Oxygen radical-induced lipid peroxidation and protein oxidative damage constitutes one of our most validated secondary injury mechanisms, and thus remains a highly rational neuroprotective target that continues to inspire a search for improved free radical scavengers and lipid peroxidation inhibiting drugs. In addition to chemically scavenging free radicals, there is increasing interest in the possibility of pharmacologically inducing endogenous enzymatic antioxidant defense mechanisms as a neuroprotective approach. Attention has recently been focused on the transcription factor Nrf2 (Nuclear factor E2-related factor) which interacts with the antioxidant response element (ARE) of various cytoprotective and free radical detoxifying genes as a potential therapeutic target for acute neurological injury. The proposed studies will examine in mouse models of focal controlled cortical impact and diffuse weight drop-induced traumatic brain injury (TBI) the time course of the endogenous induction of specific elements of the Nrf2-ARE pathway compared to the time course of brain oxidative damage in male and female mice. This will be followed by a systematic dose-response evaluation of the comparative potency and efficacy of the prototypical Nrf2-ARE inducing compound carnosic acid in both genders in regards to its ability to speed up and increase the magnitude of post-TBI Nrf2-ARE activation. The most effective dose of carnosic acid will then be examined for its ability to prevent lipid and protein oxidative damage, preserve mitochondrial respiratory and calcium (Ca++) buffering functions and attenuate Ca++-induced, calpain-mediated neuronal cytoskeletal damage, all surrogate markers of secondary brain injury. After completion of those experiments, the ability of repeated administration of the best dose of carnosic acid will be tested for actual neuroprotective effects in terms of short term (7 day) post-traumatic motor and cognitive recovery and brain tissue sparing including the therapeutic efficacy window. These studies will test the hypothesis that pharmacological Nrf2-ARE pathway activation in both focal and diffuse TBI models can be acutely neuroprotective and form the basis for the discovery of more effective and fast- acting Nrf2 inducing compounds for acute and chronic neurodegeneration.
This project will test the hypothesis that activation of the transcription factor Nrf2 (Nuclear factor E2-related factor) which interacts with the antioxidant response element (ARE) of various cytoprotective and free radical detoxifying genes is a potential pleiotropic therapeutic pathway for acute neurological injury. Using the potent Nrf2-ARE activating compound carnosic acid, we will use a careful pharmacological experimental design to examine the efficacy of that compound in mouse models of focal and diffuse traumatic brain injury (TBI). Multiple endpoints will be employed in both male and female mice including inhibition of lipid peroxidative damage, preservation of mitochondrial function and protection of intracellular calcium homeostasis followed by assessments of improvement in motor and cognitive recovery and decreased neurodegeneration.
