Repetitive Mild Traumatic Brain Injury and Transcription Factor Modulation

The worldwide incidence of traumatic brain injury (TBI) is ∼0.5% per year and the frequency is significantly higher among military personnel and athletes. Repetitive TBIs are associated with military and athletic activities, and typically involve more severe consequences. The majority of TBIs are mild; however, these still can result in long-term cognitive deficits, and there is currently no effective treatment. tert-Butylhydroquinone (tBHQ) and pioglitazone can activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma (PPAR-γ) transcription factors, respectively, and each has been shown to be neuroprotective in various model systems. We examined behavioral and gene expression changes after repetitive mild TBI followed by simultaneous treatment with both factors. We used a repetitive closed head injury of mice involving five injuries with a 1-week interval between each TBI. We found that memory performance was significantly reduced by the injuries, unless the TBIs were followed by the tBHQ and pioglitazone administrations. Certain genes; for example, growth hormone and osteopontin, were downregulated by the injury, and this was reversed by the treatment, whereas other genes; for example, a tumor necrosis factor receptor, were upregulated by the injury and restored if the post-injury treatment was administered. Analysis of gene expression levels affected by the injury and/or the treatment point to potential mechanisms that could be exploited therapeutically.