Diffuse traumatic brain injury induces synaptogenesis and consequent adverse incidents

  • Hall, Edward (PI)
  • Singh, Indrapal (CoI)
  • Lifshitz, Jonathan (Former PI)
  • Norris, Christopher (Former CoI)
  • Thomas, Theresa (Former CoI)

Grants and Contracts Details


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 a mouse model of controlled cortical impact 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. This will be followed by a systematic dose-response evaluation of the comparative potency and efficacy of two prototypical Nrf2-ARE inducing compounds - sulforaphane and carnosic acid - in regards to their ability to speed up and increase the magnitude of post-TBI Nrf2-ARE activation. The most effective dose of each compound 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 studies, the ability of repeated administration of the best dose of the two compounds 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 their therapeutic efficacy window. These studies will provide pilot data for a Federal application to fund a more comprehensive evaluation of the acute neuroprotective potential of Nrf2-ARE pathway activation in both focal and diffuse TBI models as well as a basis for the discovery of more effective and fast-acting Nrf2 inducing compounds for acute and chronic neurodegeneration.
Effective start/end date1/15/121/14/14


  • KY Spinal Cord and Head Injury Research Trust: $200,000.00


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