Toll-like receptors in ischemic stroke and other acute brain injuries

Each year a substantial number of Americans suffer from hypoxic injury to the brain due to diminished blood flow and few effective treatments are available. A fruitful area of current investigation involves toll-like receptors (TLRs), which are a family of highly conserved receptors that play a key role in the pathology of brain injury. Studies in animals deficient in specific TLRs as well as genetic data from patients with altered TLR biology suggest that the activation of TLRs exacerbates damage in the setting of ischemia. Paradoxically, the stimulation of TLRs prior to injury is known to induce a state of tolerance to subsequent ischemic injury or "preconditioning". Such preconditioning results in a profound neuroprotective effect and the mechanisms involved are under intense investigation. Understanding these divergent roles of TLRs in brain injury and neuroprotection offers great promise in the discovery of new therapeutic targets and the mitigation of ischemic brain injury in "at risk" patients through the use of prophylactic TLR stimulation as a therapeutic strategy. This chapter focuses on these two divergent roles of TLRs- one role that promotes and another that prevents ischemic injury in the brain in the context of stroke and other acute brain injuries.