PILOT: ASSESSMENT OF NEUROTROPHIN INVOLVEMENT AND ANTI-INFLAMMATORY THERAPY IN TBI

The production of neurotrophins in response to injury is complex, with cells of both the CNS and immune system capable of producing these molecules. An additional level of complexity is that neurotrophins have been shown to have both neuroprotective activities and neurodegenerative effects. Data suggest protection is generally mediated by the mature molecules, and neurodegeneration (via apoptosis) is mediated by the pro-forms; however, the in vivo relevance of pro-forms has also recently been questioned. Importantly, recent studies have reported that administration of neurotrophins has a neuroprotective effect in vivo. Thus, existing data suggest that neurotrophins play a pivotal role in regulation of inflammatory processes and in determining outcomes of TBI. We hypothesize that perturbation of NF-¿B signaling pathways in bone-marrow derived cells and/or non-hematopoietic cells in the brain will alter neurotrophin production, thereby influencing TBI outcomes. The first goal of this project is to define the kinetics of the neurotrophin response following CCI injury, and to assess the contribution of specific NF-¿B signaling pathways to the in vivo neurotrophin response.NF-¿B is a major mediator of inflammatory reactions. Acute inflammation in the brain, particularly for moderate to severe injuries, is almost certainly a major contributor to morbidity and mortality. Inflammation-induced brain swelling and accompanying changes in blood flow are among the many problems associated with an acute inflammatory response to serious brain injury. Because these acute inflammatory responses are initiated within minutes of TBI, we hypothesize that rapid intervention is desirable to ameliorate consequent inflammation associated damage. A drug that could be administered on the battlefield to troops who are suspected to have sustained a TBI injury is most desirable. The second goal of this project is to explore the potential benefit of two FDA-approved anti-inflammatory drugs for i) limiting the inflammatory response to TBI and ii) improving functional outcomes.