Date of Graduation
School of Medicine
James W Simpkins
Oxidative stress is actively involved in stroke pathogenesis; however, almost all the antioxidants that have been applied into the clinical trials fail to improve ischemic stroke outcomes. We note that most drug candidates have very limited diversity of antioxidative activities. tBHQ is a food additive, which is considered to be safe for human consumption. As both an antioxidant and an Nrf2-ARE signaling pathway inducer, tBHQ can directly eliminate ROS and activates the expression of all the antioxidative genes under Nrf2-ARE regulation. My dissertation investigated the potential clinical application of tBHQ for ischemic stroke treatment by using both in vitro glutamate-induced oxidative stress models and an in vivo murine permanent middle cerebral artery occlusion model. Our study mechanistically demonstrated the protection of tBHQ against oxidative stress-induced cytotoxicity in neurons though increasing mitochondrial antioxidative capacity and preserving mitochondrial function. However, we observed paradoxical results from our in vivo study in that tBHQ increased the mortality and worsened stroke outcomes in a pMCAO model. Further, we found that tBHQ significantly suppressed mitochondrial respiration in the cerebrovascular endothelial cells, which might results in the disruption of the BBB. Overall, my research raises safety concerns related to the use of tBHQ for human consumption or a potential therapeutic treatment for stroke.
Sun, Jiahong, "The effect of tert-butylhydroquinone, an Nrf2-ARE signaling pathway inducer, on oxidative stress-related neurodegeneration" (2015). Graduate Theses, Dissertations, and Problem Reports. 6742.