Project Summary/Abstract Traumatic brain injury (TBI) is a leading cause of death and disability with approximately 1.7 million incidents occurring each year. There is an urgent need to develop new treatments that would limit brain pathology and improve overall outcome. Recently, a signaling pathway has been described that by which the brain regulates systemic inflammation. Specifically, this pathway acts on ?7 nicotinic acetylcholine receptors (?7nAChR) present on peripheral immune cells to decrease inflammation. Activation of these receptors using chemical agonists decreases TBI-triggered inflammation, reduces blood-brain barrier permeability and improves cognitive outcome. The ?7nAChR agonist AZD0328, developed by AstraZeneca, has been shown to improve cognitive function in normal rodents and non-human primates. However, it has not been tested if AZD0328 can reduce TBI-triggered inflammation, reduce brain pathology, or improve outcome. We propose to test the overall hypothesis that AZD0328 will reduce inflammation in rats following TBI (primary outcome). Further, it is anticipated that AZD0328 will reduce BBB permeability, brain pathology and improve cognitive outcome. If beneficial effects are observed, we will proceed to the planning of a Phase II efficacy study. We propose two aims to test our hypothesis: Aim 1 (UG3): To examine if AZD0328 reduces peripheral and central inflammation and improves outcome in traumatically brain injured rats. Aim 2 (UH3): Clinical Trial Planning.