KSCHIRT: Prophylactic Treatment of Mild Traumatic Brain Injury

Abstract: Conservatively, 1.5 million Americans suffer a mild TBI each year and no drug has earned FDA approval for TBI neuroprotection. Unfortunately, it is not currently possible to predict the 15%, or roughly 200,000 people yearly, who will have long-term cognitive impairments including. Inflammation can persist for years after a TBI and is a hallmark of other neurodegenerative disorders (Parkinson’s, Alzheimer’s disease); therefore, the control of neuroinflammation is a promising avenue for achieving neuroprotection and improving patient outcomes. The nature of the injury, however, creates a formidable hurdle for the implementation of pharmacotherapy as most chronic symptoms from the mild TBI develop after brain inflammation is established. One clinically significance approach is to broadly administer therapy shortly after the injury to prophylactically modulate inflammation and prevent chronic neuroinflammation and neurodegeneration like that seen in chronic traumatic encephalopathy. Since this involves treating many people who are unlikely to experience the long-term effects of a mild TBI, targeted interventions must have a high benefit-to-risk ratio. We recently identified the commonly prescribed antibiotic, azithromycin (AZM), as an immunomodulatory agent with neuroprotective effects in spinal cord injury. Because of its safety profile, AZM is frequently prescribed as a prophylactic treatment in a number of conditions and broadly administered in at- risk disease populations. Since AZM has the correct benefit-to-risk ratio for a prophylactic treatment to reduce the risk of mild TBI-induced neuroinflammation in the 15% of patients who will benefit, the objective of this proposal is to determine the therapeutic potential of AZM for the treatment of mild TBI. We hypothesize that AZM treatment will alter inflammation and improve cognitive outcomes in a mouse model of mild closed head injury (CHI). We will test our hypothesis in two aims focused on identifying AZM as an immunomodulatory therapy for the mild CHI (Aim 1) and determining AZM’s ability to reduce the pathophysiology and cognitive impairments associated with mild CHI (Aim 2). We will use a midline CHI in mice that mimics human injury by producing bilateral diffuse pathology (chronic glial activation, axonal/vascular damage) and cognitive deficits without lesions seen on MRI or at pathology, which is the clinical definition of a mild TBI. We will use complementary molecular, histological, and gene-array outcome measures along with cognitive function tests to determine the full dose-response and therapeutic window of AZM treatment. Establishing the feasibility of AZM treatment of mild TBI will create new areas of mechanistic, drug development, and clinical research.