Targeting HMGB1/TLR4 signaling as a novel approach to treatment of cerebral ischemia.

HMGB1 is a ubiquitous, highly conserved DNA-binding protein with well-established functions in the maintenance of nuclear homeostasis. Much of the recent work about its signaling functions in the brain has focused on its proinflammatory properties and relationship to known inflammatory receptors such as toll-like receptor 4 (TLR4). HMGB1 is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain, indicating that HMGB1 acts as a novel mediator in cerebral ischemic injury. Consistently, numerous reports point to TLR4 as a pivotal player in the ischemic brain. The use of HMGB1 and TLR4 ligand as preconditioning stimulus may be benefit of the outcome of cerebral ischemia. Therefore, this review presents the latest findings supporting the involvement of HMGB1 and TLR4 in cerebral ischemia. Targeting HMGB1/TLR4 signaling may provide a novel therapeutic approach for clinical prevention of cerebral ischemic injury.