Microglial/macrophage activation contributes to neuronal injury after traumatic brain injury (TBI), primarily through release of cytokines, proteases, and reactive oxygen species. Recent studies from our lab and others show that these aspects of microglia/macrophage activation can be suppressed by limiting glucose flux through glycolysis. Activated microglia/macrophages are unique among brain cells in that they primarily utilize hexokinase-2 (Hk2) rather than hexokinase-1, thus enabling selective targeting of glycolysis in these cells. The over-riding aim of this proposal is to determine if Hk2 inhibition can suppress pathogenic aspects of microglial/macrophage activation and improve outcomes in a mouse model of TBI. We will assess microglial gene expression, cytokine expression, oxidant production, and neural and microvascular injury in transgenic mice in which Hk2 is selectively deleted in the microglial/macrophage lineage, and in wild-type mice treated with Hk2 inhibitors at time points after controlled cortical impact. A single Hk2 inhibitor will then be chosen for assessments of long term histological and behavioral outcomes after TBI. We will place a particular focus on the effects of these interventions on neurite (dendrite and axon) loss after TBI, as our findings to date indicate inflammation to be a major determinant of neurite degeneration. In parallel, studies using cultured microglia will assess the effects of Hk2 inhibition on overall glycolytic rate, gene expression and pro- and anti-inflammatory processes. These studies will also evaluate a potential mechanism by which glycolytic inhibition influences microglial/ macrophage activation. Of note, selective Hk2 inhibitors are now entering clinical use for other purposes, thus facilitating potential translation of these studies to clinical treatment of TBI.