral hypoperfusion, with this resulting in decreased oxygen flow to the brain (termed hypoxia) worsening outcomes for patients clinically. In order to elucidate the contribution of post-traumatic hypoxia in heightening neuropathology and prolonging recovery, this study employed a rat model of diffuse traumatic brain injury (TAI) both with and without post-traumatic hypoxia, with outcomes assessed spanning a behavioural to a cellular level to determine which aspects of injury were the most vulnerable to exacerbation by hypoxia. This study also sought to determine the ability of the potential neuroprotective drug erythropoietin (EPO) to ameliorate the deleterious consequences of TAI with and without hypoxia, with thorough investigation of EPOâ€™s actions in alleviating behavioural and cognitive dysfunction, through to mitigating tissue and cellular damage, minimising inflammation, and examination of the intracellular signalling pathways used by EPO to confer neuroprotection. In this study, post-traumatic hypoxia was found to critically worsen axonal pathology, heighten neuroinflammation, and contribute to poor behavioural outcomes when compared to rats undergoing TAI alone. When administered EPO, rats subjected to the combination of TAI and hypoxia were found to have markedly improved behavioural and cognitive performance, attenuated white matter damage, striking resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammatory responses, with these results coinciding with enhanced expression of EPOâ€™s cognate receptor EPOR. Fascinatingly, many of these changes occurred after a single injection of EPO, providing compelling evidence of EPOâ€™s ability as a neuroprotective agent. Interestingly, few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPOâ€™s neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.